Fatty acid breakdown

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Fatty acid breakdown

• The oxidation of fatty acids
• proceeds in three stages

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b-oxidation

• b-oxidation is catalyzed by four enzymes
• Acyl-CoA dehydrogenase
• Enoyl-CoA hydratase
• b-hydroxyacyl-CoA dehydrogenase
• Acyl-CoA acetyltransferase (thiolase)

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First step

• Isozymes of first enzyme
• confers substrate specificity
• FAD-dependent enzymes
• Reaction analogous to succinate
• dehydrogenase in citric acid
• cycle

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Electrons on FADH2 transferred to respiratory
chain
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Second step

• Adding water across a double bond
• Analogous to fumarase reaction in
• citric acid cycle

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Third step

• Dehydrogenation (oxidation)
• using NAD
• NADH is transferred to respiratory
• chain for ATP generation
• Analogous to malate dehydrogenase
• reaction of citric acid cycle

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Fourth step

• Splits off the carboxyl-end
• Acetyl-CoA and replaces it with
• Co-A Thiolase

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b-oxidation bottomline

• The first three reactions generate a much less
  stable, more easily broken C-C bond subsequently
  producing
• two carbon units
• through thiolysis

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The process gets repeated over and over until no
more acetyl-CoA can be generated

• 160-CoA CoA FAD NAD H2O ? 140-CoA
  acetyl-CoA FADH2 NADH H
• Then..
• 140-CoA CoA FAD NAD H2O ? 120-CoA
  acetyl-CoA FADH2 NADH H
• Ultimately..
• 160-CoA 7CoA 7FAD 7NAD 8H2O ?
  8acetyl-CoA 7FADH2 7NADH 7H

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Acetyl-CoA can be fed to the citric acid cycle
resulting in reducing power
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Breakdown of unsaturated fatty acids requires
additional reactions

• Bonds in unsaturated fatty acids are in the cis
  conformation, enoyl-CoA hydratase cannot work on
  as it requires a trans bond
• The actions of an isomerase and a reductase
  convert the cis bond to trans, resulting in a
  substrate for b-oxidation

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In some instances (monounsaturated), enoyl-CoA
isomerase is sufficient
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For others (polyunsaturated), both are needed
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Complete oxidation of odd-number fatty acids
requires three extra reactions

• Although common fatty acids are even numbered,
  odd numbered fatty acids do occur (ie.
  propionate)
• Oxidation of odd numbered fatty acids uses same
  pathway as even numbered
• However, ultimate substrate in breakdown has
  five, not four carbons, which is cleaved to form
  acetyl-CoA and propionyl-CoA

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Propionyl Co-A enters the citric acid cycle using
three steps

• Propionyl Co-A is carboxylated to form
  methyl-malonyl CoA (catalyzed by the biotin
  containing propionyl-CoA carboxylase)
• Recall that methyl-malonyl CoA is also a
  intermediate in the catabolism of methionine,
  isoleucine, threonine and valine to succinyl-CoA

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Methyl-malonyl-CoA undergoes two isomerization
steps to form succinyl-CoA

• Methyl-malonyl epimerase catalyzes the first
  reaction
• Methyl-malonyl-CoA mutase (a vitamin B12
  dependent enzyme) catalyzes the second to form
  succinyl-CoA

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Vitamin B12 catalyzes intramoelcular proton
exchange
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Vitamin B12 is a unique and important enzyme
cofactor

• Contains cobalt in a corrin ring system
  (analogous to heme in cytochrome)
• has a 5 deoxy adenosine (nucleoside component
• Has a dimethylbenzimidazole ribonucleotide
  component

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Attachment of upper ligand is second example of
triphosphate liberation from ATP

• Cobalamin ?
• Coenzyme B12
• The other such reaction
• where this is observed
• is formation of Ado-Met

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Proposed mechanism for methyl-malonyl CoA mutase

• Same hydrogen
• always accounted
• for

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Regulation of fatty acid oxidation

• Fatty acids in the cytosol can either be used to
  form triacylglycerols or for b-oxidation
• The rate of transfer of fatty-acyl CoA into the
  mitochondria (via carnitine) is the rate limiting
  step and the important point of regulation, once
  in the mitochondria fatty acids are committed to
  oxidation

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Malonyl-CoA is a regulatory molecule

• Malonyl-CoA (that we will talk about in more
  detail next week in lipid biosynthesis) inhibits
  carnitine acyltransferase I

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Also

• When NADH/NAD ratio is high b-hydroxyacyl-CoA
  dehydrogenase is inhibited
• Also, high concentrations of acetyl-CoA inhibit
  thiolase

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Diversity in fatty acid oxidation

• Can occur in
• multiple cellular
• compartments

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• b-oxidation in peroxisomes and glyoxysomes is to
  generate biosynthetic precursors, not energy

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Distinctions among isozymes
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Fatty acids can also undergo w oxidation in the ER

• Omega oxidation occurs at the carbon most distal
  from the carboxyl group
• This pathway involves an oxidase that uses
  molecular oxygen, and both an alcohol and
  aldehyde dehydrogenase to produce a molecule with
  a carboxyl group at each end
• Net result is dicarboxylic acids

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Omega oxidation is a minor pathway

• Although omega oxidation is normally a minor
  pathway of fatty acid metabolism, failure of
  beta-oxidation to proceed normally can result in
  increased omega oxidation activity. A lack of
  carnitine prevents fatty acids from entering
  mitochondria can lead to an accumulation of fatty
  acids in the cell and increased omega oxidation
  activity

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Alpha oxidation is another minor pathway
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Ketone bodies are formed from acetyl CoA

• Can result from fatty acid oxidation or amino
  acid oxidation (for a few that form acetyl-CoA)

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Formation of ketone bodies
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Ketone bodies can be exported for fuel
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Then broken down to get energy (NADH)