Flavin-dependent thymidylate synthase: N5 of flavin as a Methylene carrier

Abstract

Thymidylate is synthesized de novo in all living organisms for replication of genomes. The chemical transformation is reductive methylation of deoxyuridylate at C5 to form deoxythymidylate. All eukaryotes including humans complete this well-understood transformation with thymidylate synthase utilizing 6R-N5-N10-methylene-5,6,7,8-tetrahydrofolate as both a source of methylene and a reducing hydride. In 2002, flavin-dependent thymidylate synthase was discovered as a new pathway for de novo thymidylate synthesis. The flavin-dependent catalytic mechanism is different than thymidylate synthase because it requires flavin as a reducing agent and methylene transporter. This catalytic mechanism is not well-understood, but since it is known to be very different from thymidylate synthase, there is potential for mechanism-based inhibitors that can selectively inhibit the flavin-dependent enzyme to target many human pathogens with low host toxicity.

Differences in Thermal Structural Changes and Melting Between Mesophilic and Thermophilic Dihydrofolate Reductase Enzymes

“…The global conformational rigidity enhancement from Ec to TmDHFR is thus directly connected to the increased thermal stability of TmDHFR, but it cannot be the main cause of the latter's much lower activity, as already suggested by experimental studies 32 , as well as very recent simulations 39 . (We note that, not surprisingly, in T. maritima, the product of DHFR activity (tetrahydrofolate) is mainly supplied by another enzyme, the flavin-dependent thymidylate synthase 82 . )…”

Reseasrch Pogress for Thymidylate Synthase and Inhibitors in Cancers Couple in Chemical Structures

“…Thymidylate synthase (TS); drug target suitable for TS inhibitors, play a necessary role in DNA and deoxythymidine monophosphate (dTMP) synthesis, is a protein that contained genes of the nucleotide polymorphism which influenced cancer development, and commonly referred to as bi-substrate nucleotide enzyme (Khairullina et al, 2018;Karunaratne et al, 2017;Feng et al, 2019). Researchers derived cancer drug target from detection of gene(s) that changes without modification; epigenetic study, of which most studies indited Histone lysine and histone demethylase in human cancer (Yang et al, 2019;Ma QS et al, 2019).…”