Gamma-glutamylcysteine synthetase (EC 6.3.2.2) (glutamate cysteine ligase, GCL) is the first enzyme in the glutathione

Glutathione

Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...

 biosynthesis pathway.

Function

It catalyses the ATP-dependent condensation of cysteine

Cysteine

Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

 and glutamate to form the dipeptide gamma-glutamylcysteine

Gamma-Glutamylcysteine

γ-Glutamylcysteine is a precursor of glutathione. It is formed by gamma-glutamylcysteine synthetase and used by glutathione synthetase to form glutathione....

. The peptide bond

Peptide bond

This article is about the peptide link found within biological molecules, such as proteins. A similar article for synthetic molecules is being created...

 in this peptide product is between the carboxylate group of the glutamate and the amino group of the cysteine.

Structure

Glutamate cysteine ligase is a heterodimeric enzyme

Enzyme

Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 composed of two protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s.

• Glutamate cysteine ligase catalytic subunit (GCLC
  GCLC
  Glutamate--cysteine ligase catalytic subunit is an enzyme that in humans is encoded by the GCLC gene.-Further reading:...
  
  , ~73 kDa) possesses all of the catalytic properties.
• Glutamate cysteine ligase modifier subunit (GCLM
  GCLM
  Glutamate--cysteine ligase regulatory subunit is an enzyme that in humans is encoded by the GCLM gene.-Further reading:...
  
  , ~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.

Regulation

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.