Gamma-glutamylcysteine synthetase (EC 18.104.22.168) (glutamate cysteine ligase, GCL) is the first enzyme in the glutathione biosynthesis pathway.
It catalyses the ATP-dependent condensation of cysteine and glutamate to form the dipeptide gamma-glutamylcysteine. The peptide bond in this peptide product is between the carboxylate group of the glutamate and the amino group of the cysteine.
Glutamate cysteine ligase is a heterodimeric enzyme composed of two proteins.
- Glutamate cysteine ligase catalytic subunit (GCLC, ~73 kDa) possesses all of the catalytic properties.
- Glutamate cysteine ligase modifier subunit (GCLM, ~31 kDa) increases the catalytic efficiency of GCLC.
The product of the GCL-mediated condensation reaction of L-glutamate and L-cysteine is gamma-glutamylcysteine, which is readily condensed with glycine, by glutathione synthetase, to form glutathione.
Glutathione (GSH) itself acts as a feedback inhibitor of GCL activity, as one regulatory mechanism of GSH synthesis. Under normal physiologic substrate concentrations, GCLC alone may synthesize gamma-glutamylcysteine, as evidenced by mouse models lacking GCLM protein.  Feedback inhibition of GCLC activity by GSH results in relatively low tissue GSH in these Gclm-lacking mice relative to their normal wild-type counterparts, which possess GCLM. In this regard, GCLM can be seen to increase the efficiency of GSH synthesis by increasing the Ki of GSH and acting as a second line of glutathione synthesis regulation.
In general, humans do not lack either GCLC or GCLM, however there are several known genetic variabilities (such as GAG trinucleotide repeats (TNRs) and single-nucleotide polymorphisms (SNPs)) in the promoter region (5' untranslated regions (UTRs)) of both GCLC and GCLM that appear to influence the inducibility of these genes and, hence, the expression of the encoded proteins.
- ^ Njålsson R, Norgren S (2005). "Physiological and pathological aspects of GSH metabolism". Acta Paediatr 94 (2): 132–137. doi:10.1080/08035250410025285. PMID 15981742.
- ^ McConnachie LA, Mohar I et al. (2007). "Glutamate cysteine ligase modifier subunit deficiency and gender as determinants of acetaminophen-induced hepatotoxicity in mice". Toxicological Sciences 99 (2): 628–636. doi:10.1093/toxsci/kfm165. PMID 17584759.