title: The crystal structure of Leishmania major N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target.
abstract: Three enzyme activities in the protozoan Leishmania major, namely N(5),N(10)-methylenetetrahydrofolate dehydrogenase/N(5),N(10)-methenyltetrahydrofolate cyclohydrolase (DHCH) and N(10)-formyltetrahydrofolate ligase (FTL) produce the essential intermediate N(10)-formyltetrahydrofolate. Although trypanosomatids possess at least one functional DHCH, the same is not true for FTL, which is absent in Trypanosoma brucei. Here, we present the 2.7 Å resolution crystal structure of the bifunctional apo-DHCH from L. major, which is a potential drug target. Sequence alignments show that the cytosolic enzymes found in trypanosomatids share a high level of identity of approximately 60%. Additionally, residues that interact and participate in catalysis in the human homologue are conserved amongst trypanosomatid sequences and this may complicate attempts to derive potent, parasite specific DHCH inhibitors.
authors: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors: Thomas C
authors: TC
authors: Eadsforth
authors: Scott
authors: S
authors: Cameron
authors: William N
authors: WN
authors: Hunter
mesh_terms: D000595:Amino Acid Sequence; D000981:Antiprotozoal Agents / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D018320:Leishmania major / Q000201:enzymology*; D045064:Methenyltetrahydrofolate Cyclohydrolase / Q000737:chemistry* / Q000235:genetics; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000737:chemistry* / Q000235:genetics; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics; D017385:Sequence Homology; D017386:Sequence Homology, Amino Acid
chemical_list: D000981:Antiprotozoal Agents; D015800:Protozoan Proteins; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D045064:Methenyltetrahydrofolate Cyclohydrolase