Gene links: No gene identifiers were provided.

Description:
Background. gamma-glutamylcysteine synthetase (GCS) catalyzes the first step in the biosynthesis of glutathione, which in trypanosome parasites is a required precursor to trypanothione. Essential by genetic and chemical data. An inhibitor of GCS, buthionine sulfoximine was shown to give partial cure of T. brucei infections in mice (1). This inhibitor is also effective at killing parasites in vitro. Knockdown of GCS by RNAi in procyclic T. brucei cells led to growth arrest and eventual cell death through the depletion of trypanothione (2). The growth arrest is rescued by supplementation of glutathione into the media. Structure and Assay. The enzyme can be expressed to high levels in bacteria (3-5). It can be readily assayed by a coupled spectrophotometric assay that would be amenable to HTS. X-ray structures from E. coli and plant have been reported (6-8). 1. B. Arrick, O. Griffith, A. Cerami, J. Exp. Med. 153, 720 (1981). 2. T. T. Huynh, V. T. Huynh, M. A. Harmon, M. A. Phillips, J. Biol. Chem. 278, 39794 (2003). 3. D. Lueder, M. Phillips, J. Biol. Chem. 271, 17485 (1996). 4. J. Abbott et al., J. Biol. Chem. 276, 42099 (2001). 5. J. Abbott, J. Ford, M. Phillips, Biochemistry 41, 2741 (2002). 6. M. Hothorn et al., J Biol Chem 281, 27557 (Sep 15, 2006). 7. T. Hibi et al., Proc Natl Acad Sci U S A 101, 15052 (Oct 19, 2004). 8. C. Lehmann et al., Proteins 56, 376 (Aug 1, 2004). Target ID: geneDB number = Tb10.389.1360 EC number (if enzyme) = EC 6.3.2.2 target name = Glutamate-cysteine ligase, or gamma-glutamylcysteine synthetase Assay: Assay exists but not yet in microtitre plate format Availability: Can be expressed > 1 mg/L in soluble, active form Activity: Small (< 1 full time person)

Target ID: geneDB number = Tb10.389.1360 EC number (if enzyme) = EC 6.3.2.2 target name = Glutamate-cysteine

Validation: Genetic AND chemical evidence

Assay status: Assay exists but not yet in microtitre plate format

Availability: Can be expressed > 1 mg/L in soluble, active form

Activity: Small (< 1 full time person)

No references provided.