section 18.4
Synthesis of Long-Chain Saturated Fatty Acids
381
8 H
@
— ® •— ® •— O — ® — O — P — OH
HO
ATP
H O — C = = 0 8 -
Bicarbonate
ADP + H2P 0 4 + H+—
Mg
Biotin
carboxylase
<CH2) — C — NH
Lysyl
I
BCC P
R
R egen erated BCCP
FIGURE 18-11
Mechanism of carboxylation of acetyl-CoA. BCCP = Biotin carboxyl carrier protein; Ad = adenosine.
The mechanism of the carboxylation reaction consists
of two half-reactions:
biotin carboxylase
ATP + h c o ^ + BCCP <
>
Mg2+
ADP + P; + BCCP-COO
and
BCCP-COO- + acetyl-CoA ^ BCCP + malonyl-CoA
The overall reaction is
ATP + HCOJ + acetyl-CoA — malonyl-CoA + ADP + P;
The
presumed
reaction
mechanisms
are
shown
in
Figure 18-11.
Other biotin-dependent enzymes include propionyl-
CoA carboxylase and pyruvate carboxylase (Chapter 15).
The latter, like acetyl-CoA carboxylase, is subject to al-
losteric regulation. Pyruvate carboxylase, a mitochondrial
enzyme, is activated by acetyl-CoA and converts pyruvate
to oxaloacetate which, in turn, is converted to glucose via
the gluconeogenic pathway or combines with acetyl-CoA
to form citrate. Some of the citrate is transported to the cy-
tosol, where it activates the first step of fatty acid synthesis
and provides acetyl-CoA as substrate (see below). Other
carboxylation reactions use bicarbonate but are dependent
on vitamin K, the acceptor being glutamyl residues of gly-
coprotein clotting factors II, VI, IX, and X and anticlotting
factors Protein C and Protein S (Chapter 36).
Acetyl-CoA carboxylase is under short- and long-term
control. Allosteric modulation functions as a short-term
regulator. Positive modulators are citrate and isocitrate;
negative modulators are long-chain acyl-CoA derivatives.
The binding of citrate increases the activity by polymer-
ization of the protomers, whereas negative modulators fa-
vor dissociation of active polymers to inactive monomers.
Acetyl-CoA carboxylase is also regulated by covalent
modification by phosphorylation, which inhibits activity,
and by dephosphorylation, which restores activity. Phos-
phorylation can occur by action of cAMP-dependent pro-
tein kinase through /1-adrenergic agonists and glucagon
or by action of calcium-dependent protein kinase through
a-adrenergic agonists. It is not known whether the
