The crystal structure of Leishmania major N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target

Thomas C Eadsforth, Scott Cameron, William N. Hunter

    Research output: Contribution to journal › Article

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    Abstract

    Three enzyme activities in the protozoan Leishmania major, namely N5,N10-methylenetetrahydrofolate dehydrogenase/N5,N10-methenyltetrahydrofolate cyclohydrolase (DHCH) and N10-formyltetrahydrofolate ligase (FTL) produce the essential intermediate N10-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.
    Original languageEnglish
    Pages (from-to)178-185
    Number of pages8
    JournalMolecular and Biochemical Parasitology
    Volume181
    Issue number2
    Early online date15 Nov 2011
    DOIs
    Publication statusPublished - Feb 2012

    Fingerprint

    Methylenetetrahydrofolate Dehydrogenase (NADP)
    Formyltetrahydrofolates
    Leishmania major
    Ligases
    Methenyltetrahydrofolate Cyclohydrolase
    Pharmaceutical Preparations
    Sequence Alignment
    Enzymes
    Catalysis
    Parasites

    Cite this

    Eadsforth, Thomas C ; Cameron, Scott ; Hunter, William N. / The crystal structure of Leishmania major N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target. In: Molecular and Biochemical Parasitology. 2012 ; Vol. 181, No. 2. pp. 178-185.
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    title = "The crystal structure of Leishmania major N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target",
    abstract = "Three enzyme activities in the protozoan Leishmania major, namely N5,N10-methylenetetrahydrofolate dehydrogenase/N5,N10-methenyltetrahydrofolate cyclohydrolase (DHCH) and N10-formyltetrahydrofolate ligase (FTL) produce the essential intermediate N10-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 {\AA} 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.",
    author = "Eadsforth, {Thomas C} and Scott Cameron and Hunter, {William N.}",
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    Eadsforth, TC, Cameron, S & Hunter, WN 2012, 'The crystal structure of Leishmania major N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target', Molecular and Biochemical Parasitology, vol. 181, no. 2, pp. 178-185. https://doi.org/10.1016/j.molbiopara.2011.11.004

    The crystal structure of Leishmania major N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target. / Eadsforth, Thomas C; Cameron, Scott; Hunter, William N.

    In: Molecular and Biochemical Parasitology, Vol. 181, No. 2, 02.2012, p. 178-185.

    Research output: Contribution to journal › Article

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    T1 - The crystal structure of Leishmania major N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target

    AU - Eadsforth, Thomas C

    AU - Cameron, Scott

    AU - Hunter, William N.

    N1 - Copyright © 2011 Elsevier B.V. All rights reserved.

    PY - 2012/2

    Y1 - 2012/2

    N2 - Three enzyme activities in the protozoan Leishmania major, namely N5,N10-methylenetetrahydrofolate dehydrogenase/N5,N10-methenyltetrahydrofolate cyclohydrolase (DHCH) and N10-formyltetrahydrofolate ligase (FTL) produce the essential intermediate N10-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.

    AB - Three enzyme activities in the protozoan Leishmania major, namely N5,N10-methylenetetrahydrofolate dehydrogenase/N5,N10-methenyltetrahydrofolate cyclohydrolase (DHCH) and N10-formyltetrahydrofolate ligase (FTL) produce the essential intermediate N10-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.

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    Eadsforth TC, Cameron S, Hunter WN. The crystal structure of Leishmania major N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target. Molecular and Biochemical Parasitology. 2012 Feb;181(2):178-185. https://doi.org/10.1016/j.molbiopara.2011.11.004

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