Cocrystal structures of diaminopimelate decarboxylase: Mechanism, evolution, and inhibition of an antibiotic resistance accessory factor

被引：48

作者：

Ray, SS

Bonanno, JB

Rajashankar, KR

Pinho, MG

He, GS

De Lencastre, H

Tomasz, A

Burley, SK

机构：

[1] Rockefeller Univ, Mol Biophys Lab, New York, NY 10021 USA

[2] Rockefeller Univ, Microbiol Lab, New York, NY 10021 USA

[3] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA

来源：

STRUCTURE | 2002年 / 10卷 / 11期

关键词：

D O I：

10.1016/S0969-2126(02)00880-8

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：

Cocrystal structures of Methanococcus jannaschii diaminopimelate decarboxylase (DAPDC) bound to a substrate analog, azelaic acid, and its L-lysine product have been determined at 2.6 Angstrom and 2.0 Angstrom, respectively. This PLP-dependent enzyme is responsible for the final step of L-lysine biosynthesis in bacteria and plays a role in beta-lactam antibiotic resistance in Staphylococcus aureus. Substrate specificity derives from recognition of the L-chiral center of diaminopimelate and a system of ionic "molecular rulers" that dictate substrate length. A coupled-enzyme assay system permitted measurement of kinetic parameters for recombinant DAPDCs and inhibition constants (K-i) for azelaic acid (89 muM) and other substrate analogs. Implications for rational design of broad-spectrum antimicrobial agents targeted against DAPDCs of drug-resistant strains of bacterial pathogens, such as Staphylococcus aureus, are discussed.

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页码：1499 / 1508

页数：10

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