Defects in lysosomal enzyme modification for catalytic activity

Figura, Kurt Von; Borissenko, Ljudmila; Fey, Jens; Peng, Jianhe; Schmidt, Bernhard; Dierks, Thomas

doi:10.1093/acprof:oso/9780198508786.003.0005

Cited by 5 publications

(3 citation statements)

References 20 publications

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“…active site (1)(2)(3)(4)(5)(6)(7)(8)(9). In the native enzyme FGly is present as an aldehyde hydrate carrying two geminal hydroxyls at its ␤-carbon that both participate in catalysis (10 -12).…”

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confidence: 99%

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Molecular Characterization of the Human Cα-formylglycine-generating Enzyme

Preusser-Kunze¹,

Mariappan²,

Schmidt³

et al. 2005

Journal of Biological Chemistry

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139

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C␣-formylglycine (FGly) is the catalytic residue in the active site of sulfatases. In eukaryotes, it is generated in the endoplasmic reticulum by post-translational modification of a conserved cysteine residue. The FGly-generating enzyme (FGE), performing this modification, is an endoplasmic reticulum-resident enzyme that upon overexpression is secreted. Recombinant FGE was purified from cells and secretions to homogeneity. Intracellular FGE contains a high mannose type N-glycan, which is processed to the complex type in secreted FGE. Secreted FGE shows partial N-terminal trimming up to residue 73 without loosing catalytic activity. FGE is a calciumbinding protein containing an N-terminal (residues 86 -168) and a C-terminal (residues 178 -374) protease-resistant domain. The latter is stabilized by three disulfide bridges arranged in a clamp-like manner, which links the third to the eighth, the fourth to the seventh, and the fifth to the sixth cysteine residue. The innermost cysteine pair is partially reduced. The first two cysteine residues are located in the sequence preceding the Nterminal protease-resistant domain. They can form intramolecular or intermolecular disulfide bonds, the latter stabilizing homodimers. The C-terminal domain comprises the substrate binding site, as evidenced by yeast two-hybrid interaction assays and photocrosslinking of a substrate peptide to proline 182. Peptides derived from all known human sulfatases served as substrates for purified FGE indicating that FGE is sufficient to modify all sulfatases of the same species.

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“…Sulfatase activity relies on the presence of FGly. This is highlighted by multiple sulfatase deficiency (MSD), a rare inherited disorder of fatal nature that is characterized by the synthesis of catalytically inactive sulfatases lacking FGly (1,2,9,13,14).…”

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confidence: 99%

Molecular Characterization of the Human Cα-formylglycine-generating Enzyme

Preusser-Kunze¹,

Mariappan²,

Schmidt³

et al. 2005

Journal of Biological Chemistry

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139

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“…The catalytic site of pro-and eukaryotic sulfatases contains a unique amino acid, C␣-formylglycine (FGly) 1 (1)(2)(3)(4)(5)(6)(7)(8)(9). The FGly participates as an aldehyde hydrate in the catalytic cleavage of sulfate esters and thus is essential for the activity of sulfatases (10 -12).…”

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confidence: 99%

Expression, Localization, Structural, and Functional Characterization of pFGE, the Paralog of the Cα-Formylglycine-generating Enzyme

Mariappan¹,

Preusser-Kunze²,

Balleininger³

et al. 2005

Journal of Biological Chemistry

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pFGE is the paralog of the formylglycine-generating enzyme (FGE), which catalyzes the oxidation of a specific cysteine to C␣-formylglycine, the catalytic residue in the active site of sulfatases. The enzymatic activity of sulfatases depends on this posttranslational modification, and the genetic defect of FGE causes multiple sulfatase deficiency. The structural and functional properties of pFGE were analyzed. The comparison with FGE demonstrates that both share a tissue-specific expression pattern and the localization in the lumen of the endoplasmic reticulum. Both are retained in the endoplasmic reticulum by a saturable mechanism. Limited proteolytic cleavage at similar sites indicates that both also share a similar threedimensional structure. pFGE, however, is lacking the formylglycine-generating activity of FGE. Although overexpression of FGE stimulates the generation of catalytically active sulfatases, overexpression of pFGE has an inhibitory effect. In vitro pFGE interacts with sulfatasederived peptides but not with FGE. The inhibitory effect of pFGE on the generation of active sulfatases may therefore be caused by a competition of pFGE and FGE for newly synthesized sulfatase polypeptides.

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