title: The development of a new class of inhibitors for betaine-homocysteine S-methyltransferase.
abstract: 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.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Pícha
authors.forename: Václav
authors.initials: V
authors.lastname: Vaněk
authors.forename: Miloš
authors.initials: M
authors.lastname: Buděšínský
authors.forename: Jana
authors.initials: J
authors.lastname: Mládková
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Garrow
authors.forename: Jiří
authors.initials: J
authors.lastname: Jiráček
mesh_terms: D050940:Betaine-Homocysteine S-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010421:Pentanoic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C512441:5-(3-amino-3-carboxypropylsulfanyl)pentanoic acid; D004791:Enzyme Inhibitors; D010421:Pentanoic Acids; D013440:Sulfides; D050940:Betaine-Homocysteine S-Methyltransferase
keywords: 1,1′-carbonyldiimidazole; 1,8-diazabicyclo[5.4.0]undec-7-ene; Amino acid derivative; BHMT; Bioisostere; Boc; Boc(2)O; CDI; DBU; DCM; DMF; DMS; Homocysteine; IPA; Inhibitor; MsCl; N,N′-dimethylformamide; Phosphinate; Phosphonate; S-Alkylated homocysteine; TEA; TFA; TFAA; THF; betaine-homocysteine S-methyltransferase; di-tert butyl dicarbonate; dichloromethane; dimethyl sulfide; isopropyl alcohol; methanesulfonyl chloride; tert-butoxycarbonyl; tetrahydrofuran; triethylamine; trifluoroacetic acid; trifluoroacetic anhydride