Thymidylate synthase ThyX (IPR003669)

Short name: Thymidylate_synthase_ThyX

Overlapping homologous superfamilies

Family relationships



All cellular organisms need thymidylate (dTMP) for the replication of their chromosomes, as dTMP is required for the biosynthesis of dTTP, a building block of DNA. Cells can produce thymidylate either de novo from dUMP or incorporate thymidine using thymidine kinase. The de novo pathway of dTMP synthesis requires a specific enzyme, thymidylate synthase, which methylates dUMP at position 5 of the pyrimidine ring. There are two pathways for thymidylate synthesis, each utilising a different thymidylate synthase enzyme: ThyA (EC: and ThyX (EC: [PMID: 15046578]. Both enzymes convert dUMP to dTMP, but there is no sequence identity between the two enzymes, and their mechanisms of action differ [PMID: 15123820]. Only ThyX uses FAD as cofactor.

The well studied thyA proteins catalyse the reductive methylation reaction of dUMP, with methylenetetrahydrofolate (CH(2)H(4)folate) serving as one-carbon donor and as source of reductive power. On the other hand the thyX family of thymidylate synthases contains FAD that is tightly bound by a novel fold. FAD mediates hydride transfer from NADPH during catalysis. Consequently, in the reaction catalysed by thyX, CH(2)H(4)folate serves only as a carbon donor and tetrahydrofolate (and not dihydrofolate as in the case of thyA) is produced [PMID: 12029065, PMID: 16707489].

The thyX domain consists of a central alpha/beta domain and two alpha-helices located away from the central domain. The central domain is made up of a five-stranded antiparallel beta-sheet, flanked by six alpha-helices on one side of the sheet [PMID: 16707489, PMID: 12211025, PMID: 12791256]. Sequence alignments reveal a specific sequence motif R-H-R-X(7)-S (thyX motif) common to this family of proteins [PMID: 12029065].

This entry represents the flavin-dependent enzyme ThyX, which is a homotetramer bound to four FAD molecules. Under oxygen-limiting conditions, thyX can complement a thyA mutation [PMID: 12791256].

GO terms

Biological Process

GO:0006231 dTMP biosynthetic process

Molecular Function

GO:0050660 flavin adenine dinucleotide binding
GO:0050797 thymidylate synthase (FAD) activity

Cellular Component

No terms assigned in this category.

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.
PROSITE profiles