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The crystal structure of Leishmania major N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target.

Eadsforth TC, Cameron S, Hunter WN - Mol. Biochem. Parasitol. (2011)

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.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

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Comparison of the (a) NADP+ binding and (b) catalytic sites of LmDHCH (green) with HsDHCH (marine) containing the competitive inhibitor NADP+ (yellow) and LY354899 (black), respectively. Residues shown as sticks are within hydrogen bonding distance of the ligands and with labels colored according to species. The side chain of Tyr52 is disordered in the structure of LmDHCH but predicted to be ordered upon ligand binding.
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fig0035: Comparison of the (a) NADP+ binding and (b) catalytic sites of LmDHCH (green) with HsDHCH (marine) containing the competitive inhibitor NADP+ (yellow) and LY354899 (black), respectively. Residues shown as sticks are within hydrogen bonding distance of the ligands and with labels colored according to species. The side chain of Tyr52 is disordered in the structure of LmDHCH but predicted to be ordered upon ligand binding.

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 [43]. 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 [43].


The crystal structure of Leishmania major N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target.

Eadsforth TC, Cameron S, Hunter WN - Mol. Biochem. Parasitol. (2011)

Comparison of the (a) NADP+ binding and (b) catalytic sites of LmDHCH (green) with HsDHCH (marine) containing the competitive inhibitor NADP+ (yellow) and LY354899 (black), respectively. Residues shown as sticks are within hydrogen bonding distance of the ligands and with labels colored according to species. The side chain of Tyr52 is disordered in the structure of LmDHCH but predicted to be ordered upon ligand binding.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368264&req=5

fig0035: Comparison of the (a) NADP+ binding and (b) catalytic sites of LmDHCH (green) with HsDHCH (marine) containing the competitive inhibitor NADP+ (yellow) and LY354899 (black), respectively. Residues shown as sticks are within hydrogen bonding distance of the ligands and with labels colored according to species. The side chain of Tyr52 is disordered in the structure of LmDHCH but predicted to be ordered upon ligand binding.
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 [43]. 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 [43].

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.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

Show MeSH
Related in: MedlinePlus