Pathway · 6 proteins

Folate and pterin chemistry

Build and interconvert one-carbon carriers.

How it works

The pterin ring of folate is built first, starting from a 6-pyruvoyl tetrahydropterin synthase family protein, and is then decorated with p-aminobenzoate and a polyglutamate tail by folylpolyglutamate/dihydrofolate synthase.
FolD, the bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, interconverts the methylene, methenyl and formyl forms of tetrahydrofolate, while methylenetetrahydrofolate reductase produces 5-methyl-THF for methionine synthesis.
A 5-formyltetrahydrofolate cyclo-ligase and a formyltetrahydrofolate deformylase add and remove the formyl form, and TrmFO uses methylene-THF to modify uracil-54 in tRNA. One carrier pool therefore serves biosynthesis and RNA modification, and its units arrive at different oxidation levels.

Grouped by the atlas’s curated pathway map. The table order is not a proven reaction order.

Protein	EC	Reaction (UniProt)	Metal or cluster	Amino acids	Certainty
5,10-methylenetetrahydrofolate reductase	1.5.1.54	(6S)-5-methyl-5,6,7,8-tetrahydrofolate + NAD(+) = (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NADH + H(+)	—	296	Step named
5-formyltetrahydrofolate cyclo-ligase	6.3.3.2	(6S)-5-formyl-5,6,7,8-tetrahydrofolate + ATP = (6R)-5,10-methenyltetrahydrofolate + ADP + phosphate	Mg(2+)	186	Step named
Formyltetrahydrofolate deformylase	3.5.1.10	(6R)-10-formyltetrahydrofolate + H2O = (6S)-5,6,7,8-tetrahydrofolate + formate + H(+)	—	283	Step named
Bifunctional protein FolD	1.5.1.5; 3.5.4.9	(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NADP(+) = (6R)-5,10-methenyltetrahydrofolate + NADPH	—	291	Step named
tetrahydrofolate synthase	6.3.2.17	(6S)-5,6,7,8-tetrahydrofolyl-(gamma-L-Glu)(n) + L-glutamate + ATP = (6S)-5,6,7,8-tetrahydrofolyl-(gamma-L-Glu)(n+1) + ADP + phosphate + H(+)	Mg(2+)	410	Step named
6-carboxy-5,6,7,8-tetrahydropterin synthase	4.1.2.50	7,8-dihydroneopterin 3'-triphosphate + H2O = 6-carboxy-5,6,7,8-tetrahydropterin + triphosphate + acetaldehyde + 2 H(+)	Zn(2+)	162	Step named

These proteins are described under another pathway, but also take part here.

Protein	EC	Reaction (UniProt)	Metal or cluster	Amino acids	Certainty
Methylenetetrahydrofolate--tRNA-(uracil-5-)-methyltransferase TrmFOHome: RNA maturation	2.1.1.74	uridine(54) in tRNA + (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NADH + H(+) = 5-methyluridine(54) in tRNA + (6S)-5,6,7,8-tetrahydrofolate + NAD(+)	—	445	Step named

Could folate and its pterin ring have been available before this pathway existed?

1940sFolate is first isolated, from green leaves, liver and yeast.Horton et al., Principles of Biochemistry, p. 291

Naturalistic proposal

None of the books searched describes a prebiotic route to folate or to pterins.

Design analysis

Bacteria make folate from three parts: a pterin, para-aminobenzoic acid and glutamate. Each part has its own route, and all three must come together.

Sulfa drugs work because they block this assembly in bacteria; without folate, a cell cannot make DNA and RNA letters.

From the books: Horton et al., Principles of Biochemistry, p. 291; Slonczewski & Foster, Microbiology, p. 1105.

Atlas pathway grouping from the VF5 reference-genome system map (Deckert et al. 1998; Braakman & Smith 2014)