BIOMAT Database Logo BIOMAT Database Logo

gamma-Glutamyl hydrolase and folylpolyglutamate synthetase activities predict polyglutamylation of methotrexate in acute leukemias. 1997

G S Longo, and R Gorlick, and W P Tong, and S Lin, and P Steinherz, and J R Bertino
Department of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Decreased methotrexate (MTX) long-chain polyglutamate formation is associated with MTX resistance whereas high levels of MTX polyglutamate accumulation are found in the blasts of leukemia patients who respond to therapy and have improved outcome. The steady-state level of long-chain MTX polyglutamates depends on the balance of activities of two enzymes: folylpolyglutamate synthetase (FPGS), which adds glutamates to MTX in a gamma-carboxyl linkage, and gamma-glutamyl hydrolase (GGH) or conjugase, which sequentially removes the terminal glutamate residue of MTX polyglutamates. FPGS and GGH activities as well as the formation of total and long-chain MTX polyglutamates were measured after incubation with [3H]MTX in 15 blast samples from patients with acute leukemias (myeloid and lymphoid). The ratio between GGH and FPGS activities was better at predicting the amount of polyglutamate accumulated in the 24-h [3H]MTX assay compared to the determination of either activity alone. The linear regression curve relating the relative levels of long-chain polyglutamates/total polyglutamates with the ratio of GGH/FPGS showed an r value of 0.81 (P < 0.001). These data suggest that the evaluation of both these enzymes at diagnosis may be used as a predictor of MTX polyglutamylation and therefore for response to MTX therapy and outcome.

UI MeSH Term Description Entries
D007945 Leukemia, Lymphoid Leukemia associated with HYPERPLASIA of the lymphoid tissues and increased numbers of circulating malignant LYMPHOCYTES and lymphoblasts. Leukemia, Lymphocytic,Lymphocytic Leukemia,Lymphoid Leukemia,Leukemias, Lymphocytic,Leukemias, Lymphoid,Lymphocytic Leukemias,Lymphoid Leukemias
D007951 Leukemia, Myeloid Form of leukemia characterized by an uncontrolled proliferation of the myeloid lineage and their precursors (MYELOID PROGENITOR CELLS) in the bone marrow and other sites. Granulocytic Leukemia,Leukemia, Granulocytic,Leukemia, Myelocytic,Leukemia, Myelogenous,Myelocytic Leukemia,Myelogenous Leukemia,Myeloid Leukemia,Leukemia, Monocytic, Chronic,Monocytic Leukemia, Chronic,Chronic Monocytic Leukemia,Chronic Monocytic Leukemias,Granulocytic Leukemias,Leukemia, Chronic Monocytic,Leukemias, Chronic Monocytic,Leukemias, Granulocytic,Leukemias, Myelocytic,Leukemias, Myelogenous,Leukemias, Myeloid,Monocytic Leukemias, Chronic,Myelocytic Leukemias,Myelogenous Leukemias,Myeloid Leukemias
D008727 Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of TETRAHYDROFOLATE DEHYDROGENASE and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Amethopterin,Methotrexate Hydrate,Methotrexate Sodium,Methotrexate, (D)-Isomer,Methotrexate, (DL)-Isomer,Methotrexate, Dicesium Salt,Methotrexate, Disodium Salt,Methotrexate, Sodium Salt,Mexate,Dicesium Salt Methotrexate,Hydrate, Methotrexate,Sodium, Methotrexate
D010453 Peptide Synthases Ligases that catalyze the joining of adjacent AMINO ACIDS by the formation of carbon-nitrogen bonds between their carboxylic acid groups and amine groups. Peptide Synthetases,Acid-Amino-Acid Ligases,Acid Amino Acid Ligases,Ligases, Acid-Amino-Acid,Synthases, Peptide,Synthetases, Peptide
D011099 Polyglutamic Acid A peptide that is a homopolymer of glutamic acid. Polyglutamate
D011623 gamma-Glutamyl Hydrolase Catalyzes the hydrolysis of pteroylpolyglutamic acids in gamma linkage to pterolylmonoglutamic acid and free glutamic acid. EC 3.4.19.9. Conjugase,Folate Conjugase,Folyl Conjugate Synthetase,Pteroyl Polyglutamate Hydrolase,Carboxypeptidase G,Carboxypeptidase G1,Carboxypeptidase G2,Folacin Conjugase,Folate Hydrolyzing Enzyme,Folyl Poly-gamma-Glutamate Carboxypeptidase,Folyl Polyglutamate Cleavage Enzyme,Folylpolyglutamate Hydrolase,gamma Glutamyl Hydrolase
D002648 Child A person 6 to 12 years of age. An individual 2 to 5 years old is CHILD, PRESCHOOL. Children
D002675 Child, Preschool A child between the ages of 2 and 5. Children, Preschool,Preschool Child,Preschool Children
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000208 Acute Disease Disease having a short and relatively severe course. Acute Diseases,Disease, Acute,Diseases, Acute

Related Publications

G S Longo, and R Gorlick, and W P Tong, and S Lin, and P Steinherz, and J R Bertino
Role of folylpolyglutamate synthetase and folylpolyglutamate hydrolase in methotrexate accumulation and polyglutamylation in childhood leukemia.
March 1999, Blood,
G S Longo, and R Gorlick, and W P Tong, and S Lin, and P Steinherz, and J R Bertino
The role of folylpolyglutamate synthetase and gamma-glutamyl hydrolase in altering cellular folyl- and antifolylpolyglutamates.
January 1987, Advances in enzyme regulation,
G S Longo, and R Gorlick, and W P Tong, and S Lin, and P Steinherz, and J R Bertino
Evaluation of Intracellular Metabolism of Methotrexate in Hepatocytes and Embryonic Kidney Cells based on Folylpolyglutamate Synthetase and Gamma-Glutamyl Hydrolase Expression.
January 2023, Current drug metabolism,
G S Longo, and R Gorlick, and W P Tong, and S Lin, and P Steinherz, and J R Bertino
Cellular pharmacokinetic of methotrexate and its modulation by folylpolyglutamate synthetase and γ-glutamyl hydrolase in tumor cells.
January 2024, PloS one,
G S Longo, and R Gorlick, and W P Tong, and S Lin, and P Steinherz, and J R Bertino
Folylpolyglutamate synthase and gamma-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity.
January 2008, Biochemical and biophysical research communications,
G S Longo, and R Gorlick, and W P Tong, and S Lin, and P Steinherz, and J R Bertino
Hepatic gamma-glutamyl cysteine synthetase and gamma-glutamyl transpeptidase activities in galactosamine-treated rats.
February 1995, Research communications in molecular pathology and pharmacology,
G S Longo, and R Gorlick, and W P Tong, and S Lin, and P Steinherz, and J R Bertino
Methotrexate intracellular disposition in acute lymphoblastic leukemia: a mathematical model of gamma-glutamyl hydrolase activity.
July 2002, Clinical cancer research : an official journal of the American Association for Cancer Research,
G S Longo, and R Gorlick, and W P Tong, and S Lin, and P Steinherz, and J R Bertino
Measurement of gamma-glutamyl transpeptidase and gamma-glutamylcysteine synthetase activities in cells.
January 1995, Methods in enzymology,
G S Longo, and R Gorlick, and W P Tong, and S Lin, and P Steinherz, and J R Bertino
In situ determination of the molecular weight of hepatic gamma-glutamyl transferase and gamma-glutamyl hydrolase activities.
September 1982, Biochimica et biophysica acta,
G S Longo, and R Gorlick, and W P Tong, and S Lin, and P Steinherz, and J R Bertino
Effects of overexpression of gamma-Glutamyl hydrolase on methotrexate metabolism and resistance.
June 2001, Cancer research,
Copied contents to your clipboard!