INHIBITION OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME A SYNTHASE BY ANTIBIOTIC 1233A AND OTHER BETA-LACTONES

被引：33

作者：

MAYER, RJ

LOUISFLAMBERG, P

ELLIOTT, JD

FISHER, M

LEBER, J

机构：

[1] Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 1990年 / 169卷 / 02期

关键词：

D O I：

10.1016/0006-291X(90)90374-V

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

3-Hydroxy-3-methylglutaryl CoA synthase was shown to be inhibited in a time-dependent, irreversible manner by compounds containing the substituted β-lactone functionality found in the natural product 1233A. The rate of inactivation (kinact) was found to approach the rate of catalysis (kcat). The inactivation was irreversible over several hours. A related compound lacking the hydroxymethyl substituent on the β-lactone ring is a reversible inhibitor and is competitive with respect to acetylCoA. The results are consistent with β-lactone ring opening by the active site Cys to form an enzyme bound thioester. © 1990.

引用

页码：610 / 616

页数：7

共 15 条

[1] SUICIDE ENZYME INACTIVATORS
ABELES, RH
MAYCOCK, AL
[J]. ACCOUNTS OF CHEMICAL RESEARCH, 1976, 9 (09) : 313 - 319
[2] DISCOVERY, BIOCHEMISTRY AND BIOLOGY OF LOVASTATIN
ALBERTS, AW
[J]. AMERICAN JOURNAL OF CARDIOLOGY, 1988, 62 (15) : J10 - J15
[3] TOTAL SYNTHESIS OF L-659,699, A NOVEL INHIBITOR OF CHOLESTEROL-BIOSYNTHESIS
CHIANG, YCP
YANG, SS
HECK, JV
CHABALA, JC
CHANG, MN
[J]. JOURNAL OF ORGANIC CHEMISTRY, 1989, 54 (24) : 5708 - 5712
[4] CLINKENBEARD KD, 1975, J BIOL CHEM, V250, P310
[5] INHIBITION OF HYDROXYMETHYLGLUTARYL-COENZYME-A SYNTHASE BY L-659,699
GREENSPAN, MD
YUDKOVITZ, JB
LO, CYL
CHEN, JS
ALBERTS, AW
HUNT, VM
CHANG, MN
YANG, SS
THOMPSON, KL
CHIANG, YCP
CHABALA, JC
MONAGHAN, RL
SCHWARTZ, RL
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (21) : 7488 - 7492
[6] KEMPEN JH, 1987, BIOCHEM PHARMACOL, V8, P1245
[7] MEHRABIAN M, 1986, J BIOL CHEM, V261, P6249
[8] MIZIORKO HM, 1977, J BIOL CHEM, V252, P1414
[9] POTENT INHIBITORY EFFECT OF ANTIBIOTIC 1233A ON CHOLESTEROL-BIOSYNTHESIS WHICH SPECIFICALLY BLOCKS 3-HYDROXY-3-METHYLGLUTARYL COENZYME A SYNTHASE
OMURA, S
TOMODA, H
KUMAGAI, H
GREENSPAN, MD
YODKOVITZ, JB
CHEN, JS
ALBERTS, AW
MARTIN, I
MOCHALES, S
MONAGHAN, RL
CHABALA, JC
SCHWARTZ, RE
PATCHETT, AA
[J]. JOURNAL OF ANTIBIOTICS, 1987, 40 (09) : 1356 - 1357
[10] OSBORNE TF, 1988, J BIOL CHEM, V263, P3380

← 1 2 →