Structures of the hydrolase domain of human 10-formyltetrahydrofolate dehydrogenase and its complex with a substrate analogue.
10-Formyltetrahydrofolate dehydrogenase is a ubiquitously expressed enzyme in the human body. It catalyses the formation of tetrahydrofolate and carbon dioxide from 10-formyltetrahydrofolate, thereby playing an important role in the human metabolism of one-carbon units. It is a two-domain protein in which the N-terminal domain hydrolyses 10-formyltetrahydrofolate into formate and tetrahydrofolate. The high-resolution crystal structure of the hydrolase domain from human 10-formyltetrahydrofolate dehydrogenase has been determined in the presence and absence of a substrate analogue. The structures reveal conformational changes of two loops upon ligand binding, while key active-site residues appear to be pre-organized for catalysis prior to substrate binding. Two water molecules in the structures mark the positions of key oxygen moieties in the catalytic reaction and reaction geometries are proposed based on the structural data.
Kursula
Petri
P
Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden. petri.kursula@oulu.fi
Schüler
Herwig
H
Flodin
Susanne
S
Nilsson-Ehle
Petra
P
Ogg
Derek J
DJ
Savitsky
Pavel
P
Nordlund
Pär
P
Stenmark
Pål
P
D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray / Q000379:methods; D005561:Formates / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D002955:Leucovorin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013763:Tetrahydrofolates / Q000737:chemistry / Q000378:metabolism; D000099295:Formyltetrahydrofolate Dehydrogenase
D005561:Formates; D002955:Leucovorin; D000587:Oxidoreductases Acting on CH-NH Group Donors; D013763:Tetrahydrofolates; D000099295:Formyltetrahydrofolate Dehydrogenase; C030544:formic acid; C010161:10-formyltetrahydropteroylglutamic acid; C030371:5,6,7,8-tetrahydrofolic acid