FATTY ACID METABOLISM

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FATTY ACID METABOLISM
1. Fatty acid function 1) building blocks of
membrane lipids - phospholpids, glycolipids 2)
precursors for hormone or intracellular
messenger - prostaglandin, phosphatidyl
inositol 3) fuel molecules - triacylglycerols 4)
modification of proteins - covalent attachment of
fatty acids - membrane location

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2. Overview of fatty acid metabolism 1) fatty
acid degradation - oxidation double bond
formation - hydration -OH group - oxidation
ketone - cleavage 2 carbon unit 2) fatty aicd
synthesis - essentially reverse - condensation
malonyl unit (3 carbon unit ? 2 carbon unit) -
reduction OH-group - dehydration double bond
formation - reduction unsaturated hydrocarbon
chain

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3. High energy stores 1) highly reduced - 9
kcal/g vs. 4 kcal/g of carbohydrates 2)
anhydrous -  2 g of water/ 1 g of glycogen

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• 4. Hydrolysis of triacylglycerols
• 1) bile salt glycocholate (from cholesterol)
• 2) pancreatic lipase
• - triacyglycerol 2 H2O ? 2 fatty acids
  monoacylglycerol
• 3) chylomicrons
• mucosal cells 2 fatty acids monoacylglycerol
  ?
• triacylglycerol
• - lipoprotein transporting particles apoproteins
  lipids
• 4) cAMP-regulating lipase
• - triacyglycerol 3 H2O ? glycerol 3 fatty
  acids
• 5) hormonal regulation of cAMP-regulating lipase
  activity
• epinephrine, norepinephrine, glucagon,
• adrenocorticotropic hormone
• - cAMP
• - insulin

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6) glycerol - glycerol kinase   glycerol ATP ?
glycerol 3-phosphate ADP - glycerol phosphate
dehydrogenase   glycerol 3-phosphate NAD ?
dihydroxyacetone phosphate NADH

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5. ß Oxidation 1) mechanism of fatty acid
oxidation - Franz Knoop (1904) - the ? carbon
atom joined to a phenyl group 2) degradation by
oxidation at the ß carbon. - phenyl propionate ?
benzoate - phenylbutylate ? phenyl acetate

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6. Translocation of fatty acid from cytosol to
mitochondria 1) acetyl CoA synthetase -
mitochondria outer membrane - fatty acid ATP
HA-CoA ? acyl CoA AMP PPi 2) carnitine
acyltransferase I and II - acyl CoA carnitine ?
HS-CoA acyl carnitine 3) translocase

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• 7. Oxidation of fatty acid
• 1) acyl CoA dehydrogenase oxidation
• electron transport electron-transferring
  flavoprotein (ETF) ?
• ETFQ reductase (similar to succinateQ
  reductase in
• oxidative phosphorylation)
• 2) enoyl CoA hydratase hydration
• 3) L-3-hydroxyacyl CoA dehydrogenase oxidation
• 4) ß-ketothiolase thiolysis
• 5) palmitate
• - palmitoyl CoA 7 FAD 7 NAD 7 CoA 7 H2O
  ?
•   8 acetyl CoA 7 FADH2 7 NADH 7 H

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• 6) unsaturated fatty acid
• - cis-?3 double bond
•   cis-?3-enoyl CoA ? trans-?2-enoyl CoA
• - cis-?4 double bond
•   cis-?4-enoyl CoA ? 2,4-dienoyl CoA ?
• cis-?3-enoyl CoA
• - acyl CoA dehydrogenase, 2,4-dienoyl CoA
  reductase (NADPH)
• 7) odd-chain fatty acids
• - propionyl CoA ? succinyl CoA
• - propionyl CoA carboxylase propionyl CoA ?
  D-methylmalonyl CoA
• methylmalonyl racemase D-methylmalonyl CoA ?
• L-methylmalonyl CoA
• - methylmalonyl Co mutase L-methylmalonyl CoA ?
  succinyl CoA

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8. Methylmalonyl CoA mutase 1) conenzyme B12 -
cobalamin (vitamin B12) - corrin core cobalt
atom - the fifth substitution a derivative of
dimethylbezimidazole - the sixth -CN, -CH3, or
-5'-deoxyadenosyl unit - Co3 - the Co-C bond 30
kcal/mol 2) intramolecular rearrangement -
5'-deoxyadenosyl radical

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9. Fatty acid oxidation in peroxisomes 1)
peroxisome - membrane-bounded compartment 2)
oxidation - flavoprotein dehydrogenase O2 ?
H2O2

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10. Ketone bodies formation 1) under the
condition where oxaloacetate is unavailable for
TCA cycle - acetoacetate - D-3-hydroxybutylate -
ketone bodies 2) enzymes - 3-ketothiolase 2
acetyl CoA ? acetoacetyl CoA - hydroxymethylglutar
yl (HMG) Co synthase - HMG cleavage enzyme
acetoacetate acetyl CoA - D-3-hydroxybutylate
dehydrogenase 3) no conversion of fatty acids to
glucose in animals

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11. Fatty acid synthesis vs. degradation 1)
cytosol 2) acyl carrier protein (ACP) sulfhydryl
group 3) a single polypeptide chain (260-kd
fatty acid synthase) mutifunctional
enzyme 4) sequential addition of two-carbon units
from manonyl CoA 5) NADPH 6) elongation of longer
fatty acids than C16, insertion of double
bonds - other enzyme systems  

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12. Malonyl Co 1) acyl CoA carboxylase - acetyl
CoA ATP HCO3- ? manonyl CoA ADP Pi -
cofactor biotin - three components - biotin
carboxyl carrier protein - biotin carboxylase -
transcarboxylase

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• 13. Acyl carrier protein
• 1) 77 amino acids
• phosphopantetheine prosthetic group OH-Ser-ACP
  
• (adenosine bisphosphate)
• - a giant prosthetic group a macro CoA
• 2) acetyl transacylase (AT)
• - acetyl CoA ACP ? acetyl-ACP CoA
• 3) malonyl transacylase (MT)
• - malonyl CoA ACP ? malonyl-ACP CoA

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14. Synthesis of fatty acids 1) acyl-malonyl-ACP
condensing enzyme (CE) - condensation -
acetyl-ACP malonly-ACP ? acetoacetyl-ACP ACP
CO2 2) ß-ketoacyl-ACP reductase (KR) -
reduction - acetoacyl-ACP NADPH H ?
D-3-hydroxybutyryl-ACP NADP 3)
D-3-hydroxyacyl-ACP dehydratase (DH) -
hydration - D-3-hydroxybutyryl-ACP  ?
crotonyl-ACP H2O 4) enoyl-ACP reductase (ER) -
reduction - crotonyl-ACP NADPH H ?
butyryl-ACP NADP 5) thioesterase (TE) -
pamitoyl-ACP H2O ? palmitate ACP 6)
translocation of the elogating fatty acyl chain

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15. Transport of acetyl CoA from mitochondria to
cytosol 1) mitochondria - acetyl CoA
oxaloacetate ? citrate 2) cytosol - citrate ?
oxaloacetate acetyl CoA - oxaloacetate NADH
H ? malate NAD - NADP-linked malate enzyme
(malic enzyme)   malate NADP ? pyruvate CO2
NADPH H 3) mitochondria - pyruvate
carboxylase   pyruvate CO2 ATP H2O ?
oxaloacetate ADP Pi 2 H 4) total
reaction - NADP NADH ATP H2O ? NADPH
NAD ADP Pi H

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16. Control of fatty acid biosynthesis 1) acetyl
CoA carboxylase - the committed step in fatty
acid biosynthesis 2) positive effecters -
citrate - insulin 3) negative effecters -
palmitoyl CoA - AMP - glucagon - epinephrine 4)
phosphorylation of carboxylase - inactive -
AMP-activated protein kinase - protein
phopshatase 2A

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5) citrate 6) palmitoyl CoA - citrate
translocase - glucose 6-phosphate
dehydrogenase 7) long term regulation - acetyl
CoA carboxylase - fatty acid synthase

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17. Control of fatty acid degradation 1) malonyl
CoA - carnitine acyltransferase inhibition 2)
NADH - L-3-hydroxyacyl CoA dehydrogenase
inhibition 3) acetyl CoA - thiolase inhibition

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18. Synthesis of longer fatty acids (gtC16) 1) the
elongation enzyme - the cytosolic face of
endoplsmic reticulum - manolyl CoA 2)
introduction of double bonds - stearoyl CoA
NADH H O2 ? oleoyl CoA NAD 2 H2O -
NADH-cytochrome b5 reductase - cytochrome b5 -
desaturase 3) essential fatty acids - double
bonds at gtC-9 in mammals - linoleate (182
cis-?9, ?12), linolenate (183 cis-?9, ?12, ?15)

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• 19. Eicosanoid hormones
• 1) arachidonate
• - a 204 fatty acid
• - from linoleate
• - precursors for prostagladins (PGA ? PGI)
• 2) prostagladins
• - local hormones short-lived
• - PGA ? PGI
• - arachidonate ? PGH2
• - prostacyclin (PGI2)
• - thromboxane A2 (TXA2)
• - leukotriene B4
• inflammation, blood flow, ion transport across
  membranes,
• synaptic transmission, sleep
• 3) aspirin
• - prostaglandin synthase
• - cyclooxygenase component, hydroperoxygenase
  component
• - arachidonate ? PGG2 ? PGH2
• - cyclooxygenase inhibition

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