4cvy
From Proteopedia
Crystal structure of the M. tuberculosis sulfate ester dioxygenase Rv3406 in complex with iron.
Structural highlights
FunctionATSK_MYCTU Alpha-ketoglutarate-dependent sulfate ester dioxygenase, which oxidizes medium-chain alkyl-sulfate esters (PubMed:23762287). Shows preference for 2-ethylhexyl sulfate (2-EHS) in vitro, leading to the formation of succinate and 2-ethylhexanal (PubMed:23762287, PubMed:25427196). Has likely a role in sulfate scavenging in vivo (PubMed:23762287).[1] [2] Also causes the inactivation of the 2-carboxyquinoxaline Ty38c (an antitubercular compound that inhibits DprE1) via oxidative decarboxylation, using Ty38c instead of alpha-ketoglutarate as a substrate. Is thus responsible for primary resistance of M.tuberculosis to Ty38c in vitro. Overexpression of Rv3406 causes resistance to Ty38c.[3] Publication Abstract from PubMedPhenotypic screening of a quinoxaline library against replicating Mycobacterium tuberculosis led to the identification of lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC99 and MBC of 3.1 muM, Ty38c is bactericidal and active against intracellular bacteria. To investigate its mechanism of action, we isolated mutants resistant to Ty38c and sequenced their genomes. Mutations were found in rv3405c, coding for the transcriptional repressor of the divergently expressed rv3406 gene. Biochemical studies clearly showed that Rv3406 decarboxylates Ty38c into its inactive keto metabolite. The actual target was then identified by isolating Ty38c-resistant mutants of an M. tuberculosis strain lacking rv3406. Here, mutations were found in dprE1, encoding the decaprenylphosphoryl-d-ribose oxidase DprE1, essential for biogenesis of the mycobacterial cell wall. Genetics, biochemical validation, and X-ray crystallography revealed Ty38c to be a noncovalent, noncompetitive DprE1 inhibitor. Structure-activity relationship studies generated a family of DprE1 inhibitors with a range of IC50's and bactericidal activity. Co-crystal structures of DprE1 in complex with eight different quinoxaline analogs provided a high-resolution interaction map of the active site of this extremely vulnerable target in M. tuberculosis. 2-Carboxyquinoxalines Kill Mycobacterium tuberculosis through Noncovalent Inhibition of DprE1.,Neres J, Hartkoorn RC, Chiarelli LR, Gadupudi R, Pasca MR, Mori G, Venturelli A, Savina S, Makarov V, Kolly GS, Molteni E, Binda C, Dhar N, Ferrari S, Brodin P, Delorme V, Landry V, de Jesus Lopes Ribeiro AL, Farina D, Saxena P, Pojer F, Carta A, Luciani R, Porta A, Zanoni G, De Rossi E, Costi MP, Riccardi G, Cole ST ACS Chem Biol. 2014 Dec 9. PMID:25427196[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Large Structures | Mycobacterium tuberculosis | Binda C | Brodin P | Carta A | Chiarelli LR | Cole ST | Costi MP | De Rossi E | Delorme V | Dhar N | Farina D | Ferrari S | Gadupudi R | Hartkoorn RC | Kolly GS | Landry V | Luciani R | Makarov V | Molteni E | Mori G | Neres J | Pasca M | Pojer F | Porta A | Riccardi G | Salina S | Saxena P | Venturelli A | Zanoni G | De Jesus Lopes Ribeiro AL
