Phenotypes and circadian rhythm in utilization of formate in purine nucleotide biosynthesis de novo in adult humans

Academic Article

Abstract

  • Aims: Folate coenzymes and dependent enzymes introduce one carbon units at positions 2 (C2) and 8 (C8) of the purine ring during de novo biosynthesis. Formate is one source of one-carbon units. Although much is known about lower organisms, little data exists describing formate utilization for purine biosynthesis in humans. Main methods: Mass-spectrometric analysis of urinary uric acid, the final purine catabolite, following 1.0 g oral doses of sodium [13C] formate was performed and detected 13C enrichment at C2 and C8 separately. Key findings: Three phenotypes were suggested. One incorporates 13C 0.72 to 2.0% into C2 versus only 0 to 0.07% into C8. Another incorporates only 0 to 0.05% 13C into C2 or C8. A third phenotype incorporates 13C into C8 (0.15%) but C 2 incorporation (0.44%) is still greater. In subjects who incorporated 13C formate into C2, peak enrichment occurred in voids from 8-12 h (24 h clock) suggesting a circadian rhythm. Significance: Evidence that mammalian liver introduces C8 and that C2 is introduced in a non-hepatic site would explain our results. Our data are not similar to those in non-mammalian organisms or cells in culture and are not consistent with the hypothesis that formate from folate-dependent metabolism in mitochondria is a major one carbon source for purine biosynthesis. Timing of peak 13C enrichment at C2 corresponds to maximal DNA synthesis in human bone marrow. Phenotypes may explain the efficacy (or lack of) of certain anticancer and immunosuppressive drugs. © 2011 Elsevier Inc.
  • Authors

    Published In

  • Life Sciences  Journal
  • Digital Object Identifier (doi)

    Author List

  • Baggott JE; Gorman GS; Morgan SL
  • Start Page

  • 688
  • End Page

  • 692
  • Volume

  • 88
  • Issue

  • 15-16