Glutamate—cysteine ligase

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glutamate-cysteine ligase
Identifiers
EC number6.3.2.2
CAS number9023-64-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / EGO
 
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glutamate-cysteine ligase
Identifiers
EC number6.3.2.2
CAS number9023-64-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / EGO

In enzymology, a glutamate-cysteine ligase (EC 6.3.2.2) is an enzyme that catalyzes the chemical reaction

ATP + L-glutamate + L-cysteine \rightleftharpoons ADP + phosphate + gamma-L-glutamyl-L-cysteine

The 3 substrates of this enzyme are ATP, L-glutamate, and L-cysteine, whereas its 3 products are ADP, phosphate, and gamma-L-glutamyl-L-cysteine.

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.[1]

Function[edit]

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.[2]

Regulation[edit]

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.[3] 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.

Structure[edit]

Glutamate cysteine ligase is a heterodimeric enzyme composed of two proteins.

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.

As of late 2007, 6 structures have been solved for this class of enzymes, with PDB accession codes 1V4G, 1VA6, 2D32, 2D33, 2GWC, and 2GWD.

References[edit]

  1. ^ Jain, A.; Mårtensson, J.; Stole, E.; Auld, P. A.; Meister, A. (1991). "Glutathione deficiency leads to mitochondrial damage in brain". Proceedings of the National Academy of Sciences of the United States of America 88 (5): 1913–1917. doi:10.1073/pnas.88.5.1913. PMC 51136. PMID 2000395.  edit
  2. ^ Njålsson R, Norgren S (2005). "Physiological and pathological aspects of GSH metabolism". Acta Paediatr 94 (2): 132–137. doi:10.1080/08035250410025285. PMID 15981742. 
  3. ^ 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.