section 18.1
Oxidation of Fatty Acids
367
acid molecule requires expenditure of two high-energy
phosphate bonds. The reaction occurs in two steps (E =
enzyme):
RCOCr + ATP + E
S te p 1
O
E— AMP— C— R + PPi
O
li
E + R — C — S C o A + AM P
A mitochondrial acyl-CoA synthase, which utilizes GTP,
has also been identified:
R • COO“ + CoASH + GTP4“ -*
RCO • SCoA + GDP3“ + P?“
Its role is not known.
Transport of Acyl-CoA to Mitochondrial Matrix
This transport is accomplished by carnitine (L-/f-hydroxy-
y-trimethylammonium butyrate), which is required in cat-
alytic amounts for the oxidation of fatty acids (Figure
18-1). Carnitine also participates in the transport of acetyl-
CoA for cytosolic fatty acid synthesis. Two carnitine acyl-
transferases are involved in acyl-CoA transport: carnitine
palmitoyltransferase I (CPTI), located on the outer surface
of the inner mitochondrial membrane, and carnitine palmi-
toyltransferase II (CPTII), located on the inner surface.
The overall translocation reaction is as follows:
O
C H
3
II
I
R— C — S C o A + H
3
C — N + — C H
2
— C H — C H 2— C O O H
I
I
C H
3
OH
A cyl-C oA
C arn itin e
Carnitine palmitoyltransferase
C H
3
I
H
H
3
C — N + — C H
2
— C — C H 2— C O O H + C oA S H
I
I
C H
3
o
I
C = 0 -)
|
> A cyl g r o u p
R
J
The standard free-energy change of this reaction is about
zero, and therefore the O-ester bond of acylcamitine may
be considered as a high-energy linkage. Malonyl-CoA, a
precursor in the synthesis of fatty acids, is an allosteric
inhibitor of CPTI in liver and thus prevents a futile cycle
of simultaneous fatty acid oxidation and synthesis.
Carnitine is synthesized from two essential amino acids,
lysine and methionine. S-Adenosylmethionine donates
three methyl groups to a lysyl residue of a protein with
the formation of a protein-bound trimethyllysyl. Proteol-
ysis yields trimethyllysine, which is converted to carni-
tine (Figure 18-2). In humans, liver and kidney are major
sites of carnitine production; from there it is transported
to skeletal and cardiac muscle, where it cannot be synthe-
sized.
Four inherited defects of carnitine metabolism lead
to impaired utilization of long-chain fatty acids for
energy production. These include defects of plasma
C ytosol
O u te r
m em b ra n e
R — C — O H -
+A T P
Acyl-CoA
sy n th e ta s e
A M P + PR -
M itochondria
_______
Inter-
m em b ran al s p a c e
-C o A S H ----------
Inner m em b ra n e
O u te r su rfa c e
Inner su rfa c e
C arn itin e palm itoyl
O
a c y ltra n sferase I
■R— C— S C o A -
(acyl-C oA )
■
A cyl-carnitine -
' C arnitine A
(acylcam itine)
\tra n s lo c a s e
' C arnitine "
M atrix
-C oA S H
C arnitine palm itoyl
tra n s fe ra se II
— Acyl-CoA
I
ß -O xidation
F IG U R E 18-1
Role of carnitine in transport of fatty acids into the mitochondrial matrix. Entry of acyl-carnitine is linked to the exit of
carnitine, both mediated by a translocase.
