Family

Thymidylate synthase ThyX (IPR003669)

Short name: Thymidylate_synthase_ThyX

Family relationships

None.

Description

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:2.1.1.45) and ThyX (EC:2.1.1.148) [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.
HAMAP
Pfam
TIGRFAMs
SUPERFAMILY
PROSITE profiles