title: Folate-Dependent Purine Nucleotide Biosynthesis in Humans.
abstract: Purine nucleotide biosynthesis de novo (PNB) requires 2 folate-dependent transformylases-5'-phosphoribosyl-glycinamide (GAR) and 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR) transformylases-to introduce carbon 8 (C8) and carbon 2 (C2) into the purine ring. Both transformylases utilize 10-formyltetrahydrofolate (10-formyl-H4folate), where the formyl-carbon sources include ring-2-C of histidine, 3-C of serine, 2-C of glycine, and formate. Our findings in human studies indicate that glycine provides the carbon for GAR transformylase (exclusively C8), whereas histidine and formate are the predominant carbon sources for AICAR transformylase (C2). Contrary to the previous notion, these carbon sources may not supply a general 10-formyl-H4folate pool, which was believed to equally provide carbons to C8 and C2. To explain these phenomena, we postulate that GAR transformylase is in a complex with the trifunctional folate-metabolizing enzyme (TFM) and serine hydroxymethyltransferase to channel carbons of glycine and serine to C8. There is no evidence for channeling carbons of histidine and formate to AICAR transformylase (C2). GAR transformylase may require the TFM to furnish 10-formyl-H4folate immediately after its production from serine to protect its oxidation to 10-formyldihydrofolate (10-formyl-H2folate), whereas AICAR transformylase can utilize both 10-formyl-H2folate and 10-formyl-H4folate. Human liver may supply AICAR to AICAR transformylase in erythrocytes/erythroblasts. Incorporation of ring-2-C of histidine and formate into C2 of urinary uric acid presented a circadian rhythm with a peak in the morning, which corresponds to the maximum DNA synthesis in the bone marrow, and it may be useful in the timing of the administration of drugs that block PNB for the treatment of cancer and autoimmune disease.
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Baggott
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL tamurat@uab.edu.
authors.forename: Tsunenobu
authors.initials: T
authors.lastname: Tamura
mesh_terms: D002244:Carbon / Q000378:metabolism; D002940:Circadian Rhythm; D005492:Folic Acid / Q000008:administration & dosage*; D005561:Formates / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D006801:Humans; D002955:Leucovorin / Q000031:analogs & derivatives / Q000378:metabolism; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase / Q000378:metabolism; D051026:Phosphoribosylglycinamide Formyltransferase / Q000378:metabolism; D011685:Purine Nucleotides / Q000096:biosynthesis*; D012694:Serine / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism
chemical_list: D005561:Formates; D011685:Purine Nucleotides; C030544:formic acid; D014527:Uric Acid; C010161:10-formyltetrahydropteroylglutamic acid; D012694:Serine; D002244:Carbon; D005492:Folic Acid; D051026:Phosphoribosylglycinamide Formyltransferase; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D002955:Leucovorin; D005998:Glycine
keywords: folate; formate; glycine; histidine; serine; uric acid