6SCZ

Mycobacterium tuberculosis alanine racemase inhibited by DCS

6SCZ の概要

• エントリーDOI: 10.2210/pdb6scz/pdb
• 分子名称: Alanine racemase, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, GLYCEROL, ... (11 entities in total)
• 機能のキーワード: enzyme, alanine racemase, peptidoglycan biosynthesis, isomerase
• 由来する生物種: Mycobacterium tuberculosis H37Rv
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 89556.16

構造登録者

de Chiara, C.,Purkiss, A.,Prosser, G.,Homsak, M.,de Carvalho, L.P.S. (登録日: 2019-07-26, 公開日: 2020-04-01, 最終更新日: 2024-01-24)

主引用文献

de Chiara, C.,Homsak, M.,Prosser, G.A.,Douglas, H.L.,Garza-Garcia, A.,Kelly, G.,Purkiss, A.G.,Tate, E.W.,de Carvalho, L.P.S.
D-Cycloserine destruction by alanine racemase and the limit of irreversible inhibition.
Nat.Chem.Biol., 16:686-694, 2020

PubMed Abstract: The broad-spectrum antibiotic D-cycloserine (DCS) is a key component of regimens used to treat multi- and extensively drug-resistant tuberculosis. DCS, a structural analog of D-alanine, binds to and inactivates two essential enzymes involved in peptidoglycan biosynthesis, alanine racemase (Alr) and D-Ala:D-Ala ligase. Inactivation of Alr is thought to proceed via a mechanism-based irreversible route, forming an adduct with the pyridoxal 5'-phosphate cofactor, leading to bacterial death. Inconsistent with this hypothesis, Mycobacterium tuberculosis Alr activity can be detected after exposure to clinically relevant DCS concentrations. To address this paradox, we investigated the chemical mechanism of Alr inhibition by DCS. Inhibition of M. tuberculosis Alr and other Alrs is reversible, mechanistically revealed by a previously unidentified DCS-adduct hydrolysis. Dissociation and subsequent rearrangement to a stable substituted oxime explains Alr reactivation in the cellular milieu. This knowledge provides a novel route for discovery of improved Alr inhibitors against M. tuberculosis and other bacteria.

PubMed: 32203411
DOI: 10.1038/s41589-020-0498-9

実験手法

X-RAY DIFFRACTION (1.57 Å)