期刊
BIOCHEMICAL JOURNAL
卷 414, 期 -, 页码 375-381出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20080889
关键词
dithiol-dependent peroxidase; drug discovery; glutathione peroxidase; Leishmania; Trypanosoma; trypanothione
资金
- Wellcome Trust [WT 079838, WT 083481]
TbTDPX (Trypanosoma brucei tryparedoxin-dependent peroxidase) is a genetically validated drug target in the fight against African sleeping sickness. Despite its similarity to members of the GPX (glutathione peroxidase) family, TbTDPX2 is functional as a monomer, lacks a selenocysteine residue and relies instead on peroxidatic and resolving cysteine residues for catalysis and uses tryparedoxin rather than glutathione as electron donor. Kinetic studies indicate a saturable Ping Pong mechanism, unlike selenium-dependent GPXs, which display infinite K-m and V-max values. The structure of the reduced enzyme at 2.1 angstrom (0.21 nm) resolution reveals that the catalytic thiol groups are widely separated [19 angstrom (0.19 nm)] and thus unable to form a disulphide bond without a large conformational change in the secondary-structure architecture, as reported for certain plant GPXs. A model of the oxidized enzyme structure is presented and the implications for small-molecule inhibition are discussed.
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