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119 Cards in this Set
- Front
- Back
Acetyl-CoA Carboxylase
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rate limiting step of fatty acid biosynthesis
catalyst for the rxn of Acetyl-CoA + HCO3 --> Malonyl CoA Reaction is irreversible |
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3 Parts of Acetyl CoA Carboxylase and 2 steps of rxn
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3 Parts:
Biotin carrier protein biotin carboxylase transcarboxylase 2 Steps biotin carboxylation from ____ Carboxyl transfer from ___ to ___ |
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Acetyl-CoA Carboxylase Regulation
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Feedback Inhibitor: Palmitoyl-CoA
Citrate: Allosteric Activator triggered by inc. conc of mitochondrial acetyl-coa and ATP. At the same time, citrate will inhibit phosphofurctokinase-1 (glycolysis) Covalent Modification: Glucagon and epinephrine inactivte the enzyme by phosporylation |
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Steps before fatty acid synthesis
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KS gets acyl from acetyl coa, catalyzed by MT
ACP gets acyl from malonyl coa, catalyzed by AT |
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ACP
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Acyl Carrier Protein
highly exergonic thioseter bonds that fuel the unfavorable steps of synthesis (1 and 5) |
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Overview Fatty Acid
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Pre-steps:
-introduce acetyl and malonyl coa to fatty acid synthase, KS and ACP respectively 1. Condensation 2. Reduction 3. Dehydration 4. Reduction/Translocation |
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Chemical Energy Required for Biosynthesis
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ATP: necessary to attach CO2 to acetyl coa and make malonyl coa
NADPH: needed to reduce the double bonds for step 2 |
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Step 1: Fatty acid synthesis
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Condensation:
catalyzed by Beta-ketoacyl-ACP synthase (KS) acetyl group transferred from Cys-SH of KS to ACP Acetyl Coa carbons are added to malonyl coa carbons on the ACP |
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Step 2: Fatty Acid Synthesis
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Reduction
catalyzed by beta ketoacyl-ACP reductase (KR) Requires NADPH + H --> NADP+ for energy Reduces C-3 double bond with O |
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Step 3: Fatty Acid Synthesis
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Dehydration
catalyzed by beta-hydroxylacyl-ACP dehydratase (HD) Water is removed from C-2 and C-3 |
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Step 4: Fatty Acid Synthesis
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Reduction
Catalyzed by enoyl-ACP reductase (ER) NADPH + H --> NADP+ required for energy Double bond C-2 C-3 removed to form saturated carbon chain |
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Step 5: Fatty Acid Synthesis
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Translocation
Butyryl group is moved from ACP to Cys on KS enzyme so that it can go through pathway again. |
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4 catalyst in synthesis
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1. Beta ketoacly-ACP synthase KS
2. Beta ketoacyl ACP reductase (KR) 3. Beta hydroxy ACP dehydructase (HD) 4. Enoyl ACP Reductase (ER) |
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Palmitate Modification
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Elongation
Desaturation |
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Elongation
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occures in Smooth ER
uses palmioyl CoA and malonyl CoA Similar steps as synthesis but uses CoA catalyst instead of fatty acid synthase |
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Desaturation
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Occurs in smooth ER
uses Mixed Functional Oxidase common product is unsaturated ∆9 fatty acyl CoA Uses stearoyl CoA from the elongation |
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Physiologic controls of Acetyl CoA Carboxylase
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Palmitoyl CoA
ATP (glucagon stimulated) Citrate |
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Regulation of Fatty Acid Synthesis
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Substrate availability
Acetyl CoA Carboxylase Allosterically--citrate and dephosphorylation Allosterically--palmitoyl CoA and phosphorylation |
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2 fates of triglycerols
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storage of energy
maintain cellular membranes |
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2 precursors of triglycerols
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fatty acyl CoA and L-glycerol 3 Phosphate
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L-Glycerol 3-Phosphate
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important precursor in formation of triaclglycerols and glycerophospholipids
Mostly formed from dihydroxyacetone phosphate (DHAP) with NADH + H --> NAD+ using glycerol3 3-P dehydrogenase |
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Glycerol 3-P dehydrogenase
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High in adipose
present in liver when blood sugar level is high, the adipose tissue can convert sugar to fat |
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Glycerol
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Precursor to triacylglycerol and glycerophospholipids to form glycerol 3-P
Used in the liver and kidney via ATP dependent rxn with enzyme glycerol kinase |
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Glycerol Kinase
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Adds PO3 group to Glycerol in kidney and liver to form Glycerol 3-P
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Acyl Transferases
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Enzyme catalyses first stage of triacylglycerol synthesis
Adds to acyl groups to glycerol 3-P Product is phosphatidate |
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Phosphatidate
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glycerol back bone with 2 fatty acids and 1 phosphate
Precursor for all glycerol fatty acids |
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Synthesis of Phoshatidate
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Explain synthesis
where it occurs 2 precursors |
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2 Major classes of Membrane phospholipids
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Glycerophospholipids
Sphingolipids |
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General Structures of Glycerophospholipids
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Describe the general skeleton of glycerophospholipids:
Choline Ethanolamine Inositol Serine |
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Phosphatidylinositol
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Explain Synthesis: Steps and Precursors
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Cardiolipin
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Explain Synthesis: Steps and Precursors
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Synthesis for CDP-activated diacyglycerols
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Forms Cardiolipin and Phosphatidylinositol
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Synthesis for CDP-activated polar head groups
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Forms phosphatidylcholine and phosphatidylethanolamine
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Phosphatidylcholine
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Explain synthesis: Strategy 2
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Phosphatidylethanolamine
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Explain synthesis: Strategy 2
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Methylation of Polar Head Group
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Formation of phosphaditylcholine
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Synthesis Using base Exchange
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Formation of phosphatidylserine
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Phosphatidylcholine
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Explain its synthesis from phosphatidylethanolamine
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Phosphatidylserine
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Explain its synthesis froom phosphatidylethanolamine
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4 step synthesis of sphingolipids
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1. synthesis of sphinganine
2. attachment of fatty acid to yield N-acylsphinganine 3. desaturation to form ceramide 4. Attachment of head group to yield glucosylceramide or sphingomyelin |
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Sphingosine
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product of palmitoyl-CoA + Serine
Rxn requires energy from NADPH and FAD and releases CO2 |
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Ceramide
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Major intermediate of Sphingolipid formation
Formed in second step of synthesis Sphingosine + Acyl-CoA --> ceramide |
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2 Types of sphingolipid
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Glucosylceramide (aka-Cerebroside )
Sphingomyeline |
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5 Types of glycerophospholipids
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Phosphatidylinositol
Cardiolipin Phosphatidylethanolamine Phosphatidylcholine Phosphatidylserine |
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Glucosylceramide
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Sphingolipid formed from ceramide and head-group sugar attached to C-1 from UDP sugar
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Sphingomyelin
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ceramide + phosphatidylcholine--> sphingomyeline
Phosphatidylcholine serves as the donor of phosphocholine, rather than CDP-choline |
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Degredation of Glucosylceramide
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Breakdown of Glucosylceramide by Glucocerebrosidase yields Glucose and ceramide
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Niemann-Pick
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sphingomyelinase defiency
causes accumulation of sphingomyelin |
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Gaucher
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Glucocerebrosidase deficiency
Causes accumulation of glucosylceramide |
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Tay-Sachs
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Hexosaminidase A deficiency
Causes ganglioside GM2 accumulation |
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Eicosanoids
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Prostaglandins, PGE2
Thromboxanes, TXA2 Leukotrienes, LTA4 |
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Eicosanoid Synthesis:
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What is precursor? Arachidonic acid
What are major enzymes? COX, Lipoxygenase, peroxidase activity of COX |
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Cholesterol Synthesis
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What are 4 steps
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Stage 1 of Cholesterol synthesis
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What is rate limiting step
What are major enzymes |
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HMG-CoA Reductase
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Membrane protein of smooth ER
What reaction does it synthesize? What is energy requirement. Is it rate limiting |
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Stage 2 of Cholesterol Synthesis
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Formation of Isoprene Unit
∆3 isopentenyl pyrophosphate can be isomerized to dimethylallyl pyrophosphate and this is used in stage 3 |
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Stage 3 of cholesterol synthesis
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products of stage 2, isopentenyl and dimethylallyl are used to form squalene
isopentenyl + dimethylallyl --> geranyl (10C) + isopentenyl --> farnesyl (15C)+ farnesyl --> squalene (30C) |
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Prenyl transferase
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enzyme in stage 3 of cholesterol synthesis
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squalene synthesase
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enzyme of stage 3 of cholesterol synthesis
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Stage 4 Cholseterol synthesis
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conversion of squalene to the four ring steroid nucleus
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Squalene synthase
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requires NADPH and produces squalene in head-to-head synthesis
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cyclases
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squalene epoxide cyclic to form lanosterol
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lanosterol
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Formed in stage 4 of cholesterol synthesis and has characteristic 4 ring structure
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Cholesterol Synthesis enzymes
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HMG CoA synthase
HMG CoA reductase Squalene Synthase lanosterol cyclase: 2,3 oxidosqualene 7-dehydrocholesterol reductase |
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HMG CoA synthase
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Cytoplasmic, which is diff from mitochondrial enzyme which forms ketone bodies
catalyzes production of HMG CoA |
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ACAT
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Acyl-CoA: cholesterol acyltransferase
cholesterol + Acyl CoA --> cholesteryl ester + CoA Storage in the cell as lipid droplet; incorporation into lipoproteins |
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LCAT
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lecithin: cholesterol acyltransferase
cholessterol + phosphatidycholine --> cholseteryl ester + lysophosphatidylcholine storage in the blood as lipoprotein |
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Plasma lipoproteins
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Chylomicron
VLDL HDL LDL |
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HDL
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Mostly apoprotein
contains LCAT; forms cholesteryl esters from cholesterol |
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Chylomicrons
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movement of lipids from large intestine to other body parts
remenants are taken up by liver Has most amount of triglycerols |
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VLDL
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delivers endogenous lipids and cholesterol from liver to the muscle and adipose tissue
removal of triacylglycerol from VLDL eventually converts them to LDLs |
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LDL
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low density lipoprotein
very rich in cholesterol and cholesteryl esters carry the cholesterol to extrahepatic tissue that has specific plasma membranes |
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HDL
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originates in liver and smal intestine as small protein rich particle with little cholesterol and contain LCAT
can be taken up in the liver but also delivers to other tissue |
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Apoliproteins
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ApoA--HDL; activator of LCAT
ApoB 100--VLDL, LDL; ligand for receptor, structural role Apo 48--chylomicron; structural Apo C-11--chylomicron, VLDL, HDL; activator of lipoprotein lipase Apo E--chylomicron, VLDL, apoE rich HDL; ligand for receptor |
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Enzymes for lipoprotein metabolism
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LCAT
LPL HL Acid Lipase |
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Lecithin: cholesterol acyltransferase
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phosphatidylcholine and cholesterol are the substrates and occurs in lipoproteins especially nascent HDL
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Lipoprotein Lipase (LPL)
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substrates are triacylglycerol in VLDL and chylomicron and it occurs on capillary surfaces
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Hepatic lipase (HL)
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Triacylglycerol stubstate and phospholipids in IDL and HDL and occurs in the liver sinusoids
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Acid lipase
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uses triacylglycerol and cholesteryl esters and occurs in lysosomes
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Know plasma transformations of lipoproteins
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chylomicron---->chylomicron remnant (small intestine to liver)
VLDL ---> LDL (liver to liver and extrahepatic tisssue) HDL ---> apo-e rich HDL (small intestine to ?) |
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Fat utilization and regulation
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not all organs can directly use fat or fatty acid
The liver has major role in fat usage and production |
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Role of liver in fat regulation
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provides supply of glucose to other systems
regulates blood glucose by conversion to and from glycogen can produce glucose from other materials like lactate will make fatty acid when there is excess glucose and glycogen makes ketone bodies for other organs |
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Chylomicrons
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largest lipoprotein
movement of triacylglycerols |
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VLDL
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carry triglycerols and and some cholesterol
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LDL
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very rich in cholesterol and cholesterol esters
removal of triacylglycerol from VLDL produces low density lipoprotein |
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Liver after meal
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After a meal: glucose from blood ---> glycogen and fatty acid synthesis sends VLDL to adipose tissue
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Liver after fasting
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After fasting: glycogen breaks down to send glucose to blood
fatty acid from adipose tissue is used as fuel in liver |
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Adipose tissue major points
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fatty acids are transported from liver to fat as VLDL complexes
fatty acid are then reconverted to triglycerides in adipose cell for storage glycerol-3P is required by cell to make triglycerides. this must come from glucos we don't store fat without excess glucose |
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Muscle tissue fxn
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at rest: energy from b-oxidation of fatty acid
at work: internal glycogen, builds up lactate alanine can be produced Alanine and lactate are shipped to liver for conversion |
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Pentose phosphate pathway
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fermentative pathway (no O2 required)
not very energy yielding 2 major products: ribose 5 phosphate (for nucleotide synthesis) NADPH (for biosythetic reactions and antioxidant reducing) used in cells that are rapidly dividing like bone marrow, skin, intestinal mucosa, used to make RNA, DNA, and enzylmes like ATP, NADH, FADH2 and coenzyme A |
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Oxidative and non oxidative phases
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oxidative: produces NADPH and ribose 5 phosphate
non oxidative: takes 1 ripose-5P and 1 xylulose-5P and rearranges back to glucose-6P to continue with oxidative phase only occurs in tissues which NADPH is needed in high amounts |
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Where PPP occurs--needs ribose 5 phosphate
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tissue that needs lots of ribose 5 phosphate
rapidly dividing: bone marrow, skin, intestinal mucosa, tumors --->ONLY needs oxidative |
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Where PPP occurs--needs lots of NADPH
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cells synthesizing fatty acid, cholesterol, steroid:
liver, adipose, lactating mammary, adrenal cortex, gonads cells exposed to high level oxygen: erythrocytes, cornea and lens --->BOTH oxidative and non oxidative steps |
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Hexokinase/glucokinase
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catalyzes:
glucose---> Glucose 6-P |
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oxidative in PPP
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produces pentose phosphates and NADPH
4 steps: 2 involve dehydrogenase reactions that produce NADPH |
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nonoxidative in PPP
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produces Ribose 5-P AND NADPH
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Glutathione/NADPH
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important in protecting cells from highly reactive oxygen derivatives
Glutathione (GSH) is tripeptide of GLU, CYS and GLY H+ donor for proteins that have been oxidized |
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Oxidative phase Step 1
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glucose 6-P ---> 6-Phospho-glucono-lactone
Catalyzed by glucose 6-Phosphate dehydrogenase NADP+ ---> NADPH + H+ |
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Glucose 6-Phosphate Dehydrogenase
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catalyst of oxidative phase step 1 glucose 6-P --> 6-phospho-glucono-lactone
Produces NADPH |
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Oxidative phase step 2
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6-Phosphoglucono-lactone--> 6-phosphogluconate
catalysed by Lactonase |
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Oxidative Phase Step 3
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6-phosphogluconate--> D-Ribulose-5 Phosphate
Catalyzed by 6-phosphogluconate dehydrogenase Produces NADPH and releases CO2 |
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6-phosphogluconate dehydrogenase
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catalyzes step 3 of oxidative phase
6-phosphogluconate-->D-Ribulose-5-phosphate |
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Oxidative step 4
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D-ribulose-5 phosphate (ketose)--> D-Ribose-5-phosphate (aldose)
Enzyme: Phosphopentose isomerase |
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D-Ribose-5-Phosphate
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final product of oxidative phase and initiates the NON-oxidative phase
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D-Ribulose-5-Phosphate
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product of step 3 oxidative
it can be shunt off to the non-oxidative phase when you need more NADPH |
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Non oxidative phase
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2 enzyme transketolase and transaldolase transfer 2C or 3C ketose units to aldose acceptors
six 5 carbon compounds are converted to five 6 carbon compounds (glucose 6-P) which can re-enter PPP, enter glycolysis, be converted to glycogen, etc |
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Ribose 5-phosphate epimerase
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ribulose 5-P --> Xylulose 5-P
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Transketolase Reaction
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transfer of 2 carbon ketose group to an aldose receptor
just rearranging the carbons Requires TTP cofactor catalyzes rxn from 2 Five carbons --> 7C and 3C |
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Wernicke-Korsakoff syndrome
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caused by mutation in transketolase and deficiency in thiamine
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Nonoxidative step 2
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xyulose 5-P + ribose 5-P --> glyceraldehyde 3-P + sepdoheptulose 7-P
Catalyzed by transketolase/TPP cofactor |
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Nonoxidative step 3
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sedoheptulose 7-P + Glyceraldehyde 3-P --> Erythrose 4-P + fructose 6-P
Catalyzed by transaldolase |
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Transaldolase
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transports 2 OR 3 carbons
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Nonoxidative phase step 4
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xylulose 5-5 + erythrose 4-P --> glyceraldehyde 3-P + Fructose 6-P
catalyzed by Transketolase |
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Pyruvate Dehydrogenase
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Pyruvate ---> Acetyl CoA
Highly favored; irreversible 5 co-factors: Thiamine TPP Vit. B1 Niacin NAD+ Vit. B2 Riboflavin FAD Vit. B3 Pantothenate CoA Lipoate (only non vitamin) |
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plasma albumin
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major carrier of free fatty acid in blood
binds up to 10 mol.mol |
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fatty aceyl coa synthase
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catalyst for first rxn of beta oxidation
fatty acid --> fatty aceyl CoA After conversion, fatty aceyl coA enters the mitochondria |
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ketone bodies
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d-beta-hydroxybutyrate
acetoacetate acetone |
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steps of beta oxidation
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oxidation
hydrolysis oxidation thiolysis |
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Energy from beta oxidation
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Example 18 Carbon
Activation -2 ATP 9 Acetyl CoA (12 ATP each) = 108 ATP 8 FADH2 (2 ATP each) = 16ATP 8 NADH+ H (3 ATP each) = 24 ATP |