| Structural highlights
6scz is a 2 chain structure with sequence from Myctu. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| Ligands: | , , , , , , , , |
Gene: | alr, Rv3423c, MTCY78.06 (MYCTU) |
Activity: | Alanine racemase, with EC number 5.1.1.1 |
Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[ALR_MYCTU] Catalyzes the interconversion of L-alanine and D-alanine.[1]
Publication Abstract from PubMed
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.
D-Cycloserine destruction by alanine racemase and the limit of irreversible inhibition.,de Chiara C, Homsak M, Prosser GA, Douglas HL, Garza-Garcia A, Kelly G, Purkiss AG, Tate EW, de Carvalho LPS Nat Chem Biol. 2020 Mar 16. pii: 10.1038/s41589-020-0498-9. doi:, 10.1038/s41589-020-0498-9. PMID:32203411[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Strych U, Penland RL, Jimenez M, Krause KL, Benedik MJ. Characterization of the alanine racemases from two mycobacteria. FEMS Microbiol Lett. 2001 Mar 15;196(2):93-8. PMID:11267762
- ↑ de Chiara C, Homsak M, Prosser GA, Douglas HL, Garza-Garcia A, Kelly G, Purkiss AG, Tate EW, de Carvalho LPS. D-Cycloserine destruction by alanine racemase and the limit of irreversible inhibition. Nat Chem Biol. 2020 Mar 16. pii: 10.1038/s41589-020-0498-9. doi:, 10.1038/s41589-020-0498-9. PMID:32203411 doi:http://dx.doi.org/10.1038/s41589-020-0498-9
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