Regulation of malonyl-CoA concentration and turnover in the normal heart.
The goal of this study was to test the relationship between malonyl-CoA concentration and its turnover measured in isolated rat hearts perfused with NaH(13)CO(3). This turnover is a direct measurement of the flux of acetyl-CoA carboxylation in the intact heart. It also reflects the rate of malonyl-CoA decarboxylation, i.e. the only known fate of malonyl-CoA in the heart. Conditions were selected to result in stable malonyl-CoA concentrations ranging from 1.5 to 5 nmol.g wet weight-(1). The malonyl-CoA concentration was directly correlated with the turnover of malonyl-CoA, ranging from 0.7 to 4.2 nmol.min(-) (1).g wet weight(-1) (slope = 0.98, r(2) = 0.94). The V(max) activities of acetyl-CoA carboxylase and of malonyl-CoA decarboxylase exceeded the rate of malonyl-CoA turnover by 2 orders of magnitude and did not correlate with either concentration or turnover of malonyl-CoA. However, conditions of perfusion that increased acetyl-CoA supply resulted in higher turnover and concentration, demonstrating that malonyl-CoA turnover is regulated by the supply of acetyl-CoA. The only condition where the activity of malonyl-CoA decarboxylase regulated malonyl-CoA kinetics was when the enzyme was pharmacologically inhibited, resulting in increased malonyl-CoA concentration and decreased turnover. Our data show that, in the absence of enzyme inhibitors, the rate of acetyl-CoA carboxylation is the main determinant of the malonyl-CoA concentration in the heart.
Reszko
Aneta E
AE
Department of Biochemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Kasumov
Takhar
T
David
France
F
Thomas
Katherine R
KR
Jobbins
Kathryn A
KA
Cheng
Jie-Fei
JF
Lopaschuk
Gary D
GD
Dyck
Jason R B
JR
Diaz
Mireya
M
Des Rosiers
Christine
C
Stanley
William C
WC
Brunengraber
Henri
H
D000105:Acetyl Coenzyme A / Q000737:chemistry; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D001669:Biochemical Phenomena; D001671:Biochemistry; D002262:Carboxy-Lyases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000502:physiology; D007700:Kinetics; D008316:Malonyl Coenzyme A / Q000096:biosynthesis*; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D013997:Time Factors
D004791:Enzyme Inhibitors; D008316:Malonyl Coenzyme A; D000105:Acetyl Coenzyme A; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D000103:Acetyl-CoA Carboxylase