Residues in human arsenic (+3 oxidation state) methyltransferase forming potential hydrogen bond network around S-adenosylmethionine.

Residues Tyr59, Gly78, Ser79, Met103, Gln107, Ile136 and Glu137 in human arsenic (+3 oxidation state) methyltransferase (hAS3MT) were deduced to form a potential hydrogen bond network around S-adenosylmethionine (SAM) from the sequence alignment between Cyanidioschyzon merolae arsenite S-adenosylmet...

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Autores principales:	Xiangli Li, Jing Cao, Shuping Wang, Zhirong Geng, Xiaoli Song, Xin Hu, Zhilin Wang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5e68b321a1864b829103eae741e43277
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spelling	oai:doaj.org-article:5e68b321a1864b829103eae741e432772021-11-18T08:52:21ZResidues in human arsenic (+3 oxidation state) methyltransferase forming potential hydrogen bond network around S-adenosylmethionine.1932-620310.1371/journal.pone.0076709https://doaj.org/article/5e68b321a1864b829103eae741e432772013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24124590/?tool=EBIhttps://doaj.org/toc/1932-6203Residues Tyr59, Gly78, Ser79, Met103, Gln107, Ile136 and Glu137 in human arsenic (+3 oxidation state) methyltransferase (hAS3MT) were deduced to form a potential hydrogen bond network around S-adenosylmethionine (SAM) from the sequence alignment between Cyanidioschyzon merolae arsenite S-adenosylmethyltransferase (CmArsM) and hAS3MT. Herein, seven mutants Y59A, G78A, S79A, M103A, Q107A, I136A and E137A were obtained. Their catalytic activities and conformations were characterized and models were built. Y59A and G78A were completely inactive. Only 7.0%, 10.6% and 13.8% inorganic arsenic (iAs) was transformed to monomethylated arsenicals (MMA) when M103A, Q107A and I136A were used as the enzyme. The Vmax (the maximal velocity of the reaction) values of M103A, Q107A, I136A and E137A were decreased to 8%, 22%, 15% and 50% of that of WT-hAS3MT, respectively. The KM(SAM) (the Michaelis constant for SAM) values of mutants M103A, I136A and E137A were 15.7, 8.9 and 5.1 fold higher than that of WT-hAS3MT, respectively, indicating that their affinities for SAM were weakened. The altered microenvironment of SAM and the reduced capacity of binding arsenic deduced from KM(As) (the Michaelis constant for iAs) value probably synergetically reduced the catalytic activity of Q107A. The catalytic activity of S79A was higher than that of WT despite of the higher KM(SAM) , suggesting that Ser79 did not impact the catalytic activity of hAS3MT. In short, residues Tyr59 and Gly78 significantly influenced the catalytic activity of hAS3MT as well as Met103, Ile136 and Glu137 because they were closely associated with SAM-binding, while residue Gln107 did not affect SAM-binding regardless of affecting the catalytic activity of hAS3MT. Modeling and our experimental results suggest that the adenine ring of SAM is sandwiched between Ile136 and Met103, the amide group of SAM is hydrogen bonded to Gly78 in hAS3MT and SAM is bonded to Tyr59 with van der Waals, cation-π and hydrogen bonding contacts.Xiangli LiJing CaoShuping WangZhirong GengXiaoli SongXin HuZhilin WangPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 10, p e76709 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xiangli Li Jing Cao Shuping Wang Zhirong Geng Xiaoli Song Xin Hu Zhilin Wang Residues in human arsenic (+3 oxidation state) methyltransferase forming potential hydrogen bond network around S-adenosylmethionine.
description	Residues Tyr59, Gly78, Ser79, Met103, Gln107, Ile136 and Glu137 in human arsenic (+3 oxidation state) methyltransferase (hAS3MT) were deduced to form a potential hydrogen bond network around S-adenosylmethionine (SAM) from the sequence alignment between Cyanidioschyzon merolae arsenite S-adenosylmethyltransferase (CmArsM) and hAS3MT. Herein, seven mutants Y59A, G78A, S79A, M103A, Q107A, I136A and E137A were obtained. Their catalytic activities and conformations were characterized and models were built. Y59A and G78A were completely inactive. Only 7.0%, 10.6% and 13.8% inorganic arsenic (iAs) was transformed to monomethylated arsenicals (MMA) when M103A, Q107A and I136A were used as the enzyme. The Vmax (the maximal velocity of the reaction) values of M103A, Q107A, I136A and E137A were decreased to 8%, 22%, 15% and 50% of that of WT-hAS3MT, respectively. The KM(SAM) (the Michaelis constant for SAM) values of mutants M103A, I136A and E137A were 15.7, 8.9 and 5.1 fold higher than that of WT-hAS3MT, respectively, indicating that their affinities for SAM were weakened. The altered microenvironment of SAM and the reduced capacity of binding arsenic deduced from KM(As) (the Michaelis constant for iAs) value probably synergetically reduced the catalytic activity of Q107A. The catalytic activity of S79A was higher than that of WT despite of the higher KM(SAM) , suggesting that Ser79 did not impact the catalytic activity of hAS3MT. In short, residues Tyr59 and Gly78 significantly influenced the catalytic activity of hAS3MT as well as Met103, Ile136 and Glu137 because they were closely associated with SAM-binding, while residue Gln107 did not affect SAM-binding regardless of affecting the catalytic activity of hAS3MT. Modeling and our experimental results suggest that the adenine ring of SAM is sandwiched between Ile136 and Met103, the amide group of SAM is hydrogen bonded to Gly78 in hAS3MT and SAM is bonded to Tyr59 with van der Waals, cation-π and hydrogen bonding contacts.
format	article
author	Xiangli Li Jing Cao Shuping Wang Zhirong Geng Xiaoli Song Xin Hu Zhilin Wang
author_facet	Xiangli Li Jing Cao Shuping Wang Zhirong Geng Xiaoli Song Xin Hu Zhilin Wang
author_sort	Xiangli Li
title	Residues in human arsenic (+3 oxidation state) methyltransferase forming potential hydrogen bond network around S-adenosylmethionine.
title_short	Residues in human arsenic (+3 oxidation state) methyltransferase forming potential hydrogen bond network around S-adenosylmethionine.
title_full	Residues in human arsenic (+3 oxidation state) methyltransferase forming potential hydrogen bond network around S-adenosylmethionine.
title_fullStr	Residues in human arsenic (+3 oxidation state) methyltransferase forming potential hydrogen bond network around S-adenosylmethionine.
title_full_unstemmed	Residues in human arsenic (+3 oxidation state) methyltransferase forming potential hydrogen bond network around S-adenosylmethionine.
title_sort	residues in human arsenic (+3 oxidation state) methyltransferase forming potential hydrogen bond network around s-adenosylmethionine.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/5e68b321a1864b829103eae741e43277
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_version_	1718421203202342912

Residues in human arsenic (+3 oxidation state) methyltransferase forming potential hydrogen bond network around S-adenosylmethionine.

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