Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme

Thomas Dierks; Achim Dickmanns; Andrea Preusser-Kunze; Bernhard Schmidt; Malaiyalam Mariappan; Kurt von Figura; Ralf Ficner; Markus Georg Rudolph

doi:10.1016/j.cell.2005.03.001

Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme

Cell. 2005 May 20;121(4):541-552. doi: 10.1016/j.cell.2005.03.001.

Authors

Thomas Dierks¹, Achim Dickmanns², Andrea Preusser-Kunze¹, Bernhard Schmidt¹, Malaiyalam Mariappan¹, Kurt von Figura³, Ralf Ficner², Markus Georg Rudolph⁴

Affiliations

¹ Department of Biochemistry II, University of Göttingen, D-37073 Göttingen, Germany.
² Department of Molecular Structural Biology, University of Göttingen, D-37077 Göttingen, Germany.
³ Department of Biochemistry II, University of Göttingen, D-37073 Göttingen, Germany. Electronic address: kfigura@gwdg.de.
⁴ Department of Molecular Structural Biology, University of Göttingen, D-37077 Göttingen, Germany. Electronic address: markus.rudolph@bio.uni-goettingen.de.

PMID: 15907468
DOI: 10.1016/j.cell.2005.03.001

Abstract

Sulfatases are enzymes essential for degradation and remodeling of sulfate esters. Formylglycine (FGly), the key catalytic residue in the active site, is unique to sulfatases. In higher eukaryotes, FGly is generated from a cysteine precursor by the FGly-generating enzyme (FGE). Inactivity of FGE results in multiple sulfatase deficiency (MSD), a fatal autosomal recessive syndrome. Based on the crystal structure, we report that FGE is a single-domain monomer with a surprising paucity of secondary structure and adopts a unique fold. The effect of all 18 missense mutations found in MSD patients is explained by the FGE structure, providing a molecular basis of MSD. The catalytic mechanism of FGly generation was elucidated by six high-resolution structures of FGE in different redox environments. The structures allow formulation of a novel oxygenase mechanism whereby FGE utilizes molecular oxygen to generate FGly via a cysteine sulfenic acid intermediate.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alanine / analogs & derivatives
Alanine / biosynthesis
Alanine / metabolism
Amino Acid Sequence
Binding Sites / physiology
Calcium / metabolism
Catalytic Domain
Crystallography, X-Ray
Cysteine / analogs & derivatives*
Cysteine / metabolism
Glycine / analogs & derivatives*
Glycine / biosynthesis*
Glycine / metabolism
Humans
Models, Molecular
Molecular Conformation
Molecular Sequence Data
Mutation, Missense / physiology
Oxidation-Reduction
Oxidoreductases Acting on Sulfur Group Donors
Oxygen / metabolism
Protein Structure, Secondary / physiology
Sequence Homology, Amino Acid
Sphingolipidoses / genetics
Sphingolipidoses / metabolism*
Sulfatases / chemistry*
Sulfatases / genetics
Sulfatases / metabolism*
Tumor Cells, Cultured

Substances

C(alpha)-formylglycine
Oxidoreductases Acting on Sulfur Group Donors
SUMF1 protein, human
SUMF2 protein, human
Sulfatases
Cysteine
Alanine
Oxygen
Calcium
Glycine
cysteine sulfinic acid

Associated data

PDB/1Y1E
PDB/1Y1F
PDB/1Y1G
PDB/1Y1H
PDB/1Y1I
PDB/1Y1J