AJP - Heart and Circulatory Physiology, Vol 246, Issue 4 532-H541, Copyright © 1984 by American Physiological Society
Pantothenate kinase and control of CoA synthesis in heart
J. D. Robishaw and J. R. Neely
Control of coenzyme A (CoA) synthesis was studied in isolated perfused rat
hearts. The data obtained support the hypothesis that phosphorylation of
pantothenic acid by pantothenate kinase is the flux-generating reaction in
the pathway of CoA synthesis. This reaction operated in the cell far
removed from its thermodynamic equilibrium; it was saturated with
substrates under all conditions studied; and the concentration of substrate
changed in the opposite direction to flux when flux was altered. The
reaction was subject to control by external factors associated with
oxidation of glucose, pyruvate, or palmitate. CoA synthesis from
4'-phosphopantothenic acid was not inhibited by glucose and pyruvate,
suggesting that pantothenate kinase is the only reaction in the pathway
that is controlled in isolated hearts. Maximum rates of CoA synthesis in
perfused hearts with pantothenate kinase stimulation were dependent on a
supply of exogenous cysteine. Perfusate [14C]cysteine was incorporated into
intermediates of this pathway and CoA. When protected from oxidation to
cystine by low concentrations of dithiothreitol, 0.1 mM cysteine in the
perfusate resulted in maximum rates of CoA synthesis. Evidence was obtained
that indicates that addition of cysteine relieves a substrate limitation at
the 4'-phosphopantothenyl cysteine synthase reaction.
