title: Flavin-Dependent Thymidylate Synthase as a New Antibiotic Target.
abstract: In humans de novo synthesis of 2'-deoxythymidine-5'-monophosphate (dTMP), an essential building block of DNA, utilizes an enzymatic pathway requiring thymidylate synthase (TSase) and dihydrofolate reductase (DHFR). The enzyme flavin-dependent thymidylate synthase (FDTS) represents an alternative enzymatic pathway to synthesize dTMP, which is not present in human cells. A number of pathogenic bacteria, however, depend on this enzyme in lieu of or in conjunction with the analogous human pathway. Thus, inhibitors of this enzyme may serve as antibiotics. Here, we review the similarities and differences of FDTS vs. TSase including aspects of their structure and chemical mechanism. In addition, we review current progress in the search for inhibitors of flavin dependent thymidylate synthase as potential novel therapeutics.
authors.affiliation: Department of Chemistry, The University of Iowa, Iowa City, IA 52242-1727, USA. michael-a-choi@uiowa.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Chemistry, The University of Iowa, Iowa City, IA 52242-1727, USA. kalaniudara-karunaratne@uiowa.edu.
authors.forename: Kalani
authors.initials: K
authors.lastname: Karunaratne
authors.affiliation: Department of Chemistry, The University of Iowa, Iowa City, IA 52242-1727, USA. amnon-kohen@uiowa.edu.
authors.forename: Amnon
authors.initials: A
authors.lastname: Kohen
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000627:therapeutic use*; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology* / Q000472:pathogenicity; D005415:Flavins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007239:Infections / Q000188:drug therapy / Q000201:enzymology / Q000382:microbiology; D007700:Kinetics; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013938:Thymidine Monophosphate / Q000096:biosynthesis / Q000737:chemistry; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D005415:Flavins; D009097:Multienzyme Complexes; C056930:thymidylate synthase-dihydrofolate reductase; D013938:Thymidine Monophosphate; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase
keywords: antibiotic; enzyme; flavin; mechanism; thymidylate synthase