2311462 Fatty Acid Synthesis vs Beta Oxidation

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Fatty Acid Synthesis vs.Fatty Acid Synthesis vs.

Beta oxidationBeta oxidation

Michelle Jay G. FranciscoMichelle Jay G. Francisco

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Mitochondrial beta-oxidationMitochondrial beta-oxidation

Beta-oxidation is the process by whichBeta-oxidation is the process by whichlong chain fatty acyl CoA is degraded.long chain fatty acyl CoA is degraded.The products of beta-oxidation are:The products of beta-oxidation are:

acetyl CoAacetyl CoA FADH2, NADH and H+FADH2, NADH and H+ The overall reaction, using palmitoylThe overall reaction, using palmitoyl

CoA (16:0) as a model substrate:CoA (16:0) as a model substrate: 7 FAD + 7 NAD+ + 7 CoASH + 7 H2O +7 FAD + 7 NAD+ + 7 CoASH + 7 H2O +

H(CH2CH2)7CH2CO-SCoA -->H(CH2CH2)7CH2CO-SCoA -->8 CH3CO-SCoA + 7 FADH2 + 7 NADH +8 CH3CO-SCoA + 7 FADH2 + 7 NADH +7 H+7 H+

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Fate of acetyl CoAFate of acetyl CoA

Oxidation by the citric acid cycle to COOxidation by the citric acid cycle to CO22

and Hand H22O.O.

In liver only, acetyl CoA may be used for ketone bodyIn liver only, acetyl CoA may be used for ketone bodysynthesis.synthesis.

Fate of the FADHFate of the FADH22

and NADH + Hand NADH + H++

FADHFADH

22

and NADH + Hand NADH + H++ are oxidized by theare oxidized by the

mitochondrial electron transport system, yielding ATP.mitochondrial electron transport system, yielding ATP.

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Four enzymes and reactionsFour enzymes and reactions

There are four individual reactions of beta-oxidation,There are four individual reactions of beta-oxidation,each catalyzed by a separate enzyme:each catalyzed by a separate enzyme:

Dehydrogenation between the alpha and betaDehydrogenation between the alpha and betacarbons (Ccarbons (C

22

and Cand C33

) in a FAD-linked reaction.) in a FAD-linked reaction.

Hydration of the double bond by enoyl CoAHydration of the double bond by enoyl CoAhydratase.hydratase.

A second dehydrogenation in a NAD-linked reaction.A second dehydrogenation in a NAD-linked reaction. Thiolytic cleavage of the thioester by beta-ketoacylThiolytic cleavage of the thioester by beta-ketoacyl

CoA thiolase.CoA thiolase.This sequence of four steps is repeated until the fattyThis sequence of four steps is repeated until the fatty

acyl chain is completely degraded to acetyl CoA.acyl chain is completely degraded to acetyl CoA.

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Dehydrogenation occurs between the alphaDehydrogenation occurs between the alphaand beta carbons (Cand beta carbons (C22

and Cand C33) in a FAD-linked) in a FAD-linked

reaction catalyzed by acyl CoAreaction catalyzed by acyl CoAdehydrogenase.dehydrogenase.

The oxidation power of FAD is required toThe oxidation power of FAD is required tooxidize the alkyl chain, much as it is in theoxidize the alkyl chain, much as it is in thesuccinate dehydrogenase reaction of thesuccinate dehydrogenase reaction of thetricarboxylic acid cycle. The product containstricarboxylic acid cycle. The product containsa trans- double bond. Involvement of thea trans- double bond. Involvement of the

beta-carbon in this and subsequent stepsbeta-carbon in this and subsequent stepsgives the pathway its name.gives the pathway its name.

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There are three fatty acyl CoAThere are three fatty acyl CoA

dehydrogenases. Each is specific for adehydrogenases. Each is specific for adifferent acyl chain length, so differentdifferent acyl chain length, so differentenzymes are involved in different stages ofenzymes are involved in different stages ofbeta-oxidation.beta-oxidation.

Long chain fatty acyl CoA dehydrogenase (LCAD)Long chain fatty acyl CoA dehydrogenase (LCAD)acts on chains greater than C12.acts on chains greater than C12.

Medium chain fatty acyl CoA dehydrogenaseMedium chain fatty acyl CoA dehydrogenase(MCAD) acts on chains of C6 to C12.(MCAD) acts on chains of C6 to C12.

Short chain fatty acyl CoA dehydrogenase (SCAD)Short chain fatty acyl CoA dehydrogenase (SCAD)acts on chains of C4 to C6.acts on chains of C4 to C6.

MCAD deficiency is thought to be one of theMCAD deficiency is thought to be one of themost common inborn errors of metabolism.most common inborn errors of metabolism.

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Hydration of the double bond is catalyzed byHydration of the double bond is catalyzed byenoyl CoA hydratase. The product is an L-3-enoyl CoA hydratase. The product is an L-3-hydroxyacyl CoA.hydroxyacyl CoA.

A second dehydrogenation, of the alcohol,A second dehydrogenation, of the alcohol,occurs in a NAD-linked reaction catalyzed byoccurs in a NAD-linked reaction catalyzed bybeta-hydroxyacyl CoA dehydrogenase. Thebeta-hydroxyacyl CoA dehydrogenase. Theproduct is a ketone.product is a ketone.

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Thiolytic cleavage of the thioester is catalyzedThiolytic cleavage of the thioester is catalyzedby beta-ketoacyl CoA thiolase.by beta-ketoacyl CoA thiolase.

Reaction products: The products are acetylReaction products: The products are acetylCoA and a long chain fatty acyl CoA that isCoA and a long chain fatty acyl CoA that is

two carbons shorter than the original fattytwo carbons shorter than the original fattyacyl CoA.acyl CoA.

The shortened fatty acyl group is now readyThe shortened fatty acyl group is now readyfor another round of beta-oxidation. After thefor another round of beta-oxidation. After thefatty acyl CoA has been reduced to acetyl orfatty acyl CoA has been reduced to acetyl orpropionyl CoA, beta-oxidation is complete.propionyl CoA, beta-oxidation is complete.

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Regulation: This reaction is inhibited byRegulation: This reaction is inhibited by

high concentrations ofhigh concentrations ofacetyl CoA.acetyl CoA. Beta-oxidation is regulated as a wholeBeta-oxidation is regulated as a whole

primarily by fatty acid availability; onceprimarily by fatty acid availability; once

fatty acids are in the mitochondria theyfatty acids are in the mitochondria they

are oxidized as long as there isare oxidized as long as there is

adequate NADadequate NAD++ and CoA.and CoA.

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This diagram shows production of propionylThis diagram shows production of propionylCoA from an odd-chain fatty acid and theCoA from an odd-chain fatty acid and thesubsequent conversion of propionyl CoA tosubsequent conversion of propionyl CoA tosuccinyl CoA, which can be metabolizedsuccinyl CoA, which can be metabolized

through the citric (tricarboxylic) acid cycle.through the citric (tricarboxylic) acid cycle.

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SUMMARY: SynthesisSUMMARY: Synthesis

Substrate availability: availability of acetylSubstrate availability: availability of acetylgroups in the cytoplasm is regulated by thegroups in the cytoplasm is regulated by theactivity of the citrate-malate antiport. Itsactivity of the citrate-malate antiport. Itsactivity is decreased by palmitoyl CoA. Theactivity is decreased by palmitoyl CoA. Themitochondrial concentration of citrate alsomitochondrial concentration of citrate alsoaffects transport.affects transport.

Acetyl CoA carboxylase is a key enzyme ofAcetyl CoA carboxylase is a key enzyme offatty acid synthesis.fatty acid synthesis.

It is activated allosterically by citrate andIt is activated allosterically by citrate andcovalently by phosphorylation.covalently by phosphorylation. It is inhibited allosterically by palmitoyl CoAIt is inhibited allosterically by palmitoyl CoA

and covalently by dephosphorylation.and covalently by dephosphorylation.

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SUMMARY: OxidationSUMMARY: Oxidation

Oxidation is regulated at several levels, butOxidation is regulated at several levels, butprimarily by substrate availability, which inprimarily by substrate availability, which inturn is controlled hormonally.turn is controlled hormonally.

Hormone sensitive lipase in adipose tissue isHormone sensitive lipase in adipose tissue is

activated by phosphorylation (glucagon). Itsactivated by phosphorylation (glucagon). Itsactivity is low when insulin levels are high.activity is low when insulin levels are high.

High levels of malonyl CoA allostericallyHigh levels of malonyl CoA allostericallyinhibit CAT-I. This prevents beta-oxidationinhibit CAT-I. This prevents beta-oxidation

during fatty acid synthesis.during fatty acid synthesis. CoA must be available for beta-oxidation toCoA must be available for beta-oxidation to

proceed, since it is a substrate for theproceed, since it is a substrate for thethiolase reaction.thiolase reaction.

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FATTY ACID MetabolismFATTY ACID Metabolism

3 Steps of Fatty Acid Oxidation Cycle [beta3 Steps of Fatty Acid Oxidation Cycle [betaoxidation]oxidation]

1. oxidation of COOH end of free fatty1. oxidation of COOH end of free fatty acid &acid &linking FFA to CoASHlinking FFA to CoASH2. transport of fatty acyl-coA into mitoplasm from2. transport of fatty acyl-coA into mitoplasm from

cytoplasmcytoplasm

3. oxidation of fatty acyl-coA into 2 carbon fragments3. oxidation of fatty acyl-coA into 2 carbon fragmentsof Acetyl-CoAof Acetyl-CoA

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Fatty Acid SynthesisFatty Acid Synthesis Fatty Acid OxidationFatty Acid Oxidation

occurs in cytosoloccurs in cytosol occurs inoccurs in Mitochondrial matrixMitochondrial matrix

precursors linked to acyl carrier proteinprecursors linked to acyl carrier protein linked to CoAlinked to CoA

(ACP)(ACP)

enzymes are in one big complexenzymes are in one big complex series of separate enzymesseries of separate enzymes

(fatty acid synthetase)(fatty acid synthetase)

add 2-carbon groups from activatedadd 2-carbon groups from activated remove 2-carbon groups toremove 2-carbon groups toacetyl CoAacetyl CoA

acetyl CoA (which comes fromacetyl CoA (which comes from

decarboxylation of malonyl-CoA)decarboxylation of malonyl-CoA)

reductant is NADPHreductant is NADPH NAD and FAD are oxidantsNAD and FAD are oxidants

stops at 16 carbonsstops at 16 carbons not limited in length in theorynot limited in length in theory

(further elongation and double bonds(further elongation and double bonds

put in by other enzymes)put in by other enzymes)

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