Figure: folate metabolism

Introduction

Metabolism of folate centers about tetrahydrofolate which is involved two different metabolic pathways:

• methionine metabolism
• DNA synthesis

Tetrahydrofolate (THF) is an activated carrier of one carbon units.

Other carriers included S-adenosylmethionine (SAM, a carrier of -CH3) & biotin (a carrier of -CO2).

The carbon carried by THF is bound to N5 or N10 of THF or both.

The most reduced form carries a -CH3 group; the intermediate form carries a methylene group; the most oxidized forms carry a methenyl, formyl or formino group.

The one carbon units carried by THF are interconvertible.

The THF derivatives serve as methyl donors in a variety of biosyntheses:

• N5-methyl-THF -> homocysteine to methionine
• N5,N10-methylene-THF -> dUMP to dTMP & in glycine biosynthesis
• N10-formyl-THF -> biosynthesis of purines

Biochemistry

• methionine metabolism 5
  • enzyme methionine synthase
  • substrate homocysteine + 5-methyltetrahydrofolate
  • product methionine + tetrahydrofolate
• methionine metabolism 6
  • enzyme serine hydroxymethyltransferase
  • substrate tetrahydrofolate + serine
  • product N5,N10-methylene tetrahydrofolate + glycine
• methionine metabolism 7
  • enzyme methylenetetrahydrofolate reductase
  • substrate N5,N10-methylene tetrahydrofolate + NADPH
  • product N5-methyl tetrahydrofolate + NAD+
• folate metabolism 1
  • enzyme: thymidylate synthase
  • substrate: deoxyuridine monophosphate + N5,N10-methylene tetrahydrofolate
  • product: thymidine monophosphate + dihydrofolate
  • generation of thymidylate for DNA synthesis
• folate metabolism 2
  • enzyme: dihydrofolate reductase
  • substrate: dihydrofolate + NADPH + H+
  • product: tetrahydrofolate + NADP+
  • regeneration of tetrahydrofolate using reducing equivalents from NADPH
• folate metabolism 3
  • enzyme: amine oxidoreductase
  • substrate: folate + NADPH + H+
  • product: dihydrofolate + NADP+)
• folate metabolism 4
  • enzyme: transferase
  • substrate: tetrahydrofolate + formate + ATP
  • product: N10-formyl tetrahydrofolate + ADP
• folate metabolism 5
  • enzyme: isomerase
  • substrate: N10-formyl tetrahydrofolate
  • product: N5-formyl tetrahydrofolate
• folate metabolism 6
  • enzyme: dehydrogenase
  • substrate: N5,N10-methylene tetrahydrofolate + NADP+
  • product: N5,N10-methenyl tetrahydrofolate + NADPH + H+
• folate metabolism 7
  • enzyme: hydrolase
  • substrate: N5,N10-methenyl tetrahydrofolate + ADP + H2O
  • product: N10-formyl tetrahydrofolate + ATP
• folate metabolism 8
  • enzyme:bstrate aminotransferase
  • substrate: N5,N10-methenyl tetrahydrofolate + NH3
  • product: N5-formimino tetrahydrofolate