title: Structures of the hydrolase domain of human 10-formyltetrahydrofolate dehydrogenase and its complex with a substrate analogue.
abstract: 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.
authors.affiliation: Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden. petri.kursula@oulu.fi
authors.forename: Petri
authors.initials: P
authors.lastname: Kursula
authors.forename: Herwig
authors.initials: H
authors.lastname: Schüler
authors.forename: Susanne
authors.initials: S
authors.lastname: Flodin
authors.forename: Petra
authors.initials: P
authors.lastname: Nilsson-Ehle
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Ogg
authors.forename: Pavel
authors.initials: P
authors.lastname: Savitsky
authors.forename: Pär
authors.initials: P
authors.lastname: Nordlund
authors.forename: Pål
authors.initials: P
authors.lastname: Stenmark
mesh_terms: 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
chemical_list: 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