Molecule Information

General Information of the Molecule (ID: Mol04426)

• Name: Gamma-glutamyl hydrolase (GGH) ,Homo sapiens
• Synonyms: Conjugase; GH; Gamma-Glu-X carboxypeptidase
• Molecule Type: Protein
• Gene Name: GGH
• Gene ID: 8836
• Sequence:
  MASPGCLLCVLGLLLCGAASLELSRPHGDTAKKPIIGILMQKCRNKVMKNYGRYYIAASY
  VKYLESAGARVVPVRLDLTEKDYEILFKSINGILFPGGSVDLRRSDYAKVAKIFYNLSI
  Q SFDDGDYFPVWGTCLGFEELSLLISGECLLTATDTVDVAMPLNFTGGQLHSRMFQNFP
  TE LLLSLAVEPLTANFHKWSLSVKNFTMNEKLKKFFNVLTTNTDGKIEFISTMEGYKYP
  VYG VQWHPEKAPYEWKNLDGISHAPNAVKTAFYLAEFFVNEARKNNHHFKSESEEEKAL
  IYQF SPIYTGNISSFQQCYIFD
• Function: Hydrolyzes the polyglutamate sidechains ofpteroylpolyglutamates. Progressively removes gamma-glutamyl residuesfrom pteroylpoly-gamma-glutamate to yield pteroyl-alpha-glutamate and free glutamate . Mayplay an important role in the bioavailability of dietarypteroylpolyglutamates and in the metabolism of pteroylpolyglutamatesand antifolates. {ECO:0000269|PubMed:11005824,ECO:0000269|PubMed:8816764}.
• Uniprot ID: GGH_HUMAN
• Ensembl ID: ENSG0000013756313
• HGNC ID: HGNC:4248

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  DISM: Drug Inactivation by Structure Modification

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Raltitrexed

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Acute lymphoblastic leukemia [ICD-11: 2B33.3] [1]

• Resistant Disease: Acute lymphoblastic leukemia [ICD-11: 2B33.3]
• Resistant Drug: Raltitrexed
• Molecule Alteration: Mutations; G667C; F589L-G595R
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: GGH signaling pathway; Regulation; N.A.
• In Vitro Model: REH cells; Bone marrow; Homo sapiens (Human); CVCL_1650
• In Vitro Model: Nalm-6 cells; Peripheral blood; Homo sapiens (Human); CVCL_0092
• Experiment for Molecule Alteration: Immunofluorescence staining assay; Western blot assay
• Experiment for Drug Resistance: Cell viability assay; MTX polyglutamated metabolite assay; Folate growth requirement assay
• Mechanism Description: A key cofactor of several enzymes implicated in DNA synthesis, repair, and methylation, folate has been shown to be required for normal cell growth and replication and is the basis for cancer chemotherapy using antifolates. gamma-Glutamyl hydrolase (GGH) catalyzes the removal of gamma-polyglutamate tails of folylpoly-/antifolylpoly-gamma-glutamates to facilitate their export out of the cell, thereby maintaining metabolic homeostasis of folates or pharmacological efficacy of antifolates. However, the factors that control or modulate GGH function are not well understood. In this study, we show that intact GGH is not indispensable for the chemosensitivity and growth of acute lymphoblastic leukemia (ALL) cells, whereas GGH lacking N-terminal signal peptide (GGH?deltaN) confers the significant drug resistance of ALL cells to the antifolates MTX and RTX. In addition, ALL cells harboring GGH?deltaN show high susceptibility to the change in folates, and glycosylation is not responsible for these phenotypes elicited by GGH?deltaN. Mechanistically, the loss of signal peptide enhances intracellular retention of GGH and its lysosomal disposition.

References

• Ref 1: A gamma-glutamyl hydrolase lacking the signal peptide confers susceptibility to folates/antifolates in acute lymphoblastic leukemia cells. FEBS Lett. 2022 Feb;596(4):437-448.