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Structures of the hydrolase domain of human 10-formyltetrahydrofolate dehydrogenase and its complex with a substrate analogue

Kursula, Petri ; Schüler, Herwig LU orcid ; Flodin, Susanne ; Nilsson-Ehle, Petra ; Ogg, Derek J ; Savitsky, Pavel ; Nordlund, Pär and Stenmark, Pål LU orcid (2006) In Acta Crystallographica Section D: Structural Biology 62(Pt 11). p.9-1294
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... (More)

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.

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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Binding Sites, Catalysis, Crystallography, X-Ray/methods, Formates/chemistry, Humans, Leucovorin/analogs & derivatives, Oxidoreductases Acting on CH-NH Group Donors/chemistry, Protein Structure, Secondary, Protein Structure, Tertiary, Tetrahydrofolates/chemistry
in
Acta Crystallographica Section D: Structural Biology
volume
62
issue
Pt 11
pages
6 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:17057331
  • scopus:33750324298
ISSN
0907-4449
DOI
10.1107/S0907444906026849
language
English
LU publication?
no
id
4bd4a532-0961-468b-a160-fb462a4597ec
date added to LUP
2024-11-21 18:05:16
date last changed
2025-01-09 03:13:02
@article{4bd4a532-0961-468b-a160-fb462a4597ec,
  abstract     = {{<p>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.</p>}},
  author       = {{Kursula, Petri and Schüler, Herwig and Flodin, Susanne and Nilsson-Ehle, Petra and Ogg, Derek J and Savitsky, Pavel and Nordlund, Pär and Stenmark, Pål}},
  issn         = {{0907-4449}},
  keywords     = {{Binding Sites; Catalysis; Crystallography, X-Ray/methods; Formates/chemistry; Humans; Leucovorin/analogs & derivatives; Oxidoreductases Acting on CH-NH Group Donors/chemistry; Protein Structure, Secondary; Protein Structure, Tertiary; Tetrahydrofolates/chemistry}},
  language     = {{eng}},
  number       = {{Pt 11}},
  pages        = {{9--1294}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Acta Crystallographica Section D: Structural Biology}},
  title        = {{Structures of the hydrolase domain of human 10-formyltetrahydrofolate dehydrogenase and its complex with a substrate analogue}},
  url          = {{http://dx.doi.org/10.1107/S0907444906026849}},
  doi          = {{10.1107/S0907444906026849}},
  volume       = {{62}},
  year         = {{2006}},
}