Structural and mechanistic insights into type II trypanosomatid tryparedoxin-dependent peroxidases

Alphey MS, König J, Fairlamb AH (2008)
The Biochemical Journal 414(3): 375-381.

Zeitschriftenaufsatz | Veröffentlicht | Englisch
 
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Abstract / Bemerkung
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 A (0.21 nm) resolution reveals that the catalytic thiol groups are widely separated [19 A (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.
Stichworte
Peroxidases/metabolism; Peroxidases/chemistry; Molecular Sequence Data; Molecular; Models; Mitochondria/metabolism; Mitochondria/enzymology; Kinetics; Cytosol/metabolism; Cytosol/enzymology; X-Ray; Crystallography; Binding Sites; Amino Acid Sequence; Animals; Protozoan Proteins/chemistry; Protozoan Proteins/metabolism; Recombinant Proteins/chemistry; Recombinant Proteins/metabolism; Sequence Alignment; Trypanosoma brucei brucei/enzymology
Erscheinungsjahr
2008
Zeitschriftentitel
The Biochemical Journal
Band
414
Ausgabe
3
Seite(n)
375-381
ISSN
0264-6021
eISSN
1470-8728
Page URI
https://pub.uni-bielefeld.de/record/2549797

Zitieren

Alphey MS, König J, Fairlamb AH. Structural and mechanistic insights into type II trypanosomatid tryparedoxin-dependent peroxidases. The Biochemical Journal. 2008;414(3):375-381.
Alphey, M. S., König, J., & Fairlamb, A. H. (2008). Structural and mechanistic insights into type II trypanosomatid tryparedoxin-dependent peroxidases. The Biochemical Journal, 414(3), 375-381. doi:10.1042/BJ20080889
Alphey, M. S., König, J., and Fairlamb, A. H. (2008). Structural and mechanistic insights into type II trypanosomatid tryparedoxin-dependent peroxidases. The Biochemical Journal 414, 375-381.
Alphey, M.S., König, J., & Fairlamb, A.H., 2008. Structural and mechanistic insights into type II trypanosomatid tryparedoxin-dependent peroxidases. The Biochemical Journal, 414(3), p 375-381.
M.S. Alphey, J. König, and A.H. Fairlamb, “Structural and mechanistic insights into type II trypanosomatid tryparedoxin-dependent peroxidases”, The Biochemical Journal, vol. 414, 2008, pp. 375-381.
Alphey, M.S., König, J., Fairlamb, A.H.: Structural and mechanistic insights into type II trypanosomatid tryparedoxin-dependent peroxidases. The Biochemical Journal. 414, 375-381 (2008).
Alphey, Magnus S, König, Janine, and Fairlamb, Alan H. “Structural and mechanistic insights into type II trypanosomatid tryparedoxin-dependent peroxidases”. The Biochemical Journal 414.3 (2008): 375-381.

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