Identification of the first highly selective inhibitor of human lactate dehydrogenase B

Abstract Lactate dehydrogenase (LDH) catalyses the conversion of pyruvate to lactate and NADH to NAD+; it has two isoforms, LDHA and LDHB. LDHA is a promising target for cancer therapy, whereas LDHB is necessary for basal autophagy and cancer cell proliferation in oxidative and glycolytic cancer cel...

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Autores principales:	Sachio Shibata, Satoshi Sogabe, Masanori Miwa, Takuya Fujimoto, Nobuyuki Takakura, Akihiko Naotsuka, Shuji Kitamura, Tomohiro Kawamoto, Tomoyoshi Soga
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f9c30a90aae44dd1abe0ffa04ef29aac
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spelling	oai:doaj.org-article:f9c30a90aae44dd1abe0ffa04ef29aac2021-11-08T10:51:12ZIdentification of the first highly selective inhibitor of human lactate dehydrogenase B10.1038/s41598-021-00820-72045-2322https://doaj.org/article/f9c30a90aae44dd1abe0ffa04ef29aac2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-00820-7https://doaj.org/toc/2045-2322Abstract Lactate dehydrogenase (LDH) catalyses the conversion of pyruvate to lactate and NADH to NAD+; it has two isoforms, LDHA and LDHB. LDHA is a promising target for cancer therapy, whereas LDHB is necessary for basal autophagy and cancer cell proliferation in oxidative and glycolytic cancer cells. To the best of our knowledge, selective inhibitors for LDHB have not yet been reported. Here, we developed a high-throughput mass spectrometry screening system using an LDHB enzyme assay by detecting NADH and NAD+. As a result, we identified a small-molecule LDHB selective inhibitor AXKO-0046, an indole derivative. This compound exhibited uncompetitive LDHB inhibition (EC50 = 42 nM). X-ray crystallography revealed that AXKO-0046 bound to the potential allosteric site away from the LDHB catalytic active site, suggesting that targeting the tetramerisation interface of the two dimers is critical for the enzymatic activity. AXKO-0046 and its derivatives can be used to validate LDHB-associated pathways in cancer metabolism.Sachio ShibataSatoshi SogabeMasanori MiwaTakuya FujimotoNobuyuki TakakuraAkihiko NaotsukaShuji KitamuraTomohiro KawamotoTomoyoshi SogaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sachio Shibata Satoshi Sogabe Masanori Miwa Takuya Fujimoto Nobuyuki Takakura Akihiko Naotsuka Shuji Kitamura Tomohiro Kawamoto Tomoyoshi Soga Identification of the first highly selective inhibitor of human lactate dehydrogenase B
description	Abstract Lactate dehydrogenase (LDH) catalyses the conversion of pyruvate to lactate and NADH to NAD+; it has two isoforms, LDHA and LDHB. LDHA is a promising target for cancer therapy, whereas LDHB is necessary for basal autophagy and cancer cell proliferation in oxidative and glycolytic cancer cells. To the best of our knowledge, selective inhibitors for LDHB have not yet been reported. Here, we developed a high-throughput mass spectrometry screening system using an LDHB enzyme assay by detecting NADH and NAD+. As a result, we identified a small-molecule LDHB selective inhibitor AXKO-0046, an indole derivative. This compound exhibited uncompetitive LDHB inhibition (EC50 = 42 nM). X-ray crystallography revealed that AXKO-0046 bound to the potential allosteric site away from the LDHB catalytic active site, suggesting that targeting the tetramerisation interface of the two dimers is critical for the enzymatic activity. AXKO-0046 and its derivatives can be used to validate LDHB-associated pathways in cancer metabolism.
format	article
author	Sachio Shibata Satoshi Sogabe Masanori Miwa Takuya Fujimoto Nobuyuki Takakura Akihiko Naotsuka Shuji Kitamura Tomohiro Kawamoto Tomoyoshi Soga
author_facet	Sachio Shibata Satoshi Sogabe Masanori Miwa Takuya Fujimoto Nobuyuki Takakura Akihiko Naotsuka Shuji Kitamura Tomohiro Kawamoto Tomoyoshi Soga
author_sort	Sachio Shibata
title	Identification of the first highly selective inhibitor of human lactate dehydrogenase B
title_short	Identification of the first highly selective inhibitor of human lactate dehydrogenase B
title_full	Identification of the first highly selective inhibitor of human lactate dehydrogenase B
title_fullStr	Identification of the first highly selective inhibitor of human lactate dehydrogenase B
title_full_unstemmed	Identification of the first highly selective inhibitor of human lactate dehydrogenase B
title_sort	identification of the first highly selective inhibitor of human lactate dehydrogenase b
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f9c30a90aae44dd1abe0ffa04ef29aac
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Identification of the first highly selective inhibitor of human lactate dehydrogenase B

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