PROSITE documentation PDOC51331 [for PROSITE entry PS51331]

Flavin-dependent thymidylate synthase (thyX) domain profile

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, that methylates dUMP at position 5 of the pyrimidine ring. Two structurally and mechanistically distinct classes of thymidylate synthases exist. The well studied thyA proteins (EC 2.1.1.45) catalyze the reductive methylation reaction of dUMP, with methylenetetrahydrofolate (CH(2)H(4)folate) serving as one-carbon donor and as source of reductive power (see <PDOC00086>). On the other hand the thyX (EC 2.1.1.148) 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 catalyzed 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 [1,2].

The thyX domain consists of a central α/β domain and two α helices located away from the central domain (see <PDB:1KQ4>). The central domain is made up of a five-stranded antiparallel β-sheet, flanked by 6 α-helices on one side of the sheet [2,3,4]. Sequence alignments revealed a specific sequence motif R-H-R-X(7)-S (thyX motif) common to this family of proteins [1].

The profile we developed covers the entire thyX domain.