A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme.

A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme. Research Abstract Details 

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A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme. Abstract Text:

Dirk Roeser,Andrea Preusser-Kunze,Bernhard Schmidt,Kathrin Gasow,Julia G Wittmann,Thomas Dierks,Kurt von Figura,Markus Georg Rudolph,Dirk Roeser,Andrea Preusser-Kunze,Bernhard Schmidt,Kathrin Gasow,Julia G Wittmann,Thomas Dierks,Kurt von Figura,Markus Georg Rudolph,

The formylglycine (FGly)-generating enzyme (FGE) uses molecular oxygen to oxidize a conserved cysteine residue in all eukaryotic sulfatases to the catalytically active FGly. Sulfatases degrade and remodel sulfate esters, and inactivity of FGE results in multiple sulfatase deficiency, a fatal disease. The previously determined FGE crystal structure revealed two crucial cysteine residues in the active site, one of which was thought to be implicated in substrate binding. The other cysteine residue partakes in a novel oxygenase mechanism that does not rely on any cofactors. Here, we present crystal structures of the individual FGE cysteine mutants and employ chemical probing of wild-type FGE, which defined the cysteines to differ strongly in their reactivity. This striking difference in reactivity is explained by the distinct roles of these cysteine residues in the catalytic mechanism. Hitherto, an enzyme-substrate complex as an essential cornerstone for the structural evaluation of the FGly formation mechanism has remained elusive. We also present two FGE-substrate complexes with pentamer and heptamer peptides that mimic sulfatases. The peptides isolate a small cavity that is a likely binding site for molecular oxygen and could host reactive oxygen intermediates during cysteine oxidation. Importantly, these FGE-peptide complexes directly unveil the molecular bases of FGE substrate binding and specificity. Because of the conserved nature of FGE sequences in other organisms, this binding mechanism is of general validity. Furthermore, several disease-causing mutations in both FGE and sulfatases are explained by this binding mechanism.

A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme. Publishing Authors By Initials

D Roeser,A Preusser-Kunze,B Schmidt,K Gasow,JG Wittmann,T Dierks,K von Figura,MG Rudolph,D Roeser,A Preusser-Kunze,B Schmidt,K Gasow,JG Wittmann,T Dierks,K von Figura,MG Rudolph,

For similar enzymes and coenzymes: enzymes: hydrolases: esterases: sulfatases research abstracts see: enzymes and coenzymes: enzymes: hydrolases: esterases: sulfatases research

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A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Proceedings of the National Academy of Sciences of

VOLUME: 103

Page Numbers: 81-6

Journal Abbreviation: Proc. Natl. Acad. Sci. U.S.A.

ISSN: 0027-8424

DAY: 20

MONTH: 12

YEAR: 2005

A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7505876

A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme. Keywords Mesh Terms:

KEYWORDS: Sulfatases

MESH TERMS: metabolism

Chemical & Substance for Abstract: A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme. Information

Substance Name: Sulfatases

Registry Number: EC 3.1.6.-

Grant and Affiliation Information for A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme.

AFFILIATION: Department of Molecular Structural Biology, University of Göttingen, Justus-von-Liebig-Weg 11, D-37077 Göttingen, Germany.

Country: United States

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MEDLINETA: Proc Natl Acad Sci U S A

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ACCESSION NUMBER: 2AIK

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