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 journalArticlepeer-review

7 Citations (Scopus)
81 Downloads (Pure)

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
Externally publishedYes

Fingerprint Dive into the research topics of 'The crystal structure of <i>Leishmania major N<sup>5</sup>,N<sup>10</sup></i>-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target'. Together they form a unique fingerprint.

Cite this