J. Biol. Chem., Vol. 262, Issue 11, 5087-5092, 04, 1987
Inhibition of mammalian fatty acid synthetase activity by NADP involves decreased mobility of the 4'-phosphopantetheine prosthetic group
A Stern and S Smith
Mammalian fatty acid synthetase carrying a 3-keto, 3-hydroxy, or 2- enoyl
acyl-enzyme intermediate on the 4'-phosphopantetheine thiol is reversibly
inhibited by binding of NADP to the enoyl reductase domain. Acyl moieties
which can normally leave the enzyme by thioester hydrolysis or by transfer
to a CoA acceptor cannot readily be removed from the NADP-inhibited enzyme;
in addition, 3-keto or 2-enoyl moieties attached to the enzyme
4'-phosphopantetheine cannot readily be reduced when NADP is replaced by
NADPH, even though model substrates can be reduced immediately.
Reactivation of the NADP-inhibited 3-ketoacyl- enzyme, by exposure to
NADPH, is paralleled by reduction and dehydration of the 3-ketoacyl moiety
to a saturated acyl moiety without accumulation of either the 3-hydroxy or
2-enoyl acyl-enzyme intermediates, indicating that once the
4'-phosphopantetheine engages the ketoacyl moiety in the ketoreductase
domain, subsequent reactions occur very rapidly. The results are consistent
with a hypothesis which proposes that NADP binding to the enoyl reductase
domain of fatty acid synthetase carrying an acyl intermediate other than a
saturated moiety induces a conformational change in the enzyme that results
in decreased mobility of the 4'-phosphopantetheine prosthetic group. Normal
mobility of the prosthetic group, essential for transfer of acyl-enzyme
intermediates through the active sites of the various functional domains,
is restored relatively slowly when NADP is replaced by NADPH. It remains to
be determined whether this modulation by pyridine nucleotides observed in
vitro plays a role in the regulation of fatty acid synthetase activity in
vivo.
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