title: Delta-aminolevulinate dehydratase inhibition by phenyl selenoacetylene: effect of reaction with hydrogen peroxide.
abstract: The effect of phenyl selenoacetylene and its selenoxide on delta-aminolevulinate dehydratase from liver of adult rats (mammalian source) and from cucumber leaves (plant source) was investigated. In vivo, selenides can be oxidized to selenoxides by flavin-containing monooxygenases and selenoxides can regenerate selenides by thiol oxidation. The compound phenyl selenoacetylene was converted to selenoxides by reaction with hydrogen peroxide. Phenyl selenoacetylene inhibited mammalian and plant delta-aminolevulinate dehydratase with an IC50 about 250 microM and >400 microM, respectively. Its selenoxide inhibited the enzyme more strongly, with IC50 values of 45 microM and 100 microM for the mammalian and plant source, respectively. The selenoxide inhibitory action was antagonized by dithiothreitol suggesting the involvement of -SH groups. Moreover, delta-aminolevulinate dehydratase from a plant source was inhibited by the selenoxide, suggesting a possible involvement of -SH groups located at a site distinct from the region implicated in Zn2+ binding in mammalian delta-aminolevulinate dehydratase. The results of the present study suggest that (i) delta-aminolevulinate dehydratase is a potential molecular target for phenyl selenoacetylene, due to the oxidation of enzyme sulfhydryl groups, and that (ii) the monooxygenation of this selenocompound, which in vivo could be possibly mediated by flavin-containing monooxigenases, increases its inhibitory effect.
authors.affiliation: Department of Chemistry, Center of Natural and Exact Sciences, Federal University of Santa Maria, 97105-900, Santa Maria, RS, Brazil.
authors.forename: Rodrigo Cordeiro
authors.initials: RC
authors.lastname: Bolzan
authors.forename: Vanderlei
authors.initials: V
authors.lastname: Folmer
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
authors.forename: Gilson
authors.initials: G
authors.lastname: Zeni
authors.forename: Cristina Wayne
authors.initials: CW
authors.lastname: Nogueira
authors.forename: João Batista Teixeira
authors.initials: JB
authors.lastname: Rocha
authors.forename: Tatiana
authors.initials: T
authors.lastname: Emanuelli
mesh_terms: D000114:Acetylene / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D018553:Cucumis sativus / Q000737:chemistry; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008297:Male; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010936:Plant Extracts; D018515:Plant Leaves / Q000201:enzymology; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D016566:Organoselenium Compounds; D010936:Plant Extracts; C469411:phenyl selenoacetylene; D006861:Hydrogen Peroxide; D000623:Porphobilinogen Synthase; D000114:Acetylene; D004229:Dithiothreitol