An alternative flavin-dependent mechanism for thymidylate synthesis.
Although deoxythymidylate cannot be provided directly by ribonucleotide reductase, the gene encoding thymidylate synthase ThyA is absent from the genomes of a large number of nonsymbiotic microbes. We show that ThyX (Thy1) proteins of previously unknown function form a large and distinct class of thymidylate synthases. ThyX has a wide but sporadic phylogenetic distribution, almost exclusively limited to microbial genomes lacking thyA. ThyX and ThyA use different reductive mechanisms, because ThyX activity is dependent on reduced flavin nucleotides. Our findings reveal complexity in the evolution of thymidine in present-day DNA. Because ThyX proteins are found in many pathogenic microbes, they present a previously uncharacterized target for antimicrobial compounds.
Myllykallio
Hannu
H
Institut de Génétique et Microbiologie, CNRS UMR 8621, Université Paris-Sud, Orsay, France. hannu.myllykallio@igmors.u-psud.fr
Lipowski
Gerard
G
Leduc
Damien
D
Filee
Jonathan
J
Forterre
Patrick
P
Liebl
Ursula
U
D002384:Catalysis; D003856:Deoxyuracil Nucleotides / Q000378:metabolism; D004579:Electron Transport; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D005486:Flavin Mononucleotide / Q000378:metabolism; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism*; D022761:Gene Transfer, Horizontal; D019766:Genes, Archaeal; D005798:Genes, Bacterial; D016480:Helicobacter pylori / Q000201:enzymology* / Q000235:genetics; D008970:Molecular Weight; D010802:Phylogeny; D019711:Pyrococcus / Q000201:enzymology* / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D013763:Tetrahydrofolates / Q000378:metabolism; D013938:Thymidine Monophosphate / Q000096:biosynthesis*; D013940:Thymidylate Synthase / Q000737:chemistry / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism*; D014169:Transformation, Bacterial; D014542:Uridine Monophosphate / Q000378:metabolism
D003856:Deoxyuracil Nucleotides; D011994:Recombinant Proteins; D013763:Tetrahydrofolates; D005182:Flavin-Adenine Dinucleotide; D013938:Thymidine Monophosphate; C030371:5,6,7,8-tetrahydrofolic acid; D005486:Flavin Mononucleotide; C007267:2'-deoxyuridylic acid; D014542:Uridine Monophosphate; D013940:Thymidylate Synthase