Crystal structure of Trypanosoma cruzi pteridine reductase 2 in complex with a substrate and an inhibitor.
Reduced pteridines are required for a number of important cellular functions. Trypanosomatid parasites, unlike their mammalian hosts, are pteridine auxotrophs and salvage the precursor pteridines from the host and reduce them to the respective biologically active tetrahydro forms using parasite-encoded enzymes. These enzymes may offer selective drug targets. In Leishmania, pteridine reductase 1 (PTR1), the primary enzyme for reducing pterins, is also responsible for resistance to antifolate drugs. Typically, PTR1 is more active with fully oxidized biopterin and folate than with their reduced counterparts. We have identified an enzyme, TcPTR2 of Trypanosoma cruzi, which though very similar to PTR1 in its primary sequence, can reduce only dihydrobiopterin and dihydrofolate and not oxidized pteridines. The structures of an inhibitor (methotrexate) and a substrate (dihydrofolate) complex of this enzyme demonstrate that the orientation of the substrate and the inhibitor in the active site of TcPTR2 are different from each other. However, the orientation of each ligand is similar to that of the corresponding ligand in Leishmania major PTR1 complexes.
Schormann
Norbert
N
Center for Biophysical Sciences and Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Pal
Biswajit
B
Senkovich
Olga
O
Carson
Mike
M
Howard
Andrew
A
Smith
Craig
C
Delucas
Lawrence
L
Chattopadhyay
Debasish
D
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry; D005492:Folic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D007527:Isoenzymes / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D046911:Macromolecular Substances; D008727:Methotrexate / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009249:NADP / Q000737:chemistry; D010088:Oxidoreductases / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D020836:Protein Structure, Quaternary; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D016415:Sequence Alignment; D014349:Trypanosoma cruzi / Q000201:enzymology*
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D046911:Macromolecular Substances; D015800:Protozoan Proteins; C010920:dihydrofolate; D009249:NADP; D005492:Folic Acid; D010088:Oxidoreductases; C085592:pteridine reductase; D008727:Methotrexate