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PROSITE documentation PDOC51331

Flavin-dependent thymidylate synthase (thyX) domain profile





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, 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.

Note:

ThyX proteins are also known as thy1 or thymidilate synthase- complementing proteins [1,4].

Last update:

September 2007 / First entry.

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Technical section

PROSITE method (with tools and information) covered by this documentation:

THYX, PS51331; Flavin-dependent thymidylate synthase (thyX) domain profile  (MATRIX)


References

1AuthorsMyllykallio H. Lipowski G. Leduc D. Filee J. Forterre P. Liebl U.
TitleAn alternative flavin-dependent mechanism for thymidylate synthesis.
SourceScience 297:105-107(2002).
PubMed ID12029065
DOI10.1126/science.1072113

2AuthorsGraziani S. Bernauer J. Skouloubris S. Graille M. Zhou C.-Z. Marchand C. Decottignies P. van Tilbeurgh H. Myllykallio H. Liebl U.
TitleCatalytic mechanism and structure of viral flavin-dependent thymidylate synthase ThyX.
SourceJ. Biol. Chem. 281:24048-24057(2006).
PubMed ID16707489
DOI10.1074/jbc.M600745200

3AuthorsKuhn P. Lesley S.A. Mathews I.I. Canaves J.M. Brinen L.S. Dai X. Deacon A.M. Elsliger M.A. Eshaghi S. Floyd R. Godzik A. Grittini C. Grzechnik S.K. Guda C. Hodgson K.O. Jaroszewski L. Karlak C. Klock H.E. Koesema E. Kovarik J.M. Kreusch A.T. McMullan D. McPhillips T.M. Miller M.A. Miller M. Morse A. Moy K. Ouyang J. Robb A. Rodrigues K. Selby T.L. Spraggon G. Stevens R.C. Taylor S.S. van den Bedem H. Velasquez J. Vincent J. Wang X. West B. Wolf G. Wooley J. Wilson I.A.
TitleCrystal structure of thy1, a thymidylate synthase complementing protein from Thermotoga maritima at 2.25 A resolution.
SourceProteins 49:142-145(2002).
PubMed ID12211025
DOI10.1002/prot.10202

4AuthorsMathews I.I. Deacon A.M. Canaves J.M. McMullan D. Lesley S.A. Agarwalla S. Kuhn P.
TitleFunctional analysis of substrate and cofactor complex structures of a thymidylate synthase-complementing protein.
SourceStructure 11:677-690(2003).
PubMed ID12791256



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