Mutant/mutation
The mutant lacks expression of gamma-glutamylcysteine synthetase (γ-GCS).

Protein (function)
γ-GCS catalyzes the rate limiting step during GSH biosynthesis. GSH is a thiol-based tripeptide implicated in a variety of cellular processes, including detoxification of xenobiotics and protection against reactive oxygen species

In most eukaryotic organisms, redox-active enzymes, such as catalase, superoxide dismutase, and peroxidases as well as an enzymatic cascade that generates reduced electron donors, i.e. glutathione (GSH) and thioredoxin (Trx), sustain the cellular redox homeostasis. This redox network is split into two major arms, the GSH and the Trx system, that serve complementary functions in antioxidant defense and DNA synthesis. The malarial parasite Plasmodium lacks two central antioxidant enzymes: (i) catalase that typically detoxifies hydrogen peroxide and (ii) a classical glutathione peroxidase, a selenoenyzme that reduces lipid hydroperoxides to their alcohols. This apparent deficiency raises doubts about the relevance of the glutathione (GSH) pathway in detoxification of oxidative stress in Plasmodium. However, supportive of a role for GSH metabolism in the detoxification process are the observations that the P. falciparum glutathione S-tranferase enzyme, which conjugates GSH to other molecules via the sulfhydryl group, displays peroxidase activity.

Evidence has been presented that P. falciparum does not utilize GSH from the host red blood cell since the parasite membrane is neither permeable to host GSH nor γ-glutamylcysteine. Plasmodium is therefore thought to be dependent on its own GSH biosynthetic pathway. GSH is synthesized in Plasmodium by consecutive reactions facilitated by the enzymes γ-glutamylcysteine synthetase (γ-GCS) and glutathione synthetase (GS). However, it has been hypothesized that host GSH can be transported into the P. berghei food vacuole via hemoglobin-containing endocytic vesicles, based on data showing that GSH can detoxify the toxic ferriprotoporphyrin IX inside the parasite's food vacuole.

See also mutants RMgm-403 and RMgm-404 that lack expression of glutathione reductase (GR). Phenotype analyses of these mutants indicate that similar to what was reported for γ-GCS, GR is not essential for parasite blood stage development but it does play a critical role during oocyst development in the mosquito

Phenotype
Reduced growth of asexual blood stages in mice.

Additional information
Analyses are presented on the drug-sensitivity of mutants lacking γ-GCS (see for such studies also mutant RMgm-1418 and Vega-Rodriguez J et al. 2015. Implications of Glutathione Levels in the Plasmodium berghei Response to Chloroquine and Artemisinin. PLoS One 10:e0128212). 

Other mutants
See mutant RMgm-204 for an independent mutant lacking expression of γ-GCS.
RMgm-1418: A mutant over-expressing γ-GCS
RMgm-403, RMgm-404: Mutants lacking expression of glutathione reductase (GR).