TY - JOUR
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.
U2 - 10.1016/j.molbiopara.2011.11.004
DO - 10.1016/j.molbiopara.2011.11.004
M3 - Article
C2 - 22108435
VL - 181
SP - 178
EP - 185
JO - Molecular and Biochemical Parasitology
JF - Molecular and Biochemical Parasitology
SN - 0166-6851
IS - 2
ER -