Human METTL7B is an alkyl thiol methyltransferase that metabolizes hydrogen sulfide and captopril

Abstract Methylation of alkyl thiols is a biotransformation pathway designed to reduce thiol reactivity and potential toxicity, yet the gene and protein responsible for human alkyl thiol methyltransferase (TMT) activity remain unknown. Here we demonstrate with a range of experimental approaches usin...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Benjamin J. Maldonato, Drake A. Russell, Rheem A. Totah
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6dfb2e5090dd4cb1a587933d21f727de
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:6dfb2e5090dd4cb1a587933d21f727de
record_format	dspace
spelling	oai:doaj.org-article:6dfb2e5090dd4cb1a587933d21f727de2021-12-02T15:53:43ZHuman METTL7B is an alkyl thiol methyltransferase that metabolizes hydrogen sulfide and captopril10.1038/s41598-021-84218-52045-2322https://doaj.org/article/6dfb2e5090dd4cb1a587933d21f727de2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84218-5https://doaj.org/toc/2045-2322Abstract Methylation of alkyl thiols is a biotransformation pathway designed to reduce thiol reactivity and potential toxicity, yet the gene and protein responsible for human alkyl thiol methyltransferase (TMT) activity remain unknown. Here we demonstrate with a range of experimental approaches using cell lines, in vitro systems, and recombinantly expressed enzyme, that human methyltransferase-like protein 7B (METTL7B) catalyzes the transfer of a methyl group from S-adenosyl-l-methionine (AdoMet) to hydrogen sulfide (H2S) and other exogenous thiol small molecules. METTL7B gene modulation experiments, including knockdown in HepG2 cells and overexpression in HeLa cells, directly alter the methylation of the drug captopril, a historic probe substrate for TMT activity. Furthermore, recombinantly expressed and purified wild-type METTL7B methylates several thiol compounds, including H2S, 7α-thiospironolactone, l-penicillamine, and captopril, in a time- and concentration-dependent manner. Typical for AdoMet-dependent small molecule methyltransferases, S-adenosyl-l-homocysteine (AdoHcy) inhibited METTL7B activity in a competitive fashion. Similarly, mutating a conserved aspartate residue, proposed to anchor AdoMet into the active site, to an alanine (D98A) abolished methylation activity. Endogenous thiols such as glutathione and cysteine, or classic substrates for other known small molecule S-, N-, and O-methyltransferases, were not substrates for METTL7B. Our results confirm, for the first time, that METTL7B, a gene implicated in multiple disease states including rheumatoid arthritis and breast cancer, encodes a protein that methylates small molecule alkyl thiols. Identifying the catalytic function of METTL7B will enable future pharmacological research in disease pathophysiology where altered METTL7B expression and, potentially H2S levels, can disrupt cell growth and redox state.Benjamin J. MaldonatoDrake A. RussellRheem A. TotahNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Benjamin J. Maldonato Drake A. Russell Rheem A. Totah Human METTL7B is an alkyl thiol methyltransferase that metabolizes hydrogen sulfide and captopril
description	Abstract Methylation of alkyl thiols is a biotransformation pathway designed to reduce thiol reactivity and potential toxicity, yet the gene and protein responsible for human alkyl thiol methyltransferase (TMT) activity remain unknown. Here we demonstrate with a range of experimental approaches using cell lines, in vitro systems, and recombinantly expressed enzyme, that human methyltransferase-like protein 7B (METTL7B) catalyzes the transfer of a methyl group from S-adenosyl-l-methionine (AdoMet) to hydrogen sulfide (H2S) and other exogenous thiol small molecules. METTL7B gene modulation experiments, including knockdown in HepG2 cells and overexpression in HeLa cells, directly alter the methylation of the drug captopril, a historic probe substrate for TMT activity. Furthermore, recombinantly expressed and purified wild-type METTL7B methylates several thiol compounds, including H2S, 7α-thiospironolactone, l-penicillamine, and captopril, in a time- and concentration-dependent manner. Typical for AdoMet-dependent small molecule methyltransferases, S-adenosyl-l-homocysteine (AdoHcy) inhibited METTL7B activity in a competitive fashion. Similarly, mutating a conserved aspartate residue, proposed to anchor AdoMet into the active site, to an alanine (D98A) abolished methylation activity. Endogenous thiols such as glutathione and cysteine, or classic substrates for other known small molecule S-, N-, and O-methyltransferases, were not substrates for METTL7B. Our results confirm, for the first time, that METTL7B, a gene implicated in multiple disease states including rheumatoid arthritis and breast cancer, encodes a protein that methylates small molecule alkyl thiols. Identifying the catalytic function of METTL7B will enable future pharmacological research in disease pathophysiology where altered METTL7B expression and, potentially H2S levels, can disrupt cell growth and redox state.
format	article
author	Benjamin J. Maldonato Drake A. Russell Rheem A. Totah
author_facet	Benjamin J. Maldonato Drake A. Russell Rheem A. Totah
author_sort	Benjamin J. Maldonato
title	Human METTL7B is an alkyl thiol methyltransferase that metabolizes hydrogen sulfide and captopril
title_short	Human METTL7B is an alkyl thiol methyltransferase that metabolizes hydrogen sulfide and captopril
title_full	Human METTL7B is an alkyl thiol methyltransferase that metabolizes hydrogen sulfide and captopril
title_fullStr	Human METTL7B is an alkyl thiol methyltransferase that metabolizes hydrogen sulfide and captopril
title_full_unstemmed	Human METTL7B is an alkyl thiol methyltransferase that metabolizes hydrogen sulfide and captopril
title_sort	human mettl7b is an alkyl thiol methyltransferase that metabolizes hydrogen sulfide and captopril
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6dfb2e5090dd4cb1a587933d21f727de
work_keys_str_mv	AT benjaminjmaldonato humanmettl7bisanalkylthiolmethyltransferasethatmetabolizeshydrogensulfideandcaptopril AT drakearussell humanmettl7bisanalkylthiolmethyltransferasethatmetabolizeshydrogensulfideandcaptopril AT rheematotah humanmettl7bisanalkylthiolmethyltransferasethatmetabolizeshydrogensulfideandcaptopril
_version_	1718385514820665344

Human METTL7B is an alkyl thiol methyltransferase that metabolizes hydrogen sulfide and captopril

Ejemplares similares