Folate-Dependent Purine Nucleotide Biosynthesis in Humans

Area of Science:

• Biochemistry
• Metabolic pathways
• Enzymology

Background:

• De novo purine nucleotide biosynthesis (PNB) requires two folate-dependent transformylases: GAR and AICAR transformylases.
• These enzymes utilize 10-formyltetrahydrofolate (10-formyl-H4folate) for introducing carbons into the purine ring.
• Carbon sources for 10-formyl-H4folate include glycine, serine, histidine, and formate, with prior belief in a general folate pool.

Purpose of the Study:

• To investigate the specific carbon sources for GAR and AICAR transformylases in human purine biosynthesis.
• To elucidate the potential channeling of folate metabolites to these transformylases.
• To understand the implications for timing PNB-blocking drugs in cancer and autoimmune disease treatment.

Main Methods:

• Human studies were conducted to trace carbon incorporation into purine ring.
• Analysis of urinary uric acid for incorporation of histidine and formate.
• Postulation of enzyme complex formation and folate metabolite utilization.

Main Results:

• Glycine exclusively provides carbon for GAR transformylase (C8), while histidine and formate are predominant for AICAR transformylase (C2).
• Evidence suggests distinct folate pools rather than a general pool for C8 and C2 synthesis.
• GAR transformylase may be in a complex with TFM and serine hydroxymethyltransferase for carbon channeling.
• AICAR transformylase can utilize both 10-formyl-H4folate and 10-formyldihydrofolate (10-formyl-H2folate).

Conclusions:

• The study reveals specific carbon channeling for purine biosynthesis, challenging the concept of a single 10-formyl-H4folate pool.
• GAR transformylase utilizes glycine and serine carbons, potentially through enzyme complexation, while AICAR transformylase uses histidine and formate.
• The observed circadian rhythm in histidine and formate incorporation into uric acid may inform optimal drug administration timing for PNB-blocking therapies.