Unsaturated and Odd-Chain Fatty Acid Catabolism
March 24, 2003
Bryant Miles
The complete oxidation of saturated fatty acids containing an even number of carbon atoms is accomplished by the β-oxidation pathway.  Not all fatty acids are saturated or contain an even number of carbon atoms.  The oxidation of these fatty acids requires additional steps and enzymes.
I. Unsaturated Fatty Acids
Unsaturated fatty acids are found in our high fat diets.  The complete oxidation of unsaturated fatty acids presents some difficulties.  Happily most of the reactions involved in the oxidation of these unsaturated fatty acids are the same as β-oxidation.  In addition, we need two additional enzymes, an isomerase and a reductase.
Do you remember from BICH-410 palmitoleic acid?  This is a 16
carbon unsaturated fatty acid with a double bond between the C9
and the C10 carbons.  This fatty acid is activated by acyl-CoA
synthetase, transported across the mitochondrial inner membrane
by carnitine and transferred back to CoA to form palmitoyl CoA.
Palmitoyl CoA undergoes 3 cycles of β-oxidation to produce a
cis-∆3-enoyl CoA.
This cis-∆3-enoyl CoA is not a substrate for acyl CoA
dehydrogenase. The presence of the cis double bond between the
C3 and C4 carbons prevents the formation of a double bond
between the C2 and C3 carbons.
Cis-∆3-enoyl CoA isomerase converts this double bond into a
trans-∆2-double bond.  This trans-∆2-enoyl CoA is a substrate for
acyl CoA dehydrogenase and proceeds through the β-oxidation
pathway.
For our next example let us consider the oxidation of a
polyunsaturated fatty acid such as linoleate, a C18
polyunsaturated fatty acid with cis-∆9-double bond and a cis-
∆12double bond.  After three rounds of normal β-oxidation, a cis-∆3 double bond is formed which can be converted by Cis-∆3-enoyl CoA isomerase to convert the double bond to the trans-∆2-double bond.  This compound can now undergo another round of β-oxidation to form a cis- ∆4-double bond.  Dehydrogenation of this compound forms a 2, 4-dienoyl intermediate.  This 2, 4-dienoyl intermediate is not a substrate for enoyl-CoA hydratase.  2, 4-dienoyl intermediates is a substrate for 2, 4-dienoyl CoA reductase.  This enzyme uses NADPH to reduce the 2, 4-dienoyl intermediate into trans-∆3-enoyl CoA.  Cis-∆3-enoyl CoA isomerase then converts the trans-∆3-enoyl CoA to the trans-∆2-enoyl CoA which is a metabolite for β-oxidation.
The combination of Cis-∆3-enoyl CoA isomerase and 2, 4-dienoyl CoA reductase allows the oxidation of any polyunsaturated fatty acid.  Odd numbered double bonds are handled by the isomerase.  Even numbered fatty acids are handled by the reductase and the isomerase.
II. Odd Chain Fatty Acid Catabolism.
Fatty acids with an odd number of carbon atoms are relatively rare in mammals
but common in plants and marine organisms.  Odd chain fatty acids are oxidized
in the same way as even chained fatty acids up until the formation of propionyl CoA .  Propionyl CoA is converted into succinyl CoA which then enters into the citric
acid cycle. The conversion involves 3 enzymes.  The first step is the carboxylation of propionyl CoA to form D -methylmalonyl CoA by propionyl CoA carboxylase. D -Methylmalonyl CoA is converted into L -methylmalonyl CoA by methylmalonyl CoA epimerase.  L -Methylmalonyl CoA is then rearranged to form succinyl CoA by Methylmalonyl CoA mutase.  The conversion of methymalonyl CoA into Succinyl CoA is a difficult transformation because it involves the rearrangement of the skeletal carbon atoms.  The rearrangement requires a new cofactor, vitamin B 12 aka cobalamin.
H 3C C H 2
C S
O
Propionyl CoA
In the first step, propionyl CoA is carboxylated by a biotin containing enzyme, propionyl CoA carboxylase .  Recall biotin from pyruvate carboxylase of gluconeogenesis.
The first step of biotin containing enzymes is the activation of bicarbonate by ATP to form the high energy intermediate carboxyphosphate.
Carboxyphosphate then reacts with the biotin cofactor which is covalently bound by an amide bond with a lysine residue.
The result is carboyxlated biotin, ready to be transferred to an enolate nucleophile.
in the active site of this enzyme.
The enolate is an excellent nucleophile that attacks our activated CO 2 group to regenerate biotin and form D
-methylmalonyl CoA.
The next step is the epimerization of D -methylmalonyl CoA into L -methylmalonyl CoA.  The enzyme that catalyzes this reaction is methylmalonyl CoA epimerase.  The mechanism of this enzyme is shown to the left. An active site general base abstracts the proton to generate the resonance stabilized enolate intermediate which is reprotonated on the opposite face to epimerize the C2 carbon.  This reaction is fully reversible meaning this enzyme will take L -methylmalonyl CoA and epimerize it into D -methylmalonyl CoA.
D -Methylmalonyl CoA
H 2
H 2
N H H 2C
C H 2
H 2C
C H 2
reactive carbonyl species
CH NH
C O
-
HO
C
O
O -
D -Methylmalonyl CoA
Methylmalonyl CoA Epimerase
L -Methylmalonyl CoA
The third reaction is a vitamin B 12 catalyzed rearrangement which converts methylmalonyl CoA into succinyl CoA.  The enzyme is called methylmalonyl CoA mutase.
This is a difficult reaction because it involves the migration of the carbonyl-CoA group from one carbon to its neighbor.  The migration requires a cobalamin or vitamin B 12 cofactor.
Cobalamin containing enzymes are found in almost every organism.  Cobalamin containing enzymes
catalyze alkyl rearrangements, methylations and the reduction of ribonucleotides to deoxyribonucleotid
es.  The core of cobalamin is the corrin ring which is coordinated to a cobalt atom. The corrin ring is similar to porphryn rings with four pyrrole rings.  The corrin ring is more reduced than porphryn rings and has different constituents.  The cobalt atom is coordinated to the 4 planar nitrogens of the pyrroles.  The cobalt atom is axially coordinated to one of the nitrogens of a methylbenzimidazole as shown above in blue.  In vitamin B 12, the axial 6th  ligand coordinated to the cobalt atom is 5’-deoxy adenosine.  This 6th  position can also be occupied by a cyano group, a methyl group or other ligands.  In all of these compounds the cobalt is the +3 oxidation state.
Vitamin B 12 is not synthesized by animals or plants.  Only a few species of bacteria synthesize this complex coenzyme.  Carnivorous animals easily obtain sufficient amounts of vitamin B 12 from meat.  Herbivorous animals depend on their intestinal bacteria to synthesize vitamin B 12 for them.
Vitamin B 12 is one the most potent vitamins.  Of all the vitamins, Vitamin B 12 is needed in the smallest amount.  A Vitamin B 12 deficiency results in pernicious anemia.
The rearrangement reactions catalyzed by coenzyme B 12 exchange two groups attached to adjacent carbon atoms as shown to the left.  The R group can be an amino group, hydroxyl group or a substituted carbon.  In the case of methylmalonyl mutase a
hydrogen atom and the carbonyl attached of CoA concomitantly move in opposite directions.
Methylmalonyl CoA mutase is specifically binds L -methylmalonyl CoA.  The methylmalonyl CoA mutase catalyzed reaction begins with the homolytic cleavage of the Co 3+--C—bond in cobalamin as shown below.  The homolytic bond cleavage produces Co 2+
and a
-
Succinyl CoA
radical on the 5’-carbon of 5’-deoxy adenosine.  The CH2  radical is highly reactive.  This radical abstracts an hydrogen from the methyl group of methylmalonyl CoA generating a methylmalonyl radical  that undergoes rearrangement to form a succinyl CoA radical.  The succinyl CoA radical abstracts the hydrogen back from the 5’-carbon of the deoxy adenosine to yield succinyl CoA.  The radical deoxyadenosine recombines with the Co2+ cobalt to regenerate the cofactor.
The role of the cobalamin cofactor is to
serve a source of free radicals for the
abstraction of hydrogen atoms to promote
intramolecular migrations.  The cobalt
carbon is weak and readily undergoes
homolytic cleavage to generate a radical.
The active site of methylmalonyl mutase
is shown to the left.
The succinyl CoA derived from propionyl
CoA enters into the citric acid cycle where
is converted to oxaloacetate.
Oxaloacetate can be converted into
glucose by the gluconeogenic pathway.
Thus odd chain fatty acids can be used for
glucose synthesis. Alternatively succinyl CoA can be converted into malate, transported into the cytoso
l, where it is oxidatively decarboxylated into pyruvate, which is than transported back into the matrix of the mitochondria where it is converted into acetyl CoA and oxidized by the TCA into CO2.

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