section 18.1
Oxidation of Fatty Acids
373
Other Pathways of Fatty Acid Oxidation
Propionyl-CoA Oxidation
ft
-Oxidation of fatty acids with an odd number of car-
bon atoms yields propionyl-CoA. Since the concentration
of such fatty acids in the diet is small, little propionyl-CoA
is produced. Important sources of propionyl-CoA are the
catabolism of isoleucine, valine, methionine, and threo-
nine (Chapter 17). Cholesterol side chain oxidation also
yields propionyl-CoA. Thus, propionyl-CoA is derived
from the catabolism of lipids and proteins. In ruminants,
propionate is largely derived from bacterial fermentation
in the rumen.
Propionyl-CoA is converted to succinyl-CoA, which is
oxidized or converted to glucose by way of oxaloacetate
and pyruvate (gluconeogenesis; Chapter 15). Succinyl-
CoA may also form 5-aminolevulinate, a precursor of por-
phyrin biosynthesis (Chapter 29). Formation of succinyl-
CoA from propionyl-CoA requires three mitochondrial
enzymes and two vitamins (Figure 18-5).
1. Propionyl-CoA carboxylase is a tetramer of
nonidentical subunits,
a
and
/3.
The native enzyme
(M.W. ~540,000) appears to have the structure
(aft)
4
.
Biotin is bound through an amide linkage to an
£-amino group of a lysyl residue in the a-subunit.
Carboxylation is a two-step reaction similar to that of
acetyl-CoA carboxylase (see below). The first step
requires ATP and Mg2+ and fixes CO
2
with the
Sources
V aline, isoleucine '
m ethionine, threonine,
ch o lestero l side chain,
o d d-chain fatty acid s _
H
2
C — C H
3
0 = C — SC oA
Propionyl-CoA
C Q -
A T P -
A D P + q *
Propionyl-C oA
c arb o x y lase (biotin)
C O O H
C O O H
HC3— CH
M ethylm alonyl-CoA
I
ra c e m a se
0=c—
SC oA
H C — CH
3
0 = C — SC oA
L-M ethym alonyl-CoA
D-M ethylmalonyl-CoA
formation of an apoenzyme-biotin-C02 complex. In
the second step, the carboxyl group from the biotinyl
complex is transferred to propionyl-CoA to form
D-methylmalonyl-CoA.
2. Methylmalonyl-CoA racemase converts
D-methylmalonyl-CoA to the L-isomer by labilization
of an a-hydrogen atom, followed by uptake of a
proton from the medium.
3. Methylmalonyl-CoA mutase utilizes
5'-deoxyadenosylcobalamin (Chapter 38) to catalyze
intramolecular isomerization by the migration of the
-COSCoA group. The only other cobalamin-
dependent reaction in the mammalian system is
methylation of homocysteine to methionine
(Chapters 17, 27, and 38).
Inborn errors of metabolism may be due to propionyl-
CoA carboxylase deficiency, defects in biotin transport
or metabolism, methylmalonyl-CoA mutase deficiency,
or defects in adenosylcobalamin synthesis. The former
two defects result in propionic acidemia, the latter two in
methylmalonic acidemia. All cause metabolic acidosis and
developmental retardation. Organic acidemias often ex-
hibit hyperammonemia, mimicking ureagenesis disorders,
because they inhibit the formation of N-acetylglutamate,
an obligatory cofactor for carbamoyl phosphate synthase
(Chapter 17). Some of these disorders can be partly cor-
rected by administration of pharmacological doses of the
vitamin involved (Chapter 38). Dietary protein restriction
is therapeutically useful (since propionate is primarily de-
rived from amino acids). Propionic and methylmalonyl
acidemia (and aciduria) results from vitamin B
1 2
defi-
ciency (e.g., pernicious anemia; Chapter 38).
cx-Oxidation
a-Oxidation is important in the catabolism of branched-
chain fatty acids. The general reaction, catalyzed by a
monooxygenase, requires O
2
, Fe2+, and either ascorbate
or tetrahydropteridine. It has been demonstrated in plants
and in microsomes from brain and other tissues.
M ethylm alonyl-CoA
m u ta se (5'-deoxy-
R —
C H
2
— C H 2— C O O H
+
adenosyl-cobalam in)
R e d u c e d c o fa c to r
+
0
2
- ° n° ° xyaenas>
C O O H
1
OH
CH,
M etabolized in TCA cycle or
--------------*■
u sed in o th er m etabolic path w ay s
1
R— C H
2
— C H — C O O H
+
O xid ized c o fa c to r
+
H20
CH
(porphyrin sy n th esis, k eto n e body
1
utilization, etc.)
= c —
-S C o A
a-H yd roxy fatty a c id
Succinyl-C oA
F I G U R E 1 8 -5
This reaction is also a route for the synthesis of hy-
Metaboiism of propionyl-CoA.
droxy fatty acids. The a-hydroxy fatty acid can be further
