Peptidase C26, gamma-glutamyl hydrolase (IPR015527)

Short name: Pept_C26_g-glut_hydrolase

Family relationships

  • Peptidase C26 (IPR011697)
    • Peptidase C26, gamma-glutamyl hydrolase (IPR015527)


In the MEROPS database peptidases and peptidase homologues are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry based on a common structural fold:

  • Each clan is identified with two letters, the first representing the catalytic type of the families included in the clan (with the letter 'P' being used for a clan containing families of more than one of the catalytic types serine, threonine and cysteine). Some families cannot yet be assigned to clans, and when a formal assignment is required, such a family is described as belonging to clan A-, C-, M-, N-, S-, T- or U-, according to the catalytic type. Some clans are divided into subclans because there is evidence of a very ancient divergence within the clan, for example MA(E), the gluzincins, and MA(M), the metzincins.
  • Peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; N, asparagine; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In the case of the asparagine endopeptidases, the nucleophile is asparagine and all are self-processing endopeptidases.

In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding.

Cysteine peptidases have characteristic molecular topologies, which can be seen not only in their three-dimensional structures, but commonly also in the two-dimensional structures. These are peptidases in which the nucleophile is the sulphydryl group of a cysteine residue. Cysteine proteases are divided into clans (proteins which are evolutionary related), and further sub-divided into families, on the basis of the architecture of their catalytic dyad or triad [PMID: 11517925].

This entry contains cysteine peptidases belonging to MEROPS peptidase family C26 (gamma-glutamyl hydrolase, clan PC).

Gamma-glutamyl hydrolase (GH) is a lysosomal and secreted glycoprotein that hydrolyses the gamma-glutamyl tail of antifolate and folate polyglutamates. Tumour cells that have high levels of GH are inherently resistant to classical antifolates, and further resistance can be acquired by elevations in GH following exposure to this class of anti-tumour agents. The highest level of expression in normal tissues occurs in the liver and kidney in humans. GH is a low-affinity (micromolar), high-turnover enzyme that has a cysteine at the active site. GH is being evaluated as an intracellular target for inhibition in order to enhance the therapeutic activity of antifolates and fluorouracil [PMID: 10739875].

The 3-dimensional structure of GH shows a central eight-stranded beta-sheet, which is sandwiched by three and five alpha-helices on each side (see [PMID: 11953431]. The fold resembles that of glutamine amidotransferases (GATase) of class I, which are characterised by a conserved Cys-His-Glu active site. The major differences consist of extensions in four loops and at the C terminus of GGH. The active site residues are well conserved and the catalytically essential cysteine, positioned at a nucleophile elbow, suggests that GGH is a cysteine peptidase.

GO terms

Biological Process

GO:0006541 glutamine metabolic process

Molecular Function

GO:0003824 catalytic activity
GO:0008242 omega peptidase activity

Cellular Component

No terms assigned in this category.

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.
PROSITE profiles