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J. Biol. Chem., Vol. 279, Issue 42, 43982-43989, October 15, 2004

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Peptidoglycan Amidase MepA Is a LAS Metallopeptidase^*

Malgorzata Marcyjaniak, Sergey G. Odintsov, Izabela Sabala, and Matthias Bochtler¶

From the International Institute of Molecular and Cell Biology, ul. Trojdena 4, 02-109 Warsaw, Poland and the Max-Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01309 Dresden, Germany

LAS enzymes are a group of metallopeptidases that share an active site architecture and a core folding motif and have been named according to the group members lysostaphin, D-Ala-D-Ala carboxypeptidase and sonic hedgehog. Escherichia coli MepA is a periplasmic, penicillin-insensitive murein endopeptidase that cleaves the D-alanyl-meso-2,6-diamino-pimelyl amide bond in E. coli peptidoglycan. The enzyme lacks sequence similarity with other peptidases, and is currently classified as a peptidase of unknown fold and catalytic class in all major data bases. Here, we build on our observation that two motifs, characteristic of the newly described LAS group of metallopeptidases, are conserved in MepA-type sequences. We demonstrate that recombinant E. coli MepA is sensitive to metal chelators and that mutations in the predicted Zn²⁺ ligands His-113, Asp-120, and His-211 inactivate the enzyme. Moreover, we present the crystal structure of MepA. The active site of the enzyme is most similar to the active sites of lysostaphin and D-Ala-D-Ala carboxypeptidase, and the fold is most closely related to the N-domain of sonic hedgehog. We conclude that MepA-type peptidases are LAS enzymes.

Received for publication, June 16, 2004 , and in revised form, July 29, 2004.

The atomic coordinates and structure factors (codes 1U10 (Zn²⁺-containing form) and 1TZP (Zn²⁺-free form) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by Polish State Committee for Scientific Research (KBN) decisions 1789/E-529/SPB/5.PR UE/DZ 600/2002-2005 and KO89/PO4/2004 and Deutsche Forschungsgemeinschaft "Proteolyse in Prokaryonten: Kontrolle und regulatorisches Prinzip," BO1733/1-1. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 0048-22-6685193; Fax: 0048-22-6685288; E-mail: MBochtler{at}iimcb.gov.pl.

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