RGD Reference Report - The crystal structure of the hydrolase domain of 10-formyltetrahydrofolate dehydrogenase: mechanism of hydrolysis and its interplay with the dehydrogenase domain. - Rat Genome Database

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The crystal structure of the hydrolase domain of 10-formyltetrahydrofolate dehydrogenase: mechanism of hydrolysis and its interplay with the dehydrogenase domain.

Authors: Chumanevich, AA  Krupenko, SA  Davies, C 
Citation: Chumanevich AA, etal., J Biol Chem 2004 Apr 2;279(14):14355-64. Epub 2004 Jan 16.
RGD ID: 1547843
Pubmed: (View Article at PubMed) PMID:14729668
DOI: Full-text: DOI:10.1074/jbc.M313934200

10-Formyltetrahydrofolate dehydrogenase (FDH) converts 10-formyltetrahydrofolate, a precursor for nucleotide biosynthesis, to tetrahydrofolate. The protein comprises two functional domains: a hydrolase domain that removes a formyl group from 10-formyltetrahydrofolate and a NADP(+)-dependent dehydrogenase domain that reduces the formyl to carbon dioxide. As a first step toward deciphering the catalytic mechanism of the enzyme, we have determined the crystal structure of the hydrolase domain of FDH from rat, solved to 2.3-A resolution. The structure comprises two domains. As expected, domain 1 shares the same Rossmann fold as the related enzymes, methionyl-tRNA-formyltransferase and glycinamide ribonucleotide formyltransferase, but, unexpectedly, the structural similarity between the amino-terminal domain of 10-formyltetrahydrofolate dehydrogenase and methionyl-tRNA-formyltransferase extends to the C terminus of both proteins. The active site contains a molecule of beta-mercaptoethanol that is positioned between His-106 and Asp-142 and that appears to mimic the formate product. We propose a catalytic mechanism for the hydrolase reaction in which Asp-142 polarizes the catalytic water molecule and His-106 orients the carbonyl group of formyl. The structure also provides clues as to how, in the native enzyme, the hydrolase domain transfers its product to the dehydrogenase domain.

Annotation

Gene Ontology Annotations    

Biological Process

Cellular Component
cytosol  (TAS)

Molecular Function

Molecular Pathway Annotations    
Objects Annotated

Genes (Rattus norvegicus)
Aldh1l1  (aldehyde dehydrogenase 1 family, member L1)


Additional Information