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285 Cards in this Set
- Front
- Back
1. Where does digestion of proteins take place?
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Begins in the stomach and is completed in the intestine.
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2. Digestion of proteins is broken down by enzymes. How are these enzymes activated?
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The proteolytic enzymes, pepsin, trypsin, chymotrypsin, elastase and the carboxypetidases are produced as zymogens that are activated by cleavage after they enter the gastrointestinal lumen.
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3. Pepsinogen
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Secreted by the chief cells of the stomach. The gastric parietal cells secrete HCl. The acid in the stomach alters the conformation of pepsinogen so that is can cleave itself, producing the active protease pepsin.
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4. Pepsin
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Has a fairly broad specificity, but it tends to cleave peptide bonds in which the carboxyl group is provided by an aromatic or acidic amino acid.
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5. Trypsinogen
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Cleaved by enteropeptidase, secreted by the brush border cells of the small intestine, to form the active protease trypsin
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6. Trypsin
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Plays a key role by catalyzing the cleavage and activation of the other pancreatic zymogens.
Catalyzes the cleavages of chymotrypsinogen to chymotrypsin, proelastase to elastase, and the procarboxypeptidases to the carboxypeptidases. |
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7. Which pancreatic enzymes are serine proteases that act as endopeptidases?
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1. Trypsin
2. Chymotrypsin 3. Elastase |
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8. Specificity of trypsin
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Trypsin is the most specific, cleaving peptide bonds in which the carboxyl (carbonyl) group is provided by lysine or arginine.
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9. Specificity of chymotrypsin
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Chymotrypsin is less specific, but favors residues that contain hydrophobic AAs.
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10. Specificity of elastase
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Elastase cleaves not only elastin but also other proteins at bonds in which the carboxyl group is contributed by AA residues w/small side chains (alanine, glycine, and serine).
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11. Exopeptidases
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Proteases that cleave one amino acid at a time form the end of the chain.
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12. Procarboxypeptidases
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Procarboxypeptidases, zymogens produced by the pancreas, are converted by trypsin to the active carboxypeptidases.
These exopeptidases remove AAs from the carboxyl ends of peptide chains. Carboxypeptidase A releases hydrophobic AAs, whereas carboxypeptidase B releases basic amino acids (arginine and lysine) |
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13. Aminopeptidases
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Located on the brush border and cleave one AA at a time from the amino end of peptides.
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14. How are amino acids absorbed from the intestinal lumen?
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Through secondary active Na+-dependent transport systems and thru facilitated diffusion.
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15. Co-transport of Na+ and amino acids
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AA's are absorbed form the lumen of the small intestine principally by semi specific Na+-dependent transport proteins in the luminal membrane of the intestinal cell brush border.
The co-transport of Na+ and the amino acid from the outside of the apical membrane to the inside of the cell is driven by the low intracellular Na+ concentration. Low intracellular Na+ results form the pumping of Na+ out of the cell by a Na+,K+-ATPase on the serosal membrane. |
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16. What is the primary transport mechanism in this Na+ and AA co-transport?
What is the secondary mechanism? |
Primary mechanism is the creation of a sodium gradient.
The secondary mechanism is the coupling of AAs to the influx of sodium. This mechanism allows the cells to concentrate AAs from the intestinal lumen. The AAs are then transported out of the cell into the interstitial fluid, principally by facilitated transporters in the serosal membrane. |
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17. How many different Na+-dependent amino acid carriers are located in the apical brush border membrane of the epithelial cells?
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At least six.
These carriers have overlapping specificity for different amino acids. One transports neutral AAs, another transports proline and hydroxyproline, a third only acidic AAs, a fourth only basic AAs. Most AA's are transported by more than one transport system. |
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18. Amino acid transport across the serosal membrane is uni- or bi-directional?
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Bidirectional
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19. Where does Na+-dependent transport of AA's take place?
Where does facilitated transport take place? |
Na+-dependent transport takes place in the intestinal and renal epithelium but facilitated transport in other cell types.
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20. What are examples of proteins that undergo extensive synthesis and degradation?
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1. Hemoglobin
2. Muscle proteins 3. Digestive enzymes 4. Proteins of cells sloughed off from the GI tract |
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21. Lysosomal protein turnover
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Lysosomes participate in the process of autophagy, in which intracellular components are surrounded by membranes that fuse w/lysosomes, and endocytosis.
Within the lysosomes, the cathepsin family of proteases degrades the ingested proteins to individual AAs. The recycles AAs can then leave the lysosome and rejoin the intracellular AA pool. |
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22. How does a cell induce autophagy?
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Starvation of a cell is a trigger to induce this process.
This allows old proteins to be recycled and the newly released AAs to be used for new protein synthesis, to enable the cell to survive starvation conditions. |
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23. Ubiquitin
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A small protein (76 AAs) that is highly conserved. Its AA sequence in yeast and humans differs by only three residues.
It targets intracellular proteins for degradation by covalently binding to the ε-amino group of lysine residues. Often, the target protein is polyubiquitinylated, forming a long ubiquitin tail. |
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24. Ubiquitin-proteasome pathway
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After the targeted protein is polyubiquitinylated (say that 10 times fast!) a protease complex, known as the proteasome, then degrades the targeted protein, releasing intact ubiquitin that can again mark other proteins for degradation.
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25. Proteasomes
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A cylindrical 20S protein complex w/multiple internal proteolytic sites. ATP hydrolysis is used both to unfold the tagged protein and to push the protein into the core of the cylinder.
The complex is regulated by cap protein complexes, which bind the ubiquinylated protein (a step that requires ATP) and deliver them to the complex. Different cap complexes alter the specificity of the proteasome. |
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26. Most proteins with what sequence are hydrolyzed by the ubiquitin-proteasome system?
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PEST sequence
P: Proline E: Glutamate S: Serine T: Threonine |
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27. Kwashiorkor
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A common problem of children in third world countries, is caused by a deficiency of protein in a diet that is adequate in calories.
These children suffer from muscle wasting and decreased concentration of plasma proteins, particularly albumin. The result is an increase in interstitial fluid that causes edema and a distended abdomen. |
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28. Where else is elastase found?
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Also found in neutrophils. Neutrophils freq act in the lung, and elastase is sometimes released into the lung as the neutrophils work.
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29. α-1-antitrypsin deficiency
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In normal individuals, the released elastase in the lungs is block from destroying lung cells by the action of circulating α-1-antitrypsin, a protease inhibitor that is synthesized and secreted by the liver.
Individuals w/this disease have a genetic mutation that leads to the production of an inactive α-1-antitrypsin protein. The lack of enzyme activity leads to the development of emphysema caused by proteolytic destruction of lung cells. |
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30. How can α-1-antitrypsin deficiency be detected?
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Rate nephelometry.
Can be measured using a dried blood spot. The blood is solublized using a buffer, and then various amts of the blood sample are incubated w/antibodies specific for α-1-antitrypsin. The antigen-antibody complexes formed will disperse light, and the extent of light scattering is proportional to the concentration of α-1-antitrypsin in the solution. |
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31. Cystic fibrosis and pancreatic exocrine secretions
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Patients w/cystic fibrosis have a genetically determined defect in the function of the chloride channels. In the pancreatic secretory ducts, which carry pancreatic enzymes into the lumen of the small intestines, this defect causes inspissation (drying and thickening) of pancreatic exocrine secretions, leading eventually to obstruction of these ducts.
One result of this problem is the inability of pancreatic enzymes to enter the intestinal lumen to digest dietary proteins. |
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32. Why does the pancreas store a trypsin inhibitor?
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The need for the inhibitor is to block any trypsin activity that may occur from accidental trypsinogen activation.
If the inhibitor were not present, trypsinogen activation would lead to the activation of all of the zymogens in the pancreas, which would lead to the digestion of intracellular pancreatic proteins. Such episodes can lead to pancreatitis. |
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33. Hartnup disease
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A genetically determined and relatively rare autosomal recessive disorder. It is caused by a defect in the transport of neutral amino acids across both intestinal and renal epithelial cells.
The sign and symptoms, are caused, in part, by a deficiency of essential amino acids. Cystinuria and Hartnup disease involve two different transport proteins. In each case, the defect is present both in intestinal cells, causing malabsorption of the AAs from the digestive products in the intestinal lumen, and in kidney tubular cells, causing a decreased resorption of these AAs from the glomerular filtrate and an increased concentration of the AAs in the urine. |
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34. Why doe patients with cystinuria and Hartnup disease have hyperaminoaciduria w/o associated hyperaminoacidemia?
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Cystinuria and Hartnup disease involve two different transport proteins. In each case, the defect is present both in intestinal cells, causing malabsorption of the AAs from the digestive products in the intestinal lumen, and in kidney tubular cells, causing a decreased resorption of these AAs from the glomerular filtrate and an increased concentration of the AAs in the urine.
Therefore, they do not have hyperaminoacidemia (a high concentration in the blood). In these diseases, much larger amts of the affected amino acids are excreted in the urine, resulting in hyperaminoaciduria. |
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35. Hartnup disorder and pellagra
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Some patients with the Hartnup phenotype eventually develop pellagra-like manifestations, which usually include a photosensitivity rash ataxia, and neuropsychiatric symptoms. Pellagra results from a dietary deficiency of niacin or tryptophan.
Only rational treatment for these patients is to administer niacin, but the hyperaminoaciduria and intestinal transport defect do not respond to this therapy. |
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36. γ-glutamyl cycle
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This cycle is necessary for the synthesis of glutathione.
In cells of the intestine and kidney, AAs can be transported across the cell membrane by reacting w/glutathione to form a γ-glutamyl amino acid. The AA is released into the cell, and glutathione is resynthesized. However, the major role of this cycle is glutathione synthesis. |
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37. Transaminase reactions
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Transamination is the major process for removing nitrogen from amino acids.
In most instances, the nitrogen is transferred as an amino group from the original amino acid to α-ketoglutarate, forming glutamate, whereas the original AA is converted to its corresponding α-keto acid. |
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38. Example of transamination reaction
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Aspartate can be transaminated to form its corresponding α-keto acid, oxaloacetate.
In this process, the amino group is transferred to α-ketoglutarate, which is converted to its corresponding amino acid, glutamate. |
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39. Which amino acids have the ability to undergo transamination reactions?
What are the most common pair involved in these reactions? |
All AAs except lysine and threonine have the ability to undergo transamination reactions.
α-ketoglutarate and glutamate → most common pair involved in these reactions |
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40. Transamination reaction summary
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An amino group from one amino acid becomes the amino group of a second amino acid.
B/c these reactions are readily reversible, they can be used to remove nitrogen from AAs or to transfer nitrogen to α-keto acids to form amino acids. Thus, they are involved both in AA degradation and in AA synthesis |
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41. pKa of formation of ammonia from ammonium ion
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pKa = 9.3
Thus, at physiological pH, the equilibrium favors NH4+ by a factor of approximately 100:1. |
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42. Importance of ammonia (NH3)
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This is the form that can cross cell membranes. For example, NH3 passes into the urine from kidney tubule cells and decreases the acidity of the urine by binding protons, forming NH4+.
Once the NH4+ is formed, the compound can no longer freely diffuse across membranes. |
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43. Oxidative deamination of glutamate
Catalyzed by what? Cofactors? |
Catalyzed by glutamate dehydrogenase that produces ammonium ion and α-ketoglutarate.
Either NAD+ or NADP+ can serve as the cofactor. Glutamate can collect nitrogen from other AAs as a consequence of transamination reactions and then release ammonia thru the glutamate dehydrogenase reaction. This process provides one source of the ammonia that enters the urea cycle. |
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44. What are the three mammalian enzymes that can "fix" ammonia into organic molecules?
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1. Glutamate dehydrogenase
2. Glutamine synthetase 3. Carbamoyl phosphate |
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45. What AA provides nitrogen for AA synthesis?
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Glutamate
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46. What AAs provide nitrogens for the urea cycle?
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1. Glutamate
2. Aspartate |
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47. Role of alanine in transporting AA nitrogen to the liver
(AKA glucose/alanine cycle) |
Alanine is exported primarily by muscle. B/c muscle is metabolizing glucose thru glycolysis, pyruvate is available in the muscle.
The pyruvate is transaminated by glutamate to form alanine, which travels to the liver (The glutamate is formed by transamination of an AA that is being degraded) Upon arriving in the liver, alanine is transaminated to pyruvate, and the nitrogen is used for urea synthesis. The pyruvate formed is used for gluconeogenesis and the glucose exported to the muscle for use as energy. |
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48. Role of glutamine in transporting AA nitrogen to the liver
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Glutamine is synthesized from glutamate by the fixation of ammonia, requiring ATP and the enzyme glutamine synthetase.
In the liver, glutamine synthetase is located in cell surrounding the portal vein. Its major role is to convert any ammonia that has escaped from urea production into glutamine, so that free ammonia does not leave the liver and enter the circulation. |
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49. Role of PLP in transamination reactions
Where is PLP derived from? |
Pyridoxyl phosphate (PLP) → cofactor in transaminase reactions
PLP accepts an amino group from an AA and donates it to an α-keto acid. Derived from pyridoxine (vitamin B6) |
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50. Oxidative deamination
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Results in liberation of the amino group as NH4+.
Occurs primarily in the liver and kidney Can utilize NAD+ or NADP+ as a cofactor |
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51. GTP vs. ADP effects on glutamate dehydrogenase
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GTP is an allosteric inhibitor of glutamate dehydrogenase, whereas ADP is an activator
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52. Reaction scheme in the urea cycle
3 main steps... |
1. Synthesis of carbamoyl phosphate
2. Production of arginine 3. Cleavage of arginine to produce urea |
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53. Overall stoichiometry of the urea cycle
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Aspartate + NH3 + CO2 + 3 ATP
↓ Urea + Fumarate + 2 ADP + AMP + 2 Pi + PPi + 3 H2O |
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54. Step 1: Synthesis of carbamoyl phosphate
What enzyme catalyzes this step? |
NH4+, bicarbonate, and ATP react to form carbamoyl phosphate.
Carbamoyl phosphate synthetase I catalyzes this first step in the mitochondria of the liver and intestine. |
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55. Step 2: Production of arginine by the urea cycle
Part I |
1. Carbamoyl phosphate reacts w/ornithine to form citrulline.
2. The product citrulline is transported across the mitochondrial membranes in exchange for cytoplasmic ornithine and enters the cytosol. 3. In the cytosol, citrulline reacts w/aspartate to produce arginosuccinate via arginosuccinate synthetase. |
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56. Step 2: Production of arginine by the urea cycle
Part II |
4. Arginosuccinate is cleaved by arginosuccinate lyase to form fumarate and arginine.
5. Fumarate is converted to malate via cytoplasmic fumarase, which is used either for the synthesis of glucose by the gluconeogenic pathway or for the regeneration of oxaloacetate. 6. The oxaloacetate that is formed is transaminated to generate the aspartate that carries nitrogen into the urea cycle. Thus, the carbons of fumarate can be recycled to aspartate. |
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57. Step 3: Cleavage of arginine to produce urea
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Arginine is cleaved by arginase, producing urea and regenerating ornithine.
Urea is produced from the guanidinium group on the side chain of arginine. The portion of arginine originally derived from ornithine is reconverted to ornithine. This ornithine can then be transported into the mitochondrion in exchange for citrulline, where it can react w/carbamoyl phosphate, initiating another round of the cycle. |
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58. Origin of ornithine
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Although ornithine is normally regenerated by the urea cycle, ornithine also can be synthesized de novo if needed.
The reaction is an unusual transamination reaction catalyzed by ornithine aminotransferase under specific conditions in the intestine. The usual direction of this rxn is the formation of glutamate semialdehyde, which is the first step of the degradation pathway for ornithine. |
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59. What is the rate limiting step of the urea cycle?
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Allosteric activation of CPSI by N-acetyl-glutamate
This is the rate limiting step of the urea cycle. |
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60. What three things regulate the urea cycle?
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1. Regulated by substrate availability
2. Allosteric activation of CPSI by N-acetyl-glutamate (NAG) 3. Induction/repression of the synthesis of urea cycle enzymes |
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61. N-acetyl-glutamate (NAG)
How is it formed? |
Formed specifically to activate CPSI; it has no other known function.
The synthesis of NAG from acetyl CoA and glutamate is stimulated by arginine. |
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62. When arginase levels increase in the liver, what two reactions does this stimulate?
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1. Synthesis of NAG, which increases the rate at which carbamoyl phosphate is produced.
2. Produces more ornithine (via the arginase reaction), so that the cycle can operate more rapidly. |
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63. What conditions promote the induction of the urea-cycle enzymes?
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Occurs in response to conditions that require increased protein metabolism, such as a high-protein diet or prolonged fasting.
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64. What happens to the urea cycle during fasting?
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During fasting, the liver maintains blood glucose levels.
AAs from muscle protein are a major carbon source for the production of glucose by the pathway of gluconeogenesis. As AA carbons are converted to glucose, the nitrogens are converted to urea. Thus, the urinary excretion of urea is high during fasting. |
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65. What is the major AA substrate for gluconeogenesis?
What does this have to do with fasting? |
Alanine, which is synthesized in peripheral tissues to act as a nitrogen carrier.
Glucagon release, which is expected during fasting, stimulates alanine transport into the liver by activating the transcription of transport systems for alanine. |
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66. How many molecules of alanine are required to generate one molecule of glucose and one molecule of urea?
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Two molecules of alanine are required to generate one molecule of glucose and one molecule of urea.
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67. Ornithine transcarbamoylase (OTC) deficiency
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An X-linked disorder; occurs in 1/20,000 and 1/80,000 live births.
Predominantly affects males, although female carriers may become symptomatic; typically results in mental retardation When OTC is deficient, the carbamoyl phosphate that normally would enter the urea cycle accumulates and floods the pathway for pyrimidine biosynthesis. Under these conditions, excess orotic acid (orotate), an intermediate in pyrimidine biosynthesis, is excreted in the urine. |
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68. Treatment of OTC deficiency
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Limiting dietary protein
and Administration of compounds (e.g. benzoid acid and phenylacetate) that covalently bind to amino acids → nitrogen-containing molecules are then excreted in the urine |
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69. Vitamin B6 Deficiency
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Symptoms include dermatitis, microcytic anemia (small, pale red blood cells), weakness, irritability and convulsions
Inability to completely metabolize amino acids → appearance of xanthurenic acid (a degradation product of tryptophan) and other compounds in the urine Decreased ability to synthesize heme from glycine → microcytic anemia Decreased decarboxylation of amino acids to form neurotransmitters → convulsions Also required for the glycogen phosphorylase reaction. |
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70. Diagnostic values of plasma aminotranferases in liver disease
Which is more specific - ALT or AST? Which is more sensitive - ALT or AST? |
Plasma AST and ALT are typically elevated
Particularly high in conditions that cause extensive cell necrosis (e.g., severe viral hepatitis, toxic injury, prolonged circulatory collapse) ALT is more specific AST is more sensitive → liver contains larger amounts of this enzyme than ALT |
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71. Diagnostic values of plasma aminotranferases in non-hepatic disease
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Aminotransferases may be elevated (e.g., myocardial infarction, muscle disorders)
Disorders can usually be distinguished clinically from liver disease |
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72. Ammonia intoxication
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Capacity of hepatic urea cycle > normal rates of NH3 generation → levels of serum ammonia = 5-50 μM (normal range)
Compromised liver function → blood levels of NH3 can rise above 1,000 μM Ammonia has a direct neurotoxic effect on the central nervous system Ammonia intoxication → tremors, slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision High concentration of NH3 → coma and death |
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73. BUN
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Blood urea nitrogen is a measurement for the urea content of the blood.
The key to measuring BUN is to split urea into CO2 and two ammonia molecules by the enzyme urease. The ammonia levels are then determined. Once BUN is determined, the urea concentration can be determined by multiplying the nitrogen value by 2.14 |
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74. γ-aminobutryic acid (GABA) and liver disease
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An important inhibitory neurotransmitter in the brain, is also shunted into the systemic circulation in increased amts in patients with hepatic failure.
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75. Acute viral hepatitis
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The serum ALT level is often elevated to a greater extend than the serum AST level.
Alkaline phosphatase is also elevated. The rise in serum total bilirubin occurs as a result of the inability of the infected liver to conjugate bilirubin and of a partial or complete occlusion of the hepatic biliary drainage ducts caused by inflammatory swelling within the liver. |
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76. Nucleotide structure
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Nitrogenous base + Pentose monosaccharide + Phosphate group(s)
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77. Four functions of nucleotides
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1. Precursor molecules to DNA, RNA
2. Involved in energy metabolism, ATP, GTP, CTP, UTP 3. Structure of many coenzymes, NAD+, FAD, CoA 4. Activated sugars in biosynthesis pathways |
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78. Where does the uptake and synthesis of nucleotides takes place?
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Low dietary uptake in the intestine (about 5%) - mostly used by intestinal epithelial cells and thus de novo synthesis of purines and pyrimidines is required.
Most are made in the liver, however brain and immune cells also make their own. |
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79. Purine synthesis starts with...?
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Starts with 5-phosphoribosyl-1-pyrophosphate (PRPP)
All purines are built on a ribose base and PRPP is the activated source of the ribose moiety. The pyrophosphate will be replaced by the nucleic acid base. |
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80. Production of PRPP
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It is synthesized from ATP and ribose 5'-phosphate, which is produced from glucose thru the pentose phosphate pathway which is catalyzed byt he enzyme PRPP synthetase.
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81. First committed step of the purine biosynthetic pathway
What enzyme catalyzes this step? |
1. PRPP reacts w/glutamine to form 5-phosphoribosyl 1-amine.
This reaction, which produces nitrogen 9 of the purine ring, is catalyzed by glutamine phosphoribosyl amidotranferase, a highly regulated enzyme. |
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82. Second step of purine biosynthesis
What does this step require? |
An entire glycine molecule is added to the growing precursor. Glycine provides carbons 4 and 5 and nitrogen 7 of the purine ring.
This step requires energy int eh form of ATP |
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83. Step three of purine biosynthesis
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Carbon 8 is provided by N^10-formyl-FH4, nitrogen 3 by glutamine, carbon 6 by CO2, nitrogen 1 by aspartate and carbon 2 by formyl FH4.
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84. How many molecules of ATP are required to synthesize the first purine nucleotide, inosine monophosphate (IMP)?
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Six molecules of ATP
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85. Importance of folate
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Folate is essential for purine synthesis
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86. Importance of IMP
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IMP serves as a branch point from which both adenine and guanine nucleotides can be produced.
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87. Formation of AMP
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Adenosine monophosphate is derived from IMP in two steps:
1. Aspartate is added to IMP to form adenylosuccinate 2. Fumarate is then released from the adenylosuccinate by the enzyme adenylosuccinase to form AMP. In both cases, aspartate donates a nitrogen to the product, while the carbons of aspartate are released as fumarate. |
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88. Formation of GMP
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Also synthesized from IMP in two steps:
1. The hypoxanthine base is oxidized by IMP dehydrogenase to produce the base xanthine and the nucleotide xanthosine monophosphate (XMP) 2. Glutamine then donates the amide nitrogen to XMP to form GMP in a reaction that is catalyzed by GMP synthetase. This reaction requires energy in the form of ATP. |
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89. Phosphorylation of AMP and GMP
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AMP and GMP can be phosphorylated to the di- and triphosphate levels.
The production of nucleoside diphosphates requires specific nucleoside monophophate kinases, whereas the production of nucleoside triphosphates requires nucleoside diphosphate kinases. |
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90. Regulation of purine synthesis;
What four key enzymes are regulated? What do they regulate? |
1. PRPP synthetase
2. Amidophosphoribosyl transferase 3. Adenylosuccinate synthetase 4. IMP dehydrogenase 1 & 2 regulate IMP synthesis; 3 & 4 regulate the production of AMP and GMP, respectively. |
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91. How is the first committed step of purine synthesis regulated?
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Ezyme is glutamine phosphoribosyl amidotransferase.
This enzyme is strongly inhibited by GMP and AMP. The active enzyme is a monomer of 133,000 daltons but is converted to an inactive dimer (270,000 daltons) by binding of the end products. *The rate of de novo purine synthesis increases as the concentration of PRPP increases because PRPP concentrations are usually below the Km |
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92. What inhibits adenylsuccinate synthetase?
How about IMP dehydrogenase? |
AMP inhibits adenylosuccinate
GMP inhibits IMP dehydrogenase Note: the synthesis of AMP is dependent on GTP, whereas the synthesis of GMP is dependent on ATP. This serves as a type of positive regulatory mechanism to balance the pools of these precursors. |
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93. Salvaging of purine bases
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Salvage pathways are used to recover bases and nucleosides that are formed during degradation of RNA and DNA. This is important in some organs because some tissues cannot undergo de novo synthesis.
The salvaged bases and nucleosides can then be converted back into nucleotides. |
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94. What three major enzymes are required for purine salvaging?
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1. Purine nucleoside phosphorylase
2. Phosphoribosyl tranferase 3. Deaminases |
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95. Purine nucleoside phosphorylase
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This enzyme catalyzes a phosphorolysis reaction of the N-glycosidic bond that attaches the base to the sugar moiety in the nucleosides guanosine and inosine.
Thus, guanosine and inosine are converted to guanine and hypoxanthine, respectively, along with ribose 1-phosphate. The ribose-1-phosphate can be isomerized to ribose 5-phosphate, and the free bases then salvaged or degraded, depending on cellular needs. |
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96. Phosphoribosyl transferase enzymes
What are the two phosphoribosyl transferase enzymes, and what do they do? |
They catalyze the addition of a ribose 5-phosphate group from PRPP to a free base, generating a nucleotide and pyrophosphate.
Two enzymes do this: adenine phosphoribosyl transferase (ARPT) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT). The reactions they catalyze are the same, differing only in their substrate specificity. |
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97. Deaminase
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Adenosine and AMP can be deaminated by adenosine deaminase and AMP deaminase, respectively, to form inosine and IMP.
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98. What is so special about adenosine?
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Adenosine is also the only nucleoside to be directly phosphorylated to a nucleotide by adenosine kinase.
Guanosine and inosine must be converted to free bases by purine nucleoside phosphorylase before they can be converted to nucleotides by HGPRT. |
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99. Purine nucleotide cycle
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Important salvage pathway in muscle.
The net effect of these reactions is the deamination of aspartate to fumarate. Under conditions in which the muscle must generate energy, the fumarate derived from the purine nucleotide cycle is used anapleurotically to replenish TCA cycle intermediates and to allow the cycle to operate at high speed. Deficiencies in enzymes of this cycle lead to muscle fatigue during exercise. |
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100. De novo synthesis of pyrimidine nucleotides
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In the synthesis of the pyrimidine nucleotides, the base is synthesized first, and then it is attached to the ribose 5'-phosphate moiety.
The origins of the atoms of the ring are from aspartate and carbamoyl-phosphate, which are derived from CO2 and glutamine. |
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101. Steps of pyrimidine nucleotide synthesis (formation of UMP)
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*1. Glutamine combines with bicarbonate and ATP to form carbamoyl phosphate via CPS-II.
2. An entire aspartate molecule adds to carbamoyl phosphate via aspartate transcarbamoylase. 3. The molecule subsequently closes to produce a ring via dihydro-orotase 4. The enzyme orotate phosphoribosyl transferase catalyzes the transfer of ribose 5-phosphate from PRPP to orotate, producing orotidine 5'-phosphate, which is decarboxylated by orotidylic acid dehydrogenase to form uridine monophosphate (UMP) *regulated step of pathway |
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102. CAD enzymes
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In mammals, the first three enzymes of the pathway (CPS-II, aspartate transcarbamoylase, and dihydro-orotase) are located on the same polypeptide, designated as CAD
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103. UMP synthase
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The last two enzymes of the pathway are located on a polypeptide known as UMP synthase (the orotate phosphoribosyl transferase and orotidylic acid dehydrogenase)
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104. Formation of UTP and CTP
Why are these pyrimidines important? |
UMP is phosphorylated to UTP. An amino group, derived form the amide of glutamine, is added to carbon 4 to produce CTP via CTP synthetase.
UTP and CTP are precursors for the synthesis of RNA. |
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105. Salvage of pyrimidine bases
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Salvaged by a two step route:
1. Non-specific pyrimidine nucleoside phsophorylase converts the pyrimidine bases to their respective nucleosides. 2. The more specific nucleoside kinases the react w/the nucleosides, forming nucleotides. |
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106. Efficiency of pyrimidine base salvage
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The nucleoside phosphorylase-nucleoside kinase route for synthesis of pyrimidine nucleoside monophosphates is relatively inefficient for salvage of pyrimidine bases b/c of the very low concentration of bases in plasma and tissues.
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107. Preference for pyrimidine phosphorylase
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Can use all of the pyrimidines but has a preference for uracil and is sometimes called uridine phosphorylase.
The phosphorylase uses cytosine fairly well but has a very, very low affinity for thymine; therefore, a ribonucleoside containing thymine is almost never made in vivo. |
|
108. Thmine phosphorylase
|
Has a much higher affinity for thymine and adds a deoxyribose residue.
|
|
109. Thymidine kinase (TK)
|
This enzyme is allosterically inhibited by dTTP.
Activity of thymidine kinase in a given cell is closely related to the proliferative state of that cell. During the cell cycle the activity of TK rises dramatically as cells enter S-phase, and in general, rapidly dividing cells have high levels of this enzyme. |
|
110. Regulation of de novo pyrimidine synthesis
What inhibits and activates synthesis? |
The regulated step is carbamoyl phosphate synthetase II (CPS-II).
The enzyme is inhibited by UTP and activated by PRPP. Thus, as pyrimidines decrease in concentration, CPS-II is activated and pyrimidines are synthesized. *Also regulated by the cell cycle. |
|
111. How does the cell cycle regulate pyrimidine synthesis?
|
As cells approach S-phase, CPS-II becomes more sensitive to PRPP activation and less sensitive to UTP inhibition.
At the end of S-phase, the inhibition by UTP is more pronounced, and the activation by PRPP is reduced. These changes in the allosteric properties of CPS-II are related to its phosphorylation state. Phosphorylation of the enzyme by MAP kinase leads to a more easily activated enzyme, while phosphorylation at a second site by the cAMP dependent protein kinase leads to a more easily inhibited enzyme. |
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112. Production of deoxyribonucleotides
|
For DNA synthesis to occur, the ribose moiety must be reduced to deoxyribose. This reduction occurs at the diphosphate level and is catalyzed by ribonucleotide reductase, which requires the protein thioredoxin.
The deoxyribonucleoside diphosphates can be phosphorylated to the triphosphate level and used as precursors for DNA synthesis. |
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113. Regulation of ribonucleotide reductase
|
The enzyme contains two allosteric sites, one controlling the activity of the enzyme and the other controlling the substrate specificity of the enzyme.
|
|
114. Control of ribonucleotide reductase activity
|
ATP bound to the activity site activates the enzyme; dATP bound to this site inhibits the enzyme.
|
|
115. Control of ribonucleotide reductase substrate specificity
|
ATP bound to the substrate site activates the reduction of pyrimidines (CDP and UDP), to form dCDP and dUDP. The dUDP is not used for DNA synthesis; rather, it is used to produce dTTP, which then binds to the substrate site and induces the reduction of GDP.
As dGTP accumulates, it replaces dTTP in the substrate site and allows ADP to be reduced to dADP. This leads to the accumulation of dATP, which inhibits the overall activity of the enzymes. |
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116. Formation of dUMP
|
dUDP can be dephosphorylated to form dUMP or dCMP can be deaminated to form dUMP.
|
|
117. Formation of dTMP
|
Methylene FH4 transfers a methyl group to dUMP to form dTMP.
|
|
118. Formation of dTTP
|
Phosphorylation reactions produce dTTP, a precursor for DNA synthesis and a regulator of ribonucleotide reductase.
|
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119. Degradation of purine bases
|
The degradation of the purine nucleotides (AMP and GMP) occurs mainly in the liver.
Salvage enzymes are used for most of these reactions. |
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120. Degradation of AMP
|
AMP is first deaminated to produce IMP via AMP deaminase.
Then, IMP and GMP are dephosphorylated via 5'-nucleotidase, and the ribose is cleaved from the base by purine nucleoside phosphorylase. Hypoxanthine, the base produced by cleavage of IMP, is converted by xanthine oxidase to xanthine, and guanine is deaminated by the enzyme guanase to produce xanthine. The pathways for the degradation of andenine and guanine merge at this point. |
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121. Degradation of xanthine to uric acid
What enzyme accomplishes this? |
Xanthine is converted by xanthine oxidase to uric acid, which is excreted in the urine.
|
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122. Xanthine oxidase
|
This is a molybdenum-requiring enzyme that uses molecular oxygen and produces hydrogen peroxide.
Another form of xanthine oxidase uses NAD+ as the electron acceptor. |
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123. Energy expenditure of purine ring degradation
|
Little energy is derived from the purine ring degradation.
Thus, it is to the cell's advantage to recycle and salvage the ring, b/c it costs energy to produce and not much is obtained in return. |
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124. Degradation of pyrimidine bases
|
The pyrimidine nucleotides are dephosphorylated, and the nucleosides are cleaved to produce ribose 1-phosphate and the free pyrimidine bases cytosine, uracil and thymine.
These products of pyrimidine degradation are excreted in the urine or converted to CO2, H2O, and NH4+ (which forms urea). As with the purine degradation pathway, little energy can be generated by pyrimidine degradation. |
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125. Deficiency in purine nucleoside phosphorylase activity
|
Leads to an immune disorder in which T-cell immunity is compromised.
B-cell immunity, conversely, may be only slightly compromised or even normal. Children who lack this activity have recurrent infections, and more than half display neurologic complications. Symptoms of the disorder first appear at between 6 months and 4 years of age. |
|
126. Lesch-Nyhan syndrome
|
Caused by a defective HGPRT.
In this condition, purine bases cannot be salvaged. Instead, they are degraded, forming excessive amounts of uric acid. Individuals with this syndrome suffer from mental retardation and are prone to self mutilation. There is gout like damage to the brain. Treatment is allopurinol but no treatment exists for the neurological symptoms |
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127. Hereditary orotic aciduria
|
Orotic acid is excreted in the urine b/c the enzymes that convert it to uridine monophosphate, orotate phosphoribosyltransferase and orotidine 5'-phosphate decarboxylase, are defective.
Pyrimidines cannot be synthesized and normal growth does not occur. Oral administration of uridine is used to treat this condition b/c it bypasses the metabolic block and provides the body w/a source of pyrimidines. |
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128. Symptoms of hereditary orotic aciduria
|
-Occurs in the first few months of life
-Macrocytic hypochromic megaloblastic anaemia -Failure to thrive, developmental retardation -Sparse hair, cardiac malformations, bilateral strabismus, inability to sit unaided, and gross crystalluria, occasionally with ureteric obstruction, have been general findings. -Abnormalities of immune function -Heterozygotes show mild orotic aciduria but are otherwise unaffected |
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129. OTC
|
Causes elevated levels of cytoplasmic carbamoyl phosphate which leads to pyrimidine production.
Thus orotic aciduria results. |
|
130. pK of uric acid
|
pK= 5.4; It is ionized in the body to form urate.
Urate is not very soluble in an aqueous environment. The quantity in normal human blood is very close to the solubility constant. |
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121. 5-fluorouacil
|
Inhibits thymidylate synthase (dUMP-to-TMP synthesis)
Used for inhibiting cell growth in cancer cells. |
|
122. Methotrexate
|
Methotrexate inhibits dihydrofolate reductase, thereby blocking the regeneration of FH4 and de novo purine synthesis and thymidine synthesis.
|
|
123. Hydroxyurea
|
Blocks ribonucleotide reductase activity, with the goal of inhibiting DNA synthesis in leukemic cells.
|
|
124. Adenosine deaminase deficiency
|
Increases [deoxyadenosine] and this is converted back to dATP. Thus, [dATP] is 100x higher, which is toxic.
Synthesis of other 3 dNTP blocked - T and B cells are affected. 2'-deoxyadenosine also inhibits S-adenosylhomocysteine hydrolase which decreases methylation reactions vital to normal cell function. |
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125. Two kinds of joints
|
1. Solid (Non-synovial)
2. Cavitated (Synovial) |
|
126. Solid joints
|
Known as synarthroses; provide structural integrity and allow for minimal movement
No joint space; grouped according to type of connective tissue by bridges at end of bones |
|
127. Cavitated joints
|
Synovial joints
Have a joint space that allows for a wide range of motions At the ends of bones formed by endochondral ossification; strengthened by dense fibrous capsule and reinforced by tendons and ligaments; has a synovial membrane. |
|
128. Synoviocytes
|
Surface lining of synovial joints
Cuboidal cells; 1-4 layers deep; lacks a basement membrane and merges w/underlying loose CT |
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129. Synovial fluid
|
Filtrate of plasma containing hyaluronic acid
|
|
130. Osteoarthritis
|
AKA degenerative joint disease
Most common type of joint disease Characterized by progressive erosion of articular cartilage Not a disease of inflammation but rather a disease of articular cartilage in which biochemical metabolic processes result in the breakdown |
|
131. Secondary osteoarthritis
|
Involves 1 or more predisposed jonts; i.e. sports injuries.
Hands are more commonly affected in women Hips are more commonly affected in men. |
|
132. Normal articular cartilage
What is the function? |
Bathed in synovial fluid ensures friction free movement w/in the joint
Spreads the load across the joint surface to allow underlying bones to absorb shock and weight w/o being crushed. |
|
133. Aging and mechanical effects
|
Mechanical stresses important role in osteoarthritis.
Increasing age = increasing freq of arthritis Increasing occurrence in weight bearing joints Increasing freq in conditions that predispose joints to abnormal mechanical stress |
|
134. Genetic factors in osteoarthritis
|
Appears to play a role in susceptibility esp in hands and hips
Specific genes are not identified but linkage to chromosome 1 and 2 has been suggested. |
|
135. Risk of osteoarthritis
|
Increased in direct proportion to bone density.
High levels of estrogens also associated w/increased risk |
|
136. Early characterizations of osteoarthritis
Degenerating cartilage would contain what...? |
1. Increased water content
2. Decreased concentration of proteoglycans 3. Appears to have a weakening of the collagen network; presumed decreased local synthesis of Type II collagen and increased breakdown of existing collagen 4. Increased apoptosis in chondrocytes but chondrocytes are actively proliferating |
|
137. Characteristics/symptoms of osteoarthritis
|
Patients w/primary disease are asymptomatic until 5th decade
1. Achy pain that worsens w/use 2. Morning stiffness 3. Crepitus 4. Limited range of motion 5. Impingement on spinal foramina by osteophytes results in cervical and lumbar nerve root compression 6. Typically, only one or a few joints are involved |
|
138. Joints commonly involved in osteoarthritis
|
1. Hips
2. Knees 3. Lower lumbar/cervical vertebrae 4. Proximal and distal IP joints of fingers 5. First carpometacarpal joints 6. First tarsometatarsal joints in feet |
|
139. Heberden nodes
|
Characteristic in women but not in men
Prominent osteophytes at the distal IP joints of the fingers that are easily seen on xray |
|
140. Bone eburnation
|
Exposed subchondral bone plate becomes new articular surface and friction smooths and burnishes the new bone giving it the appearance of polished ivory
|
|
141. Joint mice
|
Small fractures are common and the dislodged pieces of cartilage and subchondral bone tumble into the underlying joint
|
|
142. Subchondral cyst
|
The fractured gaps allow synovial fluid to be forced into subchondral regions in one way ball valve like mechanism
The trapped fluid collection increases in size forming a fibrous walled cyst |
|
143. Synovial pannus
|
Fibrotic tissue that covers the diseased part of the joint
|
|
144. Rheumatoid arthritis
|
Chronic systemic inflammatory disorder that may affect tissues and organs (skin, blood vessels, heart, lungs, muscles) but principally attacks the joints producing a non-suppurative proliferative and inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints
Cause is unknown but autoimmunity plays a pivotal role in its chronicity and progression |
|
145. Morphological alterations of RA
|
Initially, synovium becomes edematous, thickened and hyperplastic; transforming its smooth contour to one covered by delicated and bulbous fronds
|
|
146. Seven histological features of RA
|
1. Infiltration of synovial stroma by dense perivascular inflammatory cells (B cells, CD4+ helper T cells, plasma cells, and macrophages)
2. Increased vascularity (caused by vasodilation and angiogenesis) 3. Aggregation of organizing fibrin covering portions of the synovium 4. Rice bodies floating in the joint space 5. Accumulation of neutrophils in the synovial fluid and synovium 6. Osteoclastic activity in the underlying bone which forms juxta-articular erosions and subchondral cysts and osteoporosis 7. Pannus formation |
|
147. RA nodules
|
RA noduels are most common cutaneous lesions in RA.
They form in regions of skin that are subjected to pressure (i.e. elbows, occiput, and lumbosacral area) Less commonly they form in the lungs, spleen, peri and myocardium, heart valves, aorta, and other viscera Firm, non-tender and round to oval in shape |
|
148. Rheumatoid vasculitis
|
Potentially dangerous complication of RA; particularly when it affects vital organs.
Freq segments of small arteries are obstructed by an obliterating endarteritis resulting in peripheral neuropathy, ulcers, and gangrene. Leukocytoclastic venulitis produced purpura, cutaneous ulcers and nail bed infarction |
|
149. Pathogenesis of RA
|
RA is an autoimmune disease triggered by exposure of genetically susceptible host to an unknown arthritogenic antigen.
Activation of CD4+ helper T cells and other lymphocytes, and local release of inflammatory mediators and cytokines that ultimately destroy the joint. |
|
150. Autoimmune reaction in RA
|
Activated CD4+ helper T cells and B lymphocytes as well
The target antigen is unknown. T cells function by stimulating other cells in the joint to produce cytokines that are essential mediators of the synovial reaction. Evidence exists that immune complex deposition may play some role in joint destruction. |
|
151. Four major mediators of joint injury
|
1. Cytokines
2. TNF 3. IL-1 4. TNF and IL-1 stimulate synovial cells to proliferate and produce various mediators (matrix metalloproteinases that contribute to cartilage destruction) |
|
152. RANKL
|
Produced by activated T cell and synovial fibroblasts
Activates osteoclasts and promotes bone destruction |
|
153. Genetic susceptibility of RA
|
Class II HLA locus (specifically a region of 4 AAs located in the antigen binding cleft)
May bind and display the arthritic antigen to T cells The AA sequence in the cleft is inherited |
|
154. Five characteristics/symptoms of RA
|
1. Malaise
2. Fatigue 3. Generalized musculoskeletal pain after which joints become involved 4. Small joints involved before larger ones 5. Swollen, warm, painful, and stiff joints upon arising or after painful activity |
|
155. Radiographic hallmarks of RA
|
Juxta-articular osteopaenia and bone erosions w/narrowing of the joint space from loss of articular cartilage
|
|
156. Lab Dx of RA
|
No specific lab tests but many patients have RF factor and IgM antibody reacted w/Fc portions of the patients own IgG
May not be present, but also included in differentials of other diseases so not 100% indicative |
|
157. Synovial analysis of RA
|
1. Nonspecific inflammatory arthritis
2. Neutrophils with high protein content and low mucin content |
|
158. Clinical features for a Dx of RA
|
Need at least 4 of the following criteria:
1. Morning stiffness 2. Arthritis in 3 or more joints 3. Arthritis of typical hand joints 4. Symmetric arthritis 5. Rheumatoid nodules 6. RF factor 7. Typical radiographic changes |
|
159. Treatment of RA (Four options)
|
1. Glucocorticoids
2. NSAIDS 3. Anti-rheumatic drugs (i.e. methotrexate) 4. TNF blockers |
|
160. Juvenile RA
|
Begins before age 16 and must be present for a duration of at least 6 wks
Has a 2:1 female ratio |
|
161. Differences between adult and juvenile RA
|
1. Oligoarthritis more common in juvenile
2. Systemic onset is more frequent in juvenile 3. Large joints are affected more in juvenile 4. Rheumatoid nodules and factor usually absent in juvenile 5. Anti-nuclear antibodies seropositivity is common in juvenile |
|
162. Four similarities between adult and juvenile RA
|
1. Genetic association with HLA haplotypes
2. Mycobacterial or viral infection 3. Abnormal immunoregulation with CD4+ T cells within the involved joints 4. Cytokine production |
|
163. Systemic onset of juvenile RA
|
1. High spiking fever
2. Migratory and transitory skin rash 3. Hepatosplenomegaly 4. Serositis |
|
164. Seronegative spondyloarthropathies
What are the three types? |
Produce inflammatory peripheral or axial arthritis and inflammation of the tendinous attachment
1. Ankylosing spondyloarthritis 2. Reactive arthritis 3. Psoriatic arthritis |
|
165. Ankylosing spondyloarthritis
|
A chronic inflammatory joint disease of axial joints, esp the SI joints
Includes: 1. Chronic synovitis w/destruction of articular cartilage 2. Bony ankylosis in SI and apophyseal joints 3. Inflammation of tendinoligamentous insertion points leading to bony outgrowths Become symptomatic in 2nd or 3rd decades of life Analogous to RA |
|
166. Reactive arthritis
|
Episode of non-infection arthritis that occurs w/in 1 month of a primary infection localized elsewhere in the body
Often associated w/genitourinary infections in the 2nd and 3rd decades of life Waxes and wanes over a period of several weeks to 6 months |
|
167. Psoriatic arthritis (Five features)
|
1. Distal IP joint involvement w/nail pitting
2. Asymmetrical oligoarthropathy of both large and small joints 3. Arthritis mutilans, a severe form 4. Symmetrical polyarthritis 5. Spondyloarthropathy |
|
168. Infectious arthritis
What are the four types? |
Caused by microorganisms lodging in joints during hematogenous dissemination
Includes: 1. Suppurative arthritis 2. Tuberculous arthritis 3. Lyme disease 4. Viral arthritis |
|
169. Suppurative arthritis
|
Caused by bacterial infection
Individuals w/sickle cell are prone to infection Presents w/: 1. Acutely painful hot and swollen joint w/restricted range of motion 2. Fever 3. Leukocytosis 4. Elevated sedimentation rate Occurs in hip, shoulder, elbow, wrist, and sternoclavicular |
|
170. Tuberculous arthritis
What two things does it result in? |
Chronic progressive monoarticular disease, usually develops w/adjoining osteomyelitis or after dissemination of infection from lungs.
Results in: 1. Severe destruction w/fibrous ankylosis and obliteration of joint space 2. Weight bearing joints are usually affected |
|
171. Lyme arthritis
What are four characteristics? |
Arthritis caused by lyme disease
Infected synovium takes the form of: 1. Chronic papillary synovitis w/synoviocyte hyperplasia 2. Fibrin deposition 3. Mononuclear cell infiltrates 4. Onion-skin thickening of arterial walls |
|
172. Viral arthritis
|
Occurs w/viral infections including parvovirus, rubella, and Hepatitis C
Symptoms: variable and range from acute to subacute |
|
173. Gout
|
Metabolic disorder that includes acute and chronic arthritis, uric acid deposits in and around joints and skin, renal stones, and hyperuricemia
Leads to chronic gouty arthritis and tophi deposits |
|
174. Accumulation of uric acid results from what two conditions...?
|
1. Defect in the purine uric acid metabolism leading to overproduction of uric acid
2. Primary defects in renal clearance |
|
175. Plasma urate levels above what value are considered clinically important?
|
Above 7 mg/dL is considered elevated at normal body temp and pH
|
|
176. Two pathways involved in purine synthesis
|
1. de novo pathway in which purines are made from non-purine precursors
2. *Salvage pathway; free purine bases are derived from breakdown of AAs of endo- or exogenous origins *uses the enzyme HGPRT |
|
177. Six factors that lead to gout
|
1. Age
2. Genetic predisposition 3. Heavy EtOH consumption 4. Obesity 5. Certain drugs (i.e. thiazides) 6. Lead toxicity |
|
178. Morphology of gout (four things)
|
1. Acute arthritis
2. Chronic tophaceous arthritis 3. Tophi deposits 4. Gouty nephropathy |
|
179. Chronic tophaceous arthritis
|
Evolves from the repetitive precipitation of urate crystals which may heavily encrust the articular surfaces and form visible deposits on the synovium
|
|
180. What is the pathognomonic hallmark of gout?
|
TOPHI
Formed by large aggregates of urate crystals; surrounded by intense inflammatory reaction of macrophages, lymphocytes, and large foreign body giant cells which may have partially or completely engulfed masses of crystals. |
|
181. Gouty nephropathy
|
Renal disorder associated w/deposition of monosodium urate crystals in the renal medullary interstitium.
Sometimes forms tophi, intratubular precipitations of free uric acid crystals (can form kidney stones) |
|
182. What are the four stages of gout?
How long does it take from the initial attack to reach the tophaceous stage? |
1. Asymptomatic hyperuricemia
2. Acute gouty arthritis 3. Intercritical gout 4. Chronic tophaceous gout Takes 12 years from initial attack to reach the tophaceous stage |
|
183. Locations of gout
|
First attacks are monoarticular and 50% occur in the first metatarsophalangeal joint
1. Insteps 2. Ankles 3. Heels 4. Knees 5. Wrists 6. Fingers 7. Elbows |
|
184. Dx of gout
|
Acute onset of monoarthritis in joint of lower extremity.
Intracellular needle shaped, negatively birefringent crystals are essential to Dx of acute gouty arthritis Urate crystals may also be seen in tophaceous depositis into which a joint has ruptured tophaceous deposits |
|
185. Treatment of gout uses what three drugs?
|
1. Colchicine
2. NSAIDS 3. Glucocorticoids |
|
186. Treatment of intercritical gout uses what four drugs?
|
1. Colchicine
2. NSAIDS 3. Probenecid 4. Allopurinol |
|
187. Pseudogout
|
AKA calcium pyrophosphate crystal disease (CPPD)
Intra-articular crystal formation Altered activity of the matrix enzymes that produce and degrade pyrophosphate, resulting in its accumulation and eventual recrystallization with calcium |
|
188. What are the three forms of pseudogout?
|
1. Sporadic
2. Hereditary 3. Secondary types |
|
189. Hereditary form of psuedogout
|
The crystals develop relatively early in life and forms severe osteoarthritis.
The autosomal dominant form of the disease has been shown to be related to a mutation in the ANKH gene, which encodes a transmembrane-inorganic pyrophospate transport channel. |
|
190. Secondary form of psuedogout
|
Associated w/various disroders, including previous joint damage, hyperparathyroidism, hemochromatosis, hypomagnesmia, hypothroidism, ochronosis, and diabetes
|
|
191. Morphology of pseudogout
|
The crystals first develop int he articular matrix, menisci, and intervertebral discs, and may rupture and seed the joint if large enough.
Once released into the joint, they elicit the production of IL-8 which helps produce and inflammatory reaction rich in neutrophils The neutrophils produce damage thru the release of oxygen metabolites, catabolic enzymes, and cytokines |
|
192. Dx of pseudogout
|
May mimic other disorders such as osteoarthritis or RA.
Joint involvement may be monoarticular or polyarticular Crystals are weakly birefringent and have geometric shapes; they are rarely deposited in masslike aggregates simulating tophi. |
|
193. What are the five most common joints affected in pseudogout?
Treatment? |
1. Knees
2. Wrists 3. Elbows 4. Shoulders 5. Ankles Therapy is supportive; no known treatment prevents or retards crystal formation. |
|
194. Ganglion cyst
|
A small 1 to 1.5 cm cyst that is almost always located near a joint capsule or tendon sheath.
It arises as a result of cystic or myxoid degeneration of connective tissue; the cyst wall makes a true cell lining. Fluid that fills the cyst is similar to synovial fluid; however, there is no communication with the joint space. |
|
195. Synovial cyst
|
Herniation of synovium through a joint capsule or massive enlargement of a bursa may produce a synovial cyst.
Synovial lining may be hyperplastic and contain inflammatory cells and fibrin but is otherwise unremarkable. |
|
196. Villonodular synovitis
What do they arise from? |
A term for several closely related benign neoplasms that develop in the synovial lining of joints, tendon sheaths, and bursae.
They arise from a clonal proliferation of cells and are neoplastic. |
|
197. Pigmented villonodular synovitis (PVNS)
|
The normally smooth joint synovium, most often the knee, is converted into a tangled mat by red-brown folds, finger like projections, and nodules.
Aggressive tumors erode into adjacent bones and soft tissues Usually presents as a monoarticular arthritis that affects the knee in 80% of cases. Treatment is surgery. |
|
198. Giant cell tumor of tendon sheath (GCT)
|
AKA localized nodular tenosynovitis
Usually occurs as a discrete nodule on a tendon sheath and may be attached to the synovium by a pedicle. Slow growing painless mass that freq involves the tendon sheaths along wrists and fingers Treatment is also surgery. |
|
199. Podagra
|
The first metatarsophalangeal joint is the most commonly involved joint in acute gouty arthritis
It is termed podagra |
|
200. What two metabolic disorders are associated with osteoarthritis?
|
1. Hemochromatosis
2. Ochronosis |
|
201. Primary OA
|
This is the idiopathic variety, which may be localized or generalized, and its causes are multifactorial.
|
|
202. Secondary OA
What is the most common cause? |
Occurs when a particular cause of OA overwhelms all others and serves as a sole cause of disease.
Most common cause of secondary OA is a severe joint injury, but other causes include congenital and developmental disorders (especially in the hip), inflammatory arthritis, and neurological dieases. |
|
203. What is the earliest finding associated with OA?
What happens next? |
Fibrillation of the most superficial layer of the articular cartilage.
With time, the disruption of the articular surface becomes deeper with extension fo the fibrillations to subchondral bone, fragmentation of cartilage with release into the joint, matrix degradation, and, eventually, complete loss of cartilage, leaving only exposed bone. |
|
204. Tidemark zone in OA
|
The tidemark zone, separating the calcified cartilage from the radial zone, becomes invaded with capillaries.
|
|
205. What do chondrocytes release in OA?
|
Chondrocytes initially are metabolically active and release a variety of cytokines and metalloproteinases, contributing to matrix degradation, which in the later stages results in the penetration of fissures to the subchondral bone and the release of fibrillated cartilage into the joint space.
|
|
206. What important imbalance may be "operative" in OA?
|
An imbalance between tissue inhibitors of metalloproteinases and the production of metalloproteinases may b eoperative in OA.
|
|
207. What crystals have been identified in synovial fluid and other tissues from osteoarthritic joints?
|
Calcium pyrophoshate dihydrate and apatite.
Thought these crystals clearly have potent inflammatory potential, their role in the pathogenesis of OA remains uncertain. |
|
208. What is the characteristic clinical feature of OA?
What does it result from? |
Pain. Pain is typically deep aching discomfort, slow in onset, initially aggravated with activity, improved w/rest, and localized to the involved joint.
Occasionally, pain is referred to a distant site. Pain may result form venous engorgement of subchondral bone, accumulation of fluid in the joint, or synovitis. With progressive disease, pain may occur at rest. Exacerbation of symptoms with weather changes is a common feature. |
|
209. What does the physical exam in OA reveal?
|
Reveals joint-line tenderness and bony enlargement of the joint with or without effusion. Crepitation on motion and limitation of joint motion are additional characteristic features.
|
|
210. What are the two subtypes of OA?
|
1. Nodal form of OA
2. Erosive, inflammatory form of OA |
|
211. Nodal form of OA
|
Involves primarily the distal interphalangeal joints and is the most common in middle aged women, typically with strong family history among first-degree relatives.
|
|
212. Erosive, inflammatory form of OA
|
Associated w/prominent erosive, destructive changes, especially in the finger joints, and may suggest RA, although systemic inflammatory signs and other typical features of RA (e.g., nodules, proliferative synovitis, extra-articular features, rheumatoid factor) are absent.
|
|
213. Joints involved in OA
|
1. Distal interphalangeal joints
2. Proximal interphalangeal joints 3. First carpometacarpal joints 4. Facet joints of the cervical and lumbar spine 5. Hips 6. Knees 7. First metatarsophalangeal joint |
|
214. Joint deformity associated with OA is characteristic in which locations?
|
Heberden's and Bouchard's nodes in the hands and, depending on the compartment of the knee, valgus or varus deformity.
|
|
215. What are the radiographic features of OA?
|
1. Subchondral sclerosis
2. Joint-space narrowing 3. Subchondral cysts 4. Osteophytes |
|
216. What are the available pharmacological therapies for OA?
|
1. Simple analgesics
2. NSAIDs 3. COX-2 inhibitors 4. Intra-articular corticosteroids 5. Condroprotective agents 6. Anti-depressants |
|
217. What pharmacological therapy is most effective in OA?
|
Intra-articular therapies such as corticosteroids appear to provide modest symptomatic benefit, especially in the knee.
|
|
218. What about synthetic hyaluronate injected intra-articularly?
Ok, then... what about chondroitin sulfate and glucosamine? |
Synthetic hyaluronate injected intra-articularly appear to have little if any benefit based on current evidence.
Chondroitin and glucosamine were not significantly better than placebo in reducing knee pain. |
|
219. What are the four therapeutic strategies for gout?
|
Most involve lowering the uric acid levels by:
1. Interfering w/uric acid synthesis with allopurinol 2. Increasing uric acid excretion with probenecid or sulfinpyrazone 3. Inhibiting leukocyte entry into the affected joint with colchicine 4. Administration of NSAIDs |
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220. NSAIDS
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NSAIDs inhibit cyclooxygenase (COX) and thereby inhibit prostaglandin and thromboxane synthesis.
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221. Indomethacin
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Indomethacin is a nonselective inhibitor of cyclooxygenase (COX) 1 and 2
This is one of the NSAIDs most commonly prescribed for treating acute attacks of gout. |
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222. What are the adverse effects of NSAIDs?
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The serious adverse effects of NSAIDs include bleeding, salt and water retention, and renal insufficiency.
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223. COX-2 selective inhibitors and gout
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Potentially useful for the management of acute gout attacks b/c they may decrease the risk of GI bleeding, although concerns about adverse cardiovascular effects limit their long-term use.
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224. Colchicine
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A plant alkaloid, is reserved for the treatment of acute gouty attacks. It is neither a uricosuric nor an analgesic agent, although it relives pain in acute attacks of gout.
It does not prevent the progression of gout to acute gouty arthritis but it does have a suppressive, prophylactic effect that reduces the frequency of acute attacks and relieves pain. |
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225. Mechanism of action of colchicine?
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Binds to tubulin, a microtubular protein, causing its depolymerization. This disrupts cellular functions, such as the mobility of granulocytes, thus decreasing their migration into the affected area.
Also, colchicine also blocks cell division by binding to mitotic spindles. It also inhibits the synthesis and release of the leukotrienes via inhibiting neutrophil activation. |
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226. How does colchicine inhibit neutrophil activation?
Four ways... |
1. Decreased trafficking of phagocytosed particles to lysosomes
2. Decreased release of chemotactic factor 3. Decreased motility and adhesion of neutrophils 4. Decreased tyrosine phosphorylation of neutrophil proteins, with a resulting decrease in leukotriene B4 synthesis |
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227. Therapeutic uses of colchicine?
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1. Acute gout
2. Prevention of recurrent gout attacks Anti-inflammatory activity is specific for gout, usually alleviating the pain of acute gout within twelve hours. Also used for prophylaxis of recurrent attacks. |
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228. Pharmacokinetics of colchicine
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Administered orally, followed by rapid absorption from the GI tract.
It is recycled in the bile and is excreted unchanged in the feces or urine. Concomitant administration of cyclosporine, tacrolimus, or verapamil may increase plasma levels of colchine |
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229. Adverse effects of colchicine
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Myelosupression, neuromyopathy
Diarrhea, abdominal pain, vomiting. Should not be used in pregnancy and should be used w/caution in patients with hepatic, renal or cardiovascular disease. |
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230. Contraindications of colchicine
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Severe cardiac, GI or renal disease
Hepatic failure Blood dyscrasias |
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231. What are the three inhibitors of uric acid synthesis?
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1. Allopurinol
2. Oxypurinol 3. Febuxostat |
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232. Allopurinol
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Allopurinol is a purine analog. It reduces the production of uric acid by competitively inhibiting the last two steps in uric acid biosynthesis that are catalyzed by xanthine oxidase.
When xanthine oxidase is inhibited, the circulating purine derivatives are more soluble, and therefore, are less likely to precipitate |
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233. Oxypurinol
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The oxidized form of allopurinol, known as oxypurinol, inhibits xanthine oxidase by preventing molybdenum in the active site of the enzyme from interconverting between the +4 and +6 oxidation states, essentially freezing xanthine oxidase.
Xanthine oxidase is important in purine degradation, therefore, inhibint the enzyme result in increased plasma levels of hypoxanthine and xanthine, which are more soluble. |
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234. Therapeutic uses of allopurinol and oxypurinol
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Used in the treatment of chronic gout, especially in cases caused by increased purine degradation.
1. Prevention of recurrent gout attacks 2. Cancer-related hyperuricemia 3. Calcium and uric acid renal calculus |
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235. Pharmacokinetics of allopurinol
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Completely absorbed after oral administration.
The primary metabolite is alloxanthine (oxypurinol), which is also a xanthine oxidase inhibitor. The half life of allopurinol is short (two hours), whereas the half life of oxypurinol is long (15 hours) |
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236. Adverse effects of allopurinol
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Agranulocytosis, aplastic anemia, renal failure, hepatic necrosois, toxic epidermal necrolysis
Pruritus, rash, GI disturbance |
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237. Contraindications of allopurinol
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Idiopathic hemochromatosis
Interferes with the metabolism of 6-mercaptopurine and the immunosuppressant azathioprine, requiring a reduction in dosage of these drugs |
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238. Febuxostat
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A nonpurine small molecule inhibitor of xanthine oxidase also being evaluated for the treatment of chronic gout.
Unlike allopurinol, febuxostat undergoes extensive hepatic metabolism and it may not require dose adjustment in renal insufficiency. |
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239. What are the four drugs that increase uric acid excretion?
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They are called uricosuric agents
1. Sulfinpyrazone 2. Probenecid 3. Losortan 4. Benzbromarone |
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240. What are the therapeutic uses of agents that increase uric acid excretion?
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Prevention of recurrent gout attacks.
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241. Probenecid
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Useful for the treatment of chronic hyperuricemia.
Probenecid shifts the balance between renal excretion and endogenous formation of urate, thereby lowering plasma urate, dissolving urate crystals, and reversing the crystal deposition in synovial joints. |
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242. How does probenecid work?
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Inhibitor of the basolateral anion exchanger of the proximal tubule.
This exchanger acts to enhance the secretion of many anions, including drugs. Such inhibition decreases the plasma concentration of urate by decreasing urate reabsorption. |
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243. Probenecid and urine pH
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Increasing renal urate excretion can predispose to formation of urate stones in the kidney or ureter.
This complication can be prevented by making the urine less acidic, commonly by coadministration of oral calcium citrate or sodium bicarbonate; uric acid has a pKa of 5.6 and it remains predominantly in the more soluble neutral form if the urine pH is above 6.0. |
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244. Pharmacokinetics of probenecid
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Because probenecid inhibits the secretion of most anions, the dose of other drugs excreted by this pathway should be reduced when probenecid is coadministered.
Low dose aspirin may antagonize probenecid action. It is also sometimes used to increase levels of penicllin. It can also increase the serum levels of methotrexate. It inhibits secretion of naproxen, ketoprofen, and indomethacin. |
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245. Sulfinpyrazone
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Also a uricosuric agent that acts by the same mechanism as probenecid (inhibitor of the tubular secretion of organic acids).
It is more potent than probenecid and it is effective in mild to moderate renal insufficiency. In addition to acting as a uricosuric, it has antiplatelet effects; it should therefore be used with caution in patients taking other antiplatelet agents or anticoagulants. |
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246. Drug interactions with sulfinpyrazone
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May also increase levels of penicillin and other anionic compounds; may also increase the levels of nitrofurantoin.
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247. Benzbromarone
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Also a uricosuric agent with a mechanism of action similar to that of probenecid and sulfinpyrazone.
May have greater uricosuric efficacy than probenecid and sulfinpyrazone, particularly in patients with impaired renal function. However, the frequent incidence of hepatotoxicity has limited widespread use of the drug. It is not approved for use in the US but it is available in Europe |
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248. Adverse effects of uricosuric agents
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Leukopenia, thrombocytopenia, bronchoconstriction in patients with asthma, aplastic anemia (probenecid), anaphylaxis (probenecid)
GI disturbance |
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249. Contraindications of uricosuric agents (five of them)
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1. Acute gout attack
2. Blood dyscrasias (imbalance) 3. Children under 2 yrs of age 4. Coadministration of salicylates 5. Uric acid kidney stones |
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250. Losartan
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An angiontensin II receptor antagonist that has modest uricosuric effect.
Losartan may be a logical therapeutic choice in patients with concomitant hypertension and gout, although no controlled studies have been performed to prove that losartan reduces the incidence of acute gouty attacks |
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251. What is losartan used for?
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1. Hypertension
2. Prevention of recurrent gout attacks |
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252. Adverse effects of losartan
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Angioedema, rhabdomyolysis, thrombocytopenia, anemia, fatigue, back pain, hypoglycemia
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253. Contraindications of losartan
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Pregnancy
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254. What is the name of an agent that enhances uric acid metabolism?
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Rasburicase
It is a recombinant form of Aspergillus uricase that converts sparingly soluble urate to the more soluble allantoin. |
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255. What is rasburicase used for?
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Tumor lysis syndrome.
Most mammals other than humans express the enzyme uricase, which oxidizes uric acid to allantoin, a compound that is easily excreted by the kidney. In cancer chemotherapy, the rapid lysis of tumor cells can liberate free nucleotides and greatly increase plasma urate levels, which can lead to massive renal injury. |
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256. Adverse effects of rasburicase
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Hemolysis, methemoglobinemia, neutropenia, respiratory distress, sepsis, rash, GI disturbance, fever
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257. Contraindications of rasburicase
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1. G6PD deficiency
2. Known Aspergillus sensitivity |
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258. What are the four classes of antigens that provoke an immune response in our bodies?
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The four classes of pathogen are: bacteria, viruses, fungi, and parasites (protozoa and worms).
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259. Identify the two major progenitor subsets of leukocytes
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The two major progenitor subsets of leukocytes are the common lymphoid progenitor and the myeloid progenitor.
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260. Name the white blood cells that differentiate from these two progenitor lineages
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The common lymphoid progenitor differentiates into three cell types: B cells, T cells, and natural killer (NK) cells.
The myeloid progenitor differentiates into six main cell types: basophils, eosinophils, neutrophils, mast cells, dendritic cells, and monocytes. Monocytes are circulating leukocytes that enter tissues, where they then differentiate into macrophages. |
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261. Name the primary lymphoid tissues in mammals and the main types of secondary lymphoid tissue
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The primary (or central) lymphoid tissues are the bone marrow (and liver in the fetus) and the thymus.
The main secondary (or peripheral) lymphoid tissues are the lymph nodes, spleen, and mucosa-associated lymphoid tissues (MALT). The latter include gut-associated lymphoid tissue (GALT), such as the tonsils, adenoids, appendix, and Peyer's patches, and bronchial-associated lymphoid tissues (BALT). |
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262. What is the primary lymphoid tissue and what are the principal events that take place in it?
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Primary (or central) lymphoid tissues are the anatomical locations where lymphocytes complete their development and reach the state of maturation required for recognition of and response to a potential pathogen. B cells mature in the bone marrow and fetal liver, and T cells mature in the thymus. Both lymphocyte lineages are derived from a common hematopoietic stem cell. Somatic recombination of antigen-receptor genes and negative selection of potentially autoreactive B and T cells (to produce self-tolerance) occurs in primary lymphoid tissues.
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263. What is the secondary lymphoid tissue and what are the principal events that take place in it?
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Secondary (or peripheral) lymphoid tissues provide the anatomical sites where lymphocytes encounter antigen and immune responses are induced. Antigen is delivered to the secondary lymphoid tissues through an afferent lymphatic vessel, where it is then filtered and retained for encounter with lymphocytes bearing antigen-specific receptors. Clonal selection and somatic hypermutation (in B cells) occur in secondary lymphoid tissues.
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264. In what way is the spleen different from the other secondary
lymphoid tissues? |
The spleen differs from the other secondary lymphoid tissues in that lymph does not filter through this organ. Instead, the spleen filters the blood and traps blood-borne pathogens.
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265. What molecules do B cells use to recognize foreign antigens?
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B cells recognize antigen through immunoglobulin on their surface.
After activation, B cells become plasma cells, which secrete a soluble form of this immunoglobulin as antigen-specific antibodies. |
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266. What molecules do T cells use to recognize foreign antigens?
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T cells recognize antigen through a different, although structurally related, type of molecule called the T-cell receptor on their cell surface.
The T-cell receptor is not secreted. |
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267. Explain how an antigen is prepared for T-cell recognition
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Peptides are produced and presented by mechanisms known as antigen processing and antigen presentation, respectively.
Proteins are denatured and degraded enzymatically, generating small peptide fragments that are able to bind to MHC molecules. Proteins degraded in the cytosol bind to MHC class 1 molecules, whereas proteins degraded in endocytic vesicles bind to MHC class II molecules. The ancillary cell that presents the MHC molecule:peptide complex to the T cell is referred to as the antigen-presenting cell. |
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268. What are the three mechanisms by which antibodies eradicate infections?
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1. Neutralization
2. Opsonization 3. Complement activation |
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269. Neutralization
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By binding to the surface of a pathogen antibodies interfere with the ability of the pathogen to grow and replicate.
Antibody binding to a pathogen or a bacterial toxin can also inhibit its binding to receptors on host cells and therefore prevent its entry into cells. |
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270. Opsonization
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Antibody coating the surface of a pathogen or toxin can promote phagocytosis of the antibody-covered particle. Antibodies acting in this way are known as opsonins.
The antibody-bound material interacts with Fc receptors on the surface of phagocytic cells such as macrophages and neutrophils, which bind the constant region (the stem) of the antibody. Stimulation of Fc receptors in this way stimulates engulfment and degradation of antibody-coated material by the phagocyte. |
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271. Complement activation
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IgG or IgM antibody bound to a pathogen stimulates activation of the complement system, leading to the deposition of complement proteins on the surface of the pathogen.
Certain of these act as opsonins and bind to complement receptors on phagocytic cells to stimulate phagocytosis and destruction of the pathogen. |
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272. What are the three types of unwanted and potentially harmful immune responses?
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1. Allergy
2. Autoimmune 3. Transplant rejection |
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273. Allergies
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IgE antibodies made against normally innocuous environmental antigens trigger widespread mast-cell activation.
This can lead to allergic diseases such as asthma or to a potentially fatal anaphylactic reaction. |
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274. Autoimmune reactions
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Chronic immune responses by B cells or T cells to self antigens can cause tissue damage and chronic illnesses such as diabetes, multiple sclerosis, and myasthenia gravis.
Autoimmunity is sometimes provoked as a consequence of an immune response to pathogen-derived antigen that cross-reacts on healthy host cells or tissue. |
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275. Transplant rejection
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A person's immune system will make an immune response against the foreign MHC molecules on transplanted tissue that is MHC-incompatible.
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