Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme.
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.
Dierks
Thomas
T
Department of Biochemistry II, University of Göttingen, D-37073 Göttingen, Germany.
Dickmanns
Achim
A
Department of Molecular Structural Biology, University of Göttingen, D-37077 Göttingen, Germany.
Preusser-Kunze
Andrea
A
Department of Biochemistry II, University of Göttingen, D-37073 Göttingen, Germany.
Schmidt
Bernhard
B
Department of Biochemistry II, University of Göttingen, D-37073 Göttingen, Germany.
Mariappan
Malaiyalam
M
Department of Biochemistry II, University of Göttingen, D-37073 Göttingen, Germany.
von Figura
Kurt
K
Department of Biochemistry II, University of Göttingen, D-37073 Göttingen, Germany. Electronic address: kfigura@gwdg.de.
Ficner
Ralf
R
Department of Molecular Structural Biology, University of Göttingen, D-37077 Göttingen, Germany.
Rudolph
Markus Georg
MG
Department of Molecular Structural Biology, University of Göttingen, D-37077 Göttingen, Germany. Electronic address: markus.rudolph@bio.uni-goettingen.de.
D000409:Alanine / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000502:physiology; D010084:Oxidation-Reduction; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010100:Oxygen / Q000378:metabolism; D017433:Protein Structure, Secondary / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D013106:Sphingolipidoses / Q000235:genetics / Q000378:metabolism*; D013429:Sulfatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C524739:C(alpha)-formylglycine; D050862:Oxidoreductases Acting on Sulfur Group Donors; C480483:SUMF1 protein, human; C500803:SUMF2 protein, human; D013429:Sulfatases; D003545:Cysteine; D000409:Alanine; D010100:Oxygen; D002118:Calcium; D005998:Glycine; C013461:cysteine sulfinic acid