Počet záznamů: 1
The development of a new class of inhibitors for betaine-homocysteine S-methyltransferase
- 1.0396069 - UOCHB-X 2014 RIV FR eng J - Článek v odborném periodiku
Pícha, Jan - Vaněk, Václav - Buděšínský, Miloš - Mládková, Jana - Garrow, T. A. - Jiráček, Jiří
The development of a new class of inhibitors for betaine-homocysteine S-methyltransferase.
European Journal of Medicinal Chemistry. Roč. 65, July (2013), s. 256-275. ISSN 0223-5234
Grant CEP: GA ČR(CZ) GAP207/10/1277
Institucionální podpora: RVO:61388963
Klíčová slova: BHMT * inhibitor * homocysteine * phosphonate * phosphinate * amino acid derivative * bioisostere * S-alkylated homocysteine
Kód oboru RIV: CE - Biochemie
Impakt faktor: 3.432, rok: 2013
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.
Trvalý link: http://hdl.handle.net/11104/0223944