The crystal structure of Leishmania major N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target.
Bottom Line: 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.
Affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.Show MeSH
Related in: MedlinePlus
Mentions: Attempts to obtain structures of LmDHCH ligand complexes proved fruitless and efforts to crystallize T. brucei and T. cruzi enzymes were also unsuccessful. However the similarities described allow comparisons with HsDHCH complexes (Fig. 5) to inform on aspects of molecular recognition in the active site (Fig. 6) and the potential for developing inhibitors specific for the parasite enzymes over that of the host. Of particular value is the ternary complex of HsDHCH with cofactor and the inhibitor 5,6,7,8-tetrahydro N5,N10-caronylfolic acid (LY354899, Fig. 1b, PDB code 1DIB) developed at Lilly Research Laboratories . LY354899 mimics the substrate and inhibits both HsDHCH and LmDHCH with Ki values of 18 nM and 105 nM, respectively [20,43]. It also inhibits other enzymes involved in folate metabolism, DHFR, thymidylate synthase and glycinamide ribonucleotide formyl transferase .
Affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.