3. β-oxidation
∀ β-oxidation is catalyzed by four enzymes
– Acyl-CoA dehydrogenase
– Enoyl-CoA hydratase
β-hydroxyacyl-CoA dehydrogenase
– Acyl-CoA acetyltransferase (thiolase)
4. First step
• Isozymes of first enzyme
confers substrate specificity
FAD-dependent enzymes
Reaction analogous to succinate
dehydrogenase in citric acid
cycle
9. β-oxidation bottomline
• The first three reactions generate a much
less stable, more easily broken C-C bond
subsequently producing
two carbon units
through thiolysis
10. The process gets repeated over and over until
no more acetyl-CoA can be generated
• 16:0-CoA + CoA + FAD + NAD + H2O 14:0-
CoA + acetyl-CoA + FADH2 + NADH + H+
• Then..
• 14:0-CoA + CoA + FAD + NAD + H2O 12:0-
CoA + acetyl-CoA + FADH2 + NADH + H+
• Ultimately..
• 16:0-CoA + 7CoA + 7FAD + 7NAD + 8H2O
8acetyl-CoA + 7FADH2 + 7NADH + 7H+
11. Acetyl-CoA can be fed to the citric acid
cycle resulting in reducing power
12. 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 β-oxidation
13. In some instances (monounsaturated),
enoyl-CoA isomerase is sufficient
15. 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
16. 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
17.
18. 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
20. 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
21.
22. 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
24. Regulation of fatty acid oxidation
• Fatty acids in the cytosol can either be used
to form triacylglycerols or for β-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
25. 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
26. Also…
• When [NADH]/[NAD] ratio is high β-
hydroxyacyl-CoA dehydrogenase is
inhibited
• Also, high concentrations of acetyl-CoA
inhibit thiolase
27. Diversity in fatty acid oxidation
• Can occur in
multiple cellular
compartments
28. ∀ β-oxidation in peroxisomes and
glyoxysomes is to generate biosynthetic
precursors, not energy
30. Fatty acids can also undergo ω
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
31.
32. 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