This enzyme belongs to the family of ligases, specifically those forming carbon-nitrogen bonds as acid-D-amino-acid ligases (peptide synthases). The systematic name of this enzyme class is L-glutamate:L-cysteine gamma-ligase (ADP-forming). Other names in common use include gamma-glutamylcysteine synthetase, gamma-glutamyl-L-cysteine synthetase, and gamma-glutamylcysteinyl synthetase. This enzyme participates in glutamate metabolism and glutathione metabolism, it is the first enzyme in the glutathione biosynthesis pathway. Buthionine sulfoximine and [[S-Butyl-DL-homocysteine-[S,R]-sulfoximine]] are known to inhibit this enzyme.
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.
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