Folate‑Dependent Thymidylate‑Forming Enzymes: Parallels between DNA and RNA Metabolic Enzymes and Evolutionary Implications
Hannu Myllykallio, Stephane Skouloubris, Henri Grosjean and Ursula Liebl
Enzymatic methylation of the C5 atom of uridyl to form (ribo)thymidyl occurs during the metabolism of DNA and RNA in all organisms. The first enzyme found to catalyze this fundamental reaction was thymidylate synthase ThyA that uses methylene tetrahydrofolate as carbon source and reducing agent to form thymidylate, an essential DNA precursor. Early work also indicated that the S‑adenosyl‑L‑methionine‑dependent methyltransferase TrmA catalyzes the site‑specific formation of 5‑methyluridine (m5U) in the so‑called T‑Psi‑loop (position 54) of tRNA. Recently, two novel flavoproteins were discovered that catalyze the formation of thymidyl groups using CH2‑H4folate as the carbon donor. The two thymidylate synthases (ThyA and ThyX) and ribothymidylate synthases (TrmA and TrmFO) show a mutually exclusive distribution, as almost always only one is present in a given organism. Information obtained from genetic, biochemical, structural and bioinformatics studies allows to conclude that, despite their reaction products are ubiquitous, these (ribo)thymidylate forming enzymes are not evolutionarily related. The discovery of these novel enzymes provides an excellent example of the evolutionary convergence and versatility of the DNA/RNA modification machinery resulting from molecular tinkering.