Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/s0076-6879(85)13029-6 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Folylpolyglutamate synthetase inactivation in relapsed ALL induces a druggable folate metabolic vulnerability.
Drug Resist Updat
November 2024
Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Fujian Children's Hospital, Fujian Branch of Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Fuzhou, China; Department of Pharmacology and Chemical Biology, School of Basic Medicine and Shanghai Collaborative Innovation Center for Translational Medicine Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address:
Aims: The antifolate methotrexate (MTX) is an anchor drug used in acute lymphoblastic leukemia (ALL) with poorly understood chemoresistance mechanisms in relapse. Herein we find decreased folate polyglutamylation network activities and inactivating FPGS mutations, both of which could induce MTX resistance and folate metabolic vulnerability in relapsed ALL.
Methods: We utilized integrated systems biology analysis of transcriptomic and genomic data from relapse ALL cohorts to infer hidden ALL relapse drivers and related genetic alternations during clonal evolution.
Role of Mitochondrial and Cytosolic Folylpolyglutamate Synthetase in One-Carbon Metabolism and Antitumor Efficacy of Mitochondrial-Targeted Antifolates.
Mol Pharmacol
September 2024
Department of Oncology (C.O., M.S., S.K., X.B., J.L., L.H.M., Z.H.) and Department of Pharmacology (L.H.M.), Wayne State University School of Medicine, Detroit, Michigan; Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania (M.J.N., K.S., T.M., A.S., A.G.); Department of Chemistry, Indiana University, Bloomington, Indiana (J.M.K., C.E.D.); and Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan (S.K., X.B., J.L., L.H.M., Z.H.)
Folate-dependent one-carbon (C1) metabolism encompasses distinct cytosolic and mitochondrial pathways connected by an interchange among serine, glycine, and formate. In both the cytosol and mitochondria, folates exist as polyglutamates, with polyglutamylation catalyzed by folylpolyglutamate synthetase (FPGS), including cytosolic and mitochondrial isoforms. Serine is metabolized by serine hydroxymethyltransferase (SHMT)2 in the mitochondria and generates glycine and C1 units for cellular biosynthesis in the cytosol.
View Article and Find Full Text PDFCellular pharmacokinetic of methotrexate and its modulation by folylpolyglutamate synthetase and γ-glutamyl hydrolase in tumor cells.
PLoS One
June 2024
Pharmacy Department, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong Province, China.
Background And Purpose: Clinical studies showed that prolonged infusion of methotrexate (MTX) leads to more severe adverse reactions than short infusion of MTX at the same dose. We hypothesized that it is the saturation of folate polyglutamate synthetase (FPGS) at high MTX concentration that limits the intracellular synthesis rate of methotrexate polyglutamate (MTX-PG). Due to a similar accumulation rate, a longer infusion duration may increase the concentration of MTX-PG and, result in more serious adverse reactions.
View Article and Find Full Text PDFPoly-γ-glutamylation of biomolecules.
Nat Commun
February 2024
School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
Poly-γ-glutamate tails are a distinctive feature of archaeal, bacterial, and eukaryotic cofactors, including the folates and F. Despite decades of research, key mechanistic questions remain as to how enzymes successively add glutamates to poly-γ-glutamate chains while maintaining cofactor specificity. Here, we show how poly-γ-glutamylation of folate and F by folylpolyglutamate synthases and γ-glutamyl ligases, non-homologous enzymes, occurs via processive addition of L-glutamate onto growing γ-glutamyl chain termini.
View Article and Find Full Text PDFMethotrexate-based PROTACs as DHFR-specific chemical probes.
Cell Chem Biol
February 2024
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA; Metabolic Medicine Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address:
Methotrexate (MTX) is a tight-binding dihydrofolate reductase (DHFR) inhibitor, used as both an antineoplastic and immunosuppressant therapeutic. MTX, like folate undergoes folylpolyglutamate synthetase-mediated γ-glutamylation, which affects cellular retention and target specificity. Mechanisms of MTX resistance in cancers include a decrease in MTX poly-γ-glutamylation and an upregulation of DHFR.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!