An unprecedented twist to ODCase catalytic activity

被引：35

作者：

Fujihashi, M

Bello, AM

Poduch, E

Wei, LH

Annedi, SC

Pai, EF

Kotra, LP

机构：

[1] Leslie Dan Fac Pharm, Mol Design & Inform Technol Ctr, Toronto, ON M5S 2S2, Canada

[2] Univ Toronto, Dept Chem, Dept Med Biochem, Toronto, ON M5S 1A8, Canada

[3] Univ Toronto, Dept Chem, Dept Mol & Med Genet, Toronto, ON M5S 1A8, Canada

[4] Princess Margaret Hosp, Ontario Canc Inst, Div Canc Genom & Proteom, Toronto, ON M5G 2M9, Canada

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2005年 / 127卷 / 43期

关键词：

D O I：

10.1021/ja054865u

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Orotidine-5′-monophosphate decarboxylase (ODCase) has evolved to catalyze a decarboxylation reaction, most probably via a carbanion species at the C6 position of orotidine-5′-monophosphate. We reveal an unusual biochemical pathway of conversion of 6-cyano-uridine-5′-monophosphate by ODCase to barbiturate-5′-monophosphate via perhaps an electrophilic center at the C6 position, leading to inhibition. This potential of ODCase is very useful in the design of novel inhibitors. Copyright © 2005 American Chemical Society.

引用

收藏

页码：15048 / 15050

页数：3

相关论文

共 16 条

[1] The crystal structure and mechanism of orotidine 5′-monophosphate decarboxylase [J].

Appleby, TC ;

Kinsland, C ;

Begley, TP ;

Ealick, SE .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (05) :2005-2010

[2] Structural basis for the catalytic mechanism of a proficient enzyme:: Orotidine 5′-monophosphate decarboxylase [J].

Harris, P ;

Poulsen, JCN ;

Jensen, KF ;

Larsen, S .

BIOCHEMISTRY, 2000, 39 (15) :4217-4224

[3] Substrate binding induces domain movements in orotidine 5′-monophosphate decarboxylase [J].

Harris, P ;

Poulsen, JCN ;

Jensen, KF ;

Larsen, S .

JOURNAL OF MOLECULAR BIOLOGY, 2002, 318 (04) :1019-1029

[4] Anatomy of a proficient enzyme:: The structure of orotidine 5′-monophosphate decarboxylase in the presence and absence of a potential transition state analog [J].

Miller, BG ;

Hassell, AM ;

Wolfenden, R ;

Milburn, MV ;

Short, SA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (05) :2011-2016

[5] Catalytic proficiency: The unusual case of OMP decarboxylase [J].

Miller, BG ;

Wolfenden, R .

ANNUAL REVIEW OF BIOCHEMISTRY, 2002, 71 :847-885

[6] Role of enzyme-ribofuranosyl contacts in the ground state and transition state for orotidine 5′-phosphate decarboxylase:: A role for substrate destabilization? [J].

Miller, BG ;

Butterfoss, GL ;

Short, SA ;

Wolfenden, R .

BIOCHEMISTRY, 2001, 40 (21) :6227-6232

[7] Catalytic promiscuity and the evolution of new enzymatic activities [J].

O'Brien, PJ ;

Herschlag, D .

CHEMISTRY & BIOLOGY, 1999, 6 (04) :R91-R105

[8] NATURE OF FORCES BETWEEN LARGE MOLECULES OF BIOLOGICAL INTEREST [J].

PAULING, L .

NATURE, 1948, 161 (4097) :707-709

[9] A PROFICIENT ENZYME [J].

RADZICKA, A ;

WOLFENDEN, R .

SCIENCE, 1995, 267 (5194) :90-93

[10] Equilibrium of formation of the 6-carbanion of UMP, a potential intermediate in the action of OMP decarboxylase [J].

Sievers, A ;

Wolfenden, R .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2002, 124 (47) :13986-13987