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The development of a new class of inhibitors for betaine-homocysteine S-methyltransferase

SYSNO ASEP	0396069
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	The development of a new class of inhibitors for betaine-homocysteine S-methyltransferase
Author(s)	Pícha, Jan (UOCHB-X)_{RID, ORCID} Vaněk, Václav (UOCHB-X)_{RID, ORCID} Buděšínský, Miloš (UOCHB-X)_{RID, ORCID} Mládková, Jana (UOCHB-X) Garrow, T. A. (US) Jiráček, Jiří (UOCHB-X)_{RID, ORCID}
Number of authors	6
Source Title	European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234 Roč. 65, July (2013), s. 256-275
Number of pages	20 s.
Language	eng - English
Country	FR - France
Keywords	BHMT ; inhibitor ; homocysteine ; phosphonate ; phosphinate ; amino acid derivative ; bioisostere ; S-alkylated homocysteine
Subject RIV	CE - Biochemistry
R&D Projects	GAP207/10/1277 GA ČR - Czech Science Foundation (CSF)
Institutional support	UOCHB-X - RVO:61388963
UT WOS	000322850100026
EID SCOPUS	84878214075
DOI	10.1016/j.ejmech.2013.04.039
Annotation	Betaine-homocysteine S-methyltransferase (BHMT) is an important zinc-dependent methyltransferase that uses betaine as the methyl donor for the remethylation of homocysteine to form methionine. In the liver, BHMT performs to half of the homocysteine remethylation. In this study, we systematically investigated the tolerance of the enzyme for modifications at the "homocysteine" part of the previously reported potent inhibitor (R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic acid (1). In the new compounds, which are S-alkylated homocysteine derivatives, we replaced the carboxylic group in the "homocysteine" part of inhibitor 1 with different isosteric moieties (tetrazole and oxadiazolone); we suppressed the carboxylic negative charge by amidations; we enhanced acidity by replacing the carboxylate with phosphonic or phosphinic acids; and we introduced pyrrolidine steric constraints. Some of these compounds display high affinity toward human BHMT and may be useful for further pharmacological studies of this enzyme. Although none of the new compounds were more potent inhibitors than the reference inhibitor 1, this study helped to completely define the structural requirements of the active site of BHMT and revealed the remarkable selectivity of the enzyme for homocysteine.
Workplace	Institute of Organic Chemistry and Biochemistry
Contact	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434
Year of Publishing	2014

Number of the records: 1