Transcript Fatty acid breakdown

Fatty acid breakdown
• The oxidation of fatty acids
proceeds in three stages
b-oxidation
 b-oxidation is catalyzed by four enzymes
– Acyl-CoA dehydrogenase
– Enoyl-CoA hydratase
 b-hydroxyacyl-CoA dehydrogenase
– Acyl-CoA acetyltransferase (thiolase)
First step
• Isozymes of first enzyme
confers substrate specificity
FAD-dependent enzymes
Reaction analogous to succinate
dehydrogenase in citric acid
cycle
Electrons on FADH2 transferred
to respiratory chain
Second step
Adding water across a double bond
Analogous to fumarase reaction in
citric acid cycle
Third step
Dehydrogenation (oxidation)
using NAD
NADH is transferred to respiratory
chain for ATP generation
Analogous to malate dehydrogenase
reaction of citric acid cycle
Fourth step
Splits off the carboxyl-end
Acetyl-CoA and replaces it with
Co-A – Thiolase
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
The process gets repeated over and over until
no more acetyl-CoA can be generated
• 16:0-CoA + CoA + FAD + NAD + H2O  14:0CoA + acetyl-CoA + FADH2 + NADH + H+
• Then..
• 14:0-CoA + CoA + FAD + NAD + H2O  12:0CoA + acetyl-CoA + FADH2 + NADH + H+
• Ultimately..
• 16:0-CoA + 7CoA + 7FAD + 7NAD + 8H2O 
8acetyl-CoA + 7FADH2 + 7NADH + 7H+
Acetyl-CoA can be fed to the citric acid
cycle resulting in reducing power
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
In some instances (monounsaturated),
enoyl-CoA isomerase is sufficient
For others (polyunsaturated), both are
needed
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
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
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
Vitamin B12 catalyzes
intramoelcular proton exchange
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
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
Proposed mechanism for methylmalonyl CoA mutase
• Same hydrogen
always accounted
for
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
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
Also…
• When [NADH]/[NAD] ratio is high bhydroxyacyl-CoA dehydrogenase is
inhibited
• Also, high concentrations of acetyl-CoA
inhibit thiolase
Diversity in fatty acid oxidation
• Can occur in
multiple cellular
compartments
 b-oxidation in peroxisomes and
glyoxysomes is to generate biosynthetic
precursors, not energy
Distinctions among isozymes
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
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
Alpha oxidation is another minor pathway
Ketone bodies are formed from
acetyl CoA
• Can result from fatty acid oxidation or
amino acid oxidation (for a few that form
acetyl-CoA)
Formation of ketone
bodies
Ketone bodies can be exported
for fuel
Then broken down to get energy
(NADH)