Disorders of Folate Metabolism and Transport

Summary

Folates play an essential role in one-carbon methyl transfer reactions, mediating several biological processes including DNA synthesis, regulation of gene expression through methylation and formylation reactions, embryonic central nervous system development, synthesis and breakdown of amino acids, and synthesis of thymidines, purines, and neurotransmitters (Blount et al. 1997; Linhart et al. 2009; Ghoshal et al. 2006; Pogribny et al. 2008; Fournier et al. 2002). In mammals, folates are mostly derived from exogenous sources as folate is stored in the liver for few months. The biologically active folate derivative is 5,6,7,8-tetrahydrofolate (THF). Dietary folate is absorbed in the intestine via the proton-coupled folate transporter (PCFT). In the cytoplasm, interconversion of 5,10-methylene-THF and 5,10-methenyl-THF, interconversion of 5,10-methenyl-THF and 10-formyl-THF, and reaction of THF with formate to synthesize 10-formyl-THF are mediated by the MTHFD1 gene that encodes a trifunctional protein. Metabolism of 5,10-methylene-THF to 5-methyl-THF in the liver is catalyzed by methylene-THF reductase (MTHFR). 5-Methyl-THF is then widely distributed in the bloodstream. The transport of 5-methyl-THF inside the cells is mediated by different transport systems that include the proton-coupled folate transporter (PCFT), the reduced folate carrier 1 (RFC1), and the two GPI-anchored receptors, folate receptor alpha (FRα) and beta (FRβ) (Matherly and Goldman 2003). The physiological form of folate, 5-methyl-THF, is actively transported to the central nervous system by FRα-mediated endocytosis in choroid epithelial cells, reaching a higher concentration in the cerebrospinal fluid when compared to the serum. FRα is a high-affinity low-capacity receptor that functions at a nanomolar range of extracellular folate concentrations (Weitman et al. 1992). Glutamate formiminotransferase-cyclodeaminase (FTCD) is a bifunctional enzyme that catalyzes the folate-dependent degradation of N-formimino-l-glutamic acid (FIGLU) to form 5,10-methenyltetrahydrofolate, glutamate, and ammonia, the final two reactions of the pathway responsible for the degradation of l-histidine. Thus far, seven different inherited disorders of folate metabolism are known which lead to folate deficiency including hereditary folate malabsorption, folate receptor alpha deficiency, 5,10-methylenete-THF reductase deficiency, 5,10-methenyl-THF synthetase deficiency, dihydrofolate reductase deficiency, and 5,10-methylenete-THF dehydrogenase deficiency (Watkins et al. 2011; Watkins and Rosenblatt 2012). Reduced folate carrier deficiency presenting with recurrent megaloblastic anemia has been reported very recently in a single patient carrying a homozygous deletion of the Phe212 residue (Svaton et al. 2020). Glutamate formimino transferase deficiency is considered as a non-disease, despite being former characterized by megaloblastic anemia, mental retardation and elevated urine FIGLU following a histidine load (Hilton et al. 2003). Mitochondrial 10-formyltetrahydrofolate dehydrogenase, encoded by ALDH1L2, affects mitochondrial pool of metabolites relevant to beta-oxidation of fatty acids and presents with neuro-ichthyotic syndrome (Sarret et al. 2019). For more details on FIGLU-uria, see Chap. 71.