6SCZ

Mycobacterium tuberculosis alanine racemase inhibited by DCS

Summary for 6SCZ

• Entry DOI: 10.2210/pdb6scz/pdb
• Descriptor: Alanine racemase, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, GLYCEROL, ... (11 entities in total)
• Functional Keywords: enzyme, alanine racemase, peptidoglycan biosynthesis, isomerase
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 2
• Total formula weight: 89556.16

Authors

de Chiara, C.,Purkiss, A.,Prosser, G.,Homsak, M.,de Carvalho, L.P.S. (deposition date: 2019-07-26, release date: 2020-04-01, Last modification date: 2024-01-24)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.57 Å)