No abstract

Chronic smoking is associated with a lower systemic status of several B vitamins, reduced oral folate, and changes in folate form distribution in the mouth. However, the cytologic damage that is evident in the mouths of smokers does not correlate with oral folate status.

10-Formyltetrahydrofolate dehydrogenase (FDH) catalyzes the NADP؉ -dependent conversion of 10-formyltetrahydrofolate to CO 2 and tetrahydrofolate (THF) and is an abundant high affinity folatebinding protein. Although several activities have been ascribed to FDH, its metabolic role in folate-mediated one-carbon metabolism is not well understood. FDH has been proposed to: 1) inhibit purine biosynthesis by depleting 10-formyl-THF pools, 2) maintain cellular folate concentrations by sequestering THF, 3) deplete the supply of folateactivated one-carbon units, and 4) stimulate the generation of THFactivated one-carbon unit synthesis by channeling folate cofactors to other folate-dependent enzymes. The metabolic functions of FDH were investigated in neuroblastoma, which do not contain detectable levels of FDH. Both low and high FDH expression reduced total cellular folate concentrations by 60%, elevated rates of folate catabolism, and depleted cellular 5-methyl-THF and S-adenosylmethionine levels. Low FDH expression increased the formyl-THF/THF ratio nearly 10-fold, whereas THF accounted for nearly 50% of total folate in neuroblastoma with high FDH expression. FDH expression did not affect the enrichment of exogenous formate into methionine, serine, or purines and did not suppress de novo purine nucleotide biosynthesis. We conclude that low FDH expression facilitates the incorporation of one-carbon units into the one-carbon pool, whereas high levels of FDH expression deplete the folate-activated one-carbon pool by catalyzing the conversion of 10-formyl-THF to THF. Furthermore, FDH does not increase cellular folate concentrations by sequestering THF in neuroblastoma nor does it inhibit or regulate de novo purine biosynthesis. FDH expression does deplete cellular 5-methyl-THF and S-adenosylmethionine levels indicating that FDH impairs the folate-dependent homocysteine remethylation cycle. Tetrahydrofolate (THF)2 polyglutamates are cofactors that function as one-carbon donors and acceptors in a set of reactions known as folate-mediated one-carbon metabolism, which occurs both in the cytoplasm and in mitochondria (see Fig. 1) (1). THF cofactors carry onecarbon units at three oxidation states ranging from formate to methanol (2). The biologically active THF derivatives contain a reduced pteridine and a polyglutamate peptide consisting of five to eight glutamate residues linked by ␥-peptide bonds (3). Cytoplasmic folate-mediated onecarbon metabolism is required for the de novo synthesis of purines (supplies the carbon-2 and carbon-8 of the purine ring) and thymidylate (methylation of dUMP to dTMP), and also for remethylation of homocysteine to methionine (2, 3). Methionine can be converted to S-adenosylmethionine (SAM) and serve as a methyl donor for numerous methylation reactions, including the methylation of DNA, RNA, and proteins. Serine is a primary source of folate-activated one-carbon units (4). Cytoplasmic serine hydroxymethyltransferase (cSHMT) catalyzes the THF-dependent aldol cleavage of serine to methylene-THF and...