Inhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production

Abstract Ergothioneine (EGT) is a low molecular weight histidine betaine essential in all domains of life but only synthesized by selected few organisms. Synthesis of EGT by Mycobacterium tuberculosis (M. tb) is critical for maintaining bioenergetic homeostasis and protecting the bacterium from alky...

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Autores principales:	Thanuja D. Sudasinghe, Michael T. Banco, Donald R. Ronning
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0eb527d020d64de395a2bd8ce27323b5
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spelling	oai:doaj.org-article:0eb527d020d64de395a2bd8ce27323b52021-11-21T12:19:42ZInhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production10.1038/s41598-021-01526-62045-2322https://doaj.org/article/0eb527d020d64de395a2bd8ce27323b52021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01526-6https://doaj.org/toc/2045-2322Abstract Ergothioneine (EGT) is a low molecular weight histidine betaine essential in all domains of life but only synthesized by selected few organisms. Synthesis of EGT by Mycobacterium tuberculosis (M. tb) is critical for maintaining bioenergetic homeostasis and protecting the bacterium from alkylating agents, oxidative stress, and anti-tubercular drugs. EgtD, an S-adenosylmethionine-dependent methyltransferase (AdoMet), catalyzes the trimethylation of L-Histidine to initiate EGT biosynthesis and this reaction has been shown to be essential for EGT production in mycobacteria and for long-term infection of murine macrophages by M. tb. In this work, library screening and structure-guided strategies identified multiple classes of M. tb EgtD inhibitors that bind in various regions of the enzyme active site. X-ray crystal structures of EgtD-inhibitor complexes confirm that L-Histidine analogs bind solely to the L-Histidine binding site while drug-like inhibitors, such as TGX-221, and S-Glycyl-H-1152 span both the L-Histidine and AdoMet binding sites. These enzyme-inhibitor complexes provide detailed structural information of compound scaffolds useful for developing more potent inhibitors that could shorten Tuberculosis treatment regimens by weakening important bacterial defenses.Thanuja D. SudasingheMichael T. BancoDonald R. RonningNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thanuja D. Sudasinghe Michael T. Banco Donald R. Ronning Inhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production
description	Abstract Ergothioneine (EGT) is a low molecular weight histidine betaine essential in all domains of life but only synthesized by selected few organisms. Synthesis of EGT by Mycobacterium tuberculosis (M. tb) is critical for maintaining bioenergetic homeostasis and protecting the bacterium from alkylating agents, oxidative stress, and anti-tubercular drugs. EgtD, an S-adenosylmethionine-dependent methyltransferase (AdoMet), catalyzes the trimethylation of L-Histidine to initiate EGT biosynthesis and this reaction has been shown to be essential for EGT production in mycobacteria and for long-term infection of murine macrophages by M. tb. In this work, library screening and structure-guided strategies identified multiple classes of M. tb EgtD inhibitors that bind in various regions of the enzyme active site. X-ray crystal structures of EgtD-inhibitor complexes confirm that L-Histidine analogs bind solely to the L-Histidine binding site while drug-like inhibitors, such as TGX-221, and S-Glycyl-H-1152 span both the L-Histidine and AdoMet binding sites. These enzyme-inhibitor complexes provide detailed structural information of compound scaffolds useful for developing more potent inhibitors that could shorten Tuberculosis treatment regimens by weakening important bacterial defenses.
format	article
author	Thanuja D. Sudasinghe Michael T. Banco Donald R. Ronning
author_facet	Thanuja D. Sudasinghe Michael T. Banco Donald R. Ronning
author_sort	Thanuja D. Sudasinghe
title	Inhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production
title_short	Inhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production
title_full	Inhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production
title_fullStr	Inhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production
title_full_unstemmed	Inhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production
title_sort	inhibitors of mycobacterium tuberculosis egtd target both substrate binding sites to limit hercynine production
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/0eb527d020d64de395a2bd8ce27323b5
work_keys_str_mv	AT thanujadsudasinghe inhibitorsofmycobacteriumtuberculosisegtdtargetbothsubstratebindingsitestolimithercynineproduction AT michaeltbanco inhibitorsofmycobacteriumtuberculosisegtdtargetbothsubstratebindingsitestolimithercynineproduction AT donaldrronning inhibitorsofmycobacteriumtuberculosisegtdtargetbothsubstratebindingsitestolimithercynineproduction
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Inhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production

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