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Literature summary for 6.3.2.17 extracted from

  • Wojtuszkiewicz, A.; Raz, S.; Stark, M.; Assaraf, Y.G.; Jansen, G.; Peters, G.J.; Sonneveld, E.; Kaspers, G.J.; Cloos, J.
    Folylpolyglutamate synthetase splicing alterations in acute lymphoblastic leukemia are provoked by methotrexate and other chemotherapeutics and mediate chemoresistance (2016), Int. J. Cancer, 138, 1645-1656 .
    View publication on PubMed

Cloned(Commentary)

Cloned (Comment) Organism
gene FPGS, DNA and amino acid sequence determination and analysis of splicing variants, quantitative RT- and real-time-PCR analyses of FPGS enzyme expression and splicing patterns. FPGS splicing alterations are abundant in blasts of acute lymphoblastic leukemia (ALL) patients, overview Homo sapiens

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate Homo sapiens
-
ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens
-
-
-

Source Tissue

Source Tissue Comment Organism Textmining
B-lymphocyte
-
Homo sapiens
-
bone marrow cell
-
Homo sapiens
-
CCRF-CEM cell
-
Homo sapiens
-
CEM cell
-
Homo sapiens
-
culture condition:CD34+ cell
-
Homo sapiens
-
leukemia cell
-
Homo sapiens
-
monocyte
-
Homo sapiens
-
peripheral blood cell
-
Homo sapiens
-
T-lymphocyte
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + tetrahydropteroyl-[gamma-Glu]n + L-glutamate
-
Homo sapiens ADP + phosphate + tetrahydropteroyl-[gamma-Glu]n+1
-
?

Synonyms

Synonyms Comment Organism
Folylpolyglutamate synthetase
-
Homo sapiens
FPGS
-
Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
37
-
assay at Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
8.8 8.9 assay at Homo sapiens

Cofactor

Cofactor Comment Organism Structure
ATP
-
Homo sapiens

General Information

General Information Comment Organism
malfunction a spectrum of FPGS splicing alterations occur in humans, including exon skipping and intron retention, all of which prove to frequently emerge in both pediatric and adult leukemia patient specimens. These splicing alterations result in loss of FPGS function. Pulse-exposure of leukemia cells to antifolates and other chemotherapeutics markedly enhance the prevalence of several FPGS splicing alterations in antifolate-resistant cells, but not in their parental antifolate-sensitive counterparts. An assortment of deleterious FPGS splicing alterations may constitute a mechanism of antifolate resistance in childhood acute lymphoblastic leukemia (ALL) Homo sapiens
additional information structural and functional consequences of splicing alterations on FPGS protein, the relationship between FPGS splicing alterations and MTX resistance, overview Homo sapiens
physiological function the cytotoxic activity of various antifolates is largely dependent on the activity of folylpolyglutamate synthetase (FPGS). The latter enzyme catalyzes the addition of multiple glutamate residues (i.e. polyglutamylation) to both folates and antifolates upon their entry into the cell. This unique metabolic conversion dramatically enhances the intracellular retention of antifolates including methotreaxate (MTX) as the polyglutamate forms of antifolates are no longer substrates of various efflux transporters. Polyglutamylation also decreases the Ki of MTX and other antifolates like pemetrexed to their target enzymes including dihydrofolate reductase and thymidylate synthase Homo sapiens