Enzymes involved in folate metabolism and its implication for cancer treatment

Abstract

BACKGROUND/OBJECTIVES: Folate plays a critical role in DNA synthesis and methylation. Intracellular folate homeostasis is maintained by the enzymes folylpolyglutamate synthase (FPGS) and γ-glutamyl hydrolase (GGH). FPGS adds glutamate residues to folate upon its entry into the cell through a process known as polyglutamylation to enhance folate retention in the cell and to maintain a steady supply of utilizable folate derivatives for folate-dependent enzyme reactions. Thereafter, GGH catalyzes the hydrolysis of polyglutamylated folate into monoglutamylated folate, which can subsequently be exported from the cell. The objective of this review is to summarize the scientific evidence available on the effects of intracellular folate homeostasis-associated enzymes on cancer chemotherapy. METHODS: This review discusses the effects of FPGS and GGH on chemosensitivity to cancer chemotherapeutic agents such as antifolates, such as methotrexate, and 5-fluorouracil. RESULTS AND DISCUSSION: Polyglutamylated (anti)folates are better substrates for intracellular folate-dependent enzymes and retained for longer within cells. In addition to polyglutamylation of (anti)folates, FPGS and GGH modulate intracellular folate concentrations, which are an important determinant of chemosensitivity of cancer cells toward chemotherapeutic agents. Therefore, FPGS and GGH affect chemosensitivity to antifolates and 5-fluorouracil by altering intracellular retention status of antifolates and folate cofactors such as 5,10-methylenetetrahydrofolate, subsequently influencing the cytotoxic effects of 5-fluorouracil, respectively. Generally, high FPGS and/or low GGH activity is associated with increased chemosensitivity of cancer cells to methotrexate and 5-fluorouracil, while low FPGS and/or high GGH activity seems to correspond to resistance to these drugs. Further preclinical and clinical studies elucidating the pharmocogenetic ramifications of these enzyme-induced changes are warranted to provide a framework for developing rational, effective, safe, and customized chemotherapeutic practices.

Changes in Body Composition Are Associated with Metabolic Changes and the Risk of Metabolic Syndrome

“…A previous study [ 20 ], using a representative sample of the Korean population from the Korean National Health and Nutrition Examination Survey (KNHANES), included multivariable linear regressions to derive the prediction equations for lean body mass index (LBMI), body fat mass index (BFMI), and appendicular skeletal mass index (ASMI). The following variables were used to derive the prediction equations: LBM, ASM, and BFM from whole-body dual-energy X-ray absorptiometry as dependent variables; and age, anthropometric measurements (height, body weight, and WC), blood test (serum creatinine levels), health-related behaviors (physical activity level, smoking status, and alcohol intake) as independent variables that can be related to factors that affect the body composition.…”

“…The ICCs were all >0.9. Each of the prediction equations showed a high predictive power for each body composition [ 20 ] (LBMI, ASMI, and BFMI) and a low bias in the Bland–Altman plot, with good agreement between the actual measured and predicted values estimated by the suggested prediction equation when applied in large-scale population studies. In this study, each participant’s LBMI (kg/m 2 ), BFMI (kg/m 2 ), and ASMI (kg/m 2 ) were calculated using the prediction equations presented in the Supplementary Data .…”

Elevated Expression of Gamma-Glutamyl Hydrolase Is Associated With Poor Prognosis and Altered Immune Signature in Uterine Corpus Endometrial Carcinoma

“…Therefore, the relative expression status of key enzymes involved in folate metabolism is worthy of study in gynecological tumors. GGH is a lysosomal enzyme that catalyzes the formation of monoglutamyl folate, which in turn influences DNA synthesis ( Kim, 2020 ). It is highly expressed in the human kidneys, liver, fetal tissue, and placenta, whereas its expression in the spleen, lungs, small intestine, and peripheral blood leukocytes is relatively low ( Yin et al, 2003 ).…”

“…Previous studies have shown that activation of MAPK, KRAS, or STAT3 pathways alter cell proliferation, apoptosis, and other biological behaviors that influence the occurrence and progression of UCEC ( Fathi et al, 2018 ; Li et al, 2018 ; Sideris et al, 2019 ). It was also reported that changes in the GGH-dependent regulation of folate concentration affect intracellular mitochondrial metabolism, gene expression, DNA methylation, and DNA repair efficiency ( Kim et al, 2015 ; Kim, 2020 ). Higher expression of GGH can accelerate the conversion of polyglutamyl folate to the monoglutamyl form and reduce total folate levels.…”

Melatonin modulates metabolic remodeling in HNSCC by suppressing MTHFD1L‐formate axis

“…19,20 Increased folate cycle-driven metabolism is important for maintaining the malignant phenotypes of cancer cells. 21,22 Methylenetetrahydrofolate dehydrogenase1 like (MTHFD1L) is a mitochondrial enzyme of the folate cycle that catalyzes the reaction of 10-formyltetrahydrofolate to formate and tetrahydrofolate (THF). Formate then enters the cytoplasmic compartment and serves as an important source of one-carbon donor molecules.…”