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

Thomas C. Eadsforth, Scott Cameron, William N. Hunter

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    7 Citations (Scopus)

    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 angstrom 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. (C) 2011 Elsevier B.V. All rights reserved.

    Original languageEnglish
    Pages (from-to)178-185
    Number of pages8
    JournalMolecular and Biochemical Parasitology
    Volume181
    Issue number2
    DOIs
    Publication statusPublished - Feb 2012

    Cite this

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    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 angstrom 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. (C) 2011 Elsevier B.V. All rights reserved.",
    author = "Eadsforth, {Thomas C.} and Scott Cameron and Hunter, {William N.}",
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    T1 - The crystal structure of Leishmania major N-5,N-10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target

    AU - Eadsforth, Thomas C.

    AU - Cameron, Scott

    AU - Hunter, William N.

    PY - 2012/2

    Y1 - 2012/2

    N2 - 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 angstrom 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. (C) 2011 Elsevier B.V. All rights reserved.

    AB - 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 angstrom 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. (C) 2011 Elsevier B.V. All rights reserved.

    U2 - 10.1016/j.molbiopara.2011.11.004

    DO - 10.1016/j.molbiopara.2011.11.004

    M3 - Article

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    JO - Molecular and Biochemical Parasitology

    JF - Molecular and Biochemical Parasitology

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