Structure of sulfamidase provides insight into the molecular pathology of mucopolysaccharidosis IIIA

Sidhu, Navdeep Singh; Schreiber, Kathrin; Pröpper, Kevin; Becker, Stefan; Usón, Isabel; Sheldrick, George M.; Gärtner, Jutta; Krätzner, Ralph; Steinfeld, Robert

doi:10.1107/s1399004714002739

Cited by 34 publications

(39 citation statements)

References 81 publications

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“…This relationship further extends to other putative bacterial PEA-transferases as well as sulphatases and phosphatases (choline sulphatase (PDB 4UG4, RMSD 2.9, 270 Cα), arylsulphatase (3ED4, RMSD 3.2, 259 Cα), N-sulphoglucosamine sulphohydrolase24 (4MIV, RMSD 3.0, 262 Cα) and alkaline phosphatase (2×98, RMSD 3.0, 229 Cα)). Thus, like LptA and EptC, MCR-1 can be assigned as a member of the alkaline phosphatase (AP) metalloenzyme superfamily.…”

Section: Discussionmentioning

confidence: 54%

Insights into the Mechanistic Basis of Plasmid-Mediated Colistin Resistance from Crystal Structures of the Catalytic Domain of MCR-1

Hinchliffe

Qin

Portal

et al. 2017

Sci Rep

125

189

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The polymixin colistin is a “last line” antibiotic against extensively-resistant Gram-negative bacteria. Recently, the mcr-1 gene was identified as a plasmid-mediated resistance mechanism in human and animal Enterobacteriaceae, with a wide geographical distribution and many producer strains resistant to multiple other antibiotics. mcr-1 encodes a membrane-bound enzyme catalysing phosphoethanolamine transfer onto bacterial lipid A. Here we present crystal structures revealing the MCR-1 periplasmic, catalytic domain to be a zinc metalloprotein with an alkaline phosphatase/sulphatase fold containing three disulphide bonds. One structure captures a phosphorylated form representing the first intermediate in the transfer reaction. Mutation of residues implicated in zinc or phosphoethanolamine binding, or catalytic activity, restores colistin susceptibility of recombinant E. coli. Zinc deprivation reduces colistin MICs in MCR-1-producing laboratory, environmental, animal and human E. coli. Conversely, over-expression of the disulphide isomerase DsbA increases the colistin MIC of laboratory E. coli. Preliminary density functional theory calculations on cluster models suggest a single zinc ion may be sufficient to support phosphoethanolamine transfer. These data demonstrate the importance of zinc and disulphide bonds to MCR-1 activity, suggest that assays under zinc-limiting conditions represent a route to phenotypic identification of MCR-1 producing E. coli, and identify key features of the likely catalytic mechanism.

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Section: Discussionmentioning

confidence: 54%

Insights into the Mechanistic Basis of Plasmid-Mediated Colistin Resistance from Crystal Structures of the Catalytic Domain of MCR-1

Hinchliffe

Qin

Portal

et al. 2017

Sci Rep

125

189

View full text Add to dashboard Cite

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“…3b), which could originate from natural substrate encountered in cells during expression. An alternative interpretation that this is a phosphate picked up from the storage buffer, as proposed for SGSH21, cannot be excluded on the crystallographic evidence. However, the higher stability of sulfate esters makes this the more likely interpretation.…”

Section: Resultsmentioning

confidence: 96%

Insights into Hunter syndrome from the structure of iduronate-2-sulfatase

et al. 2017

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Hunter syndrome is a rare but devastating childhood disease caused by mutations in the IDS gene encoding iduronate-2-sulfatase, a crucial enzyme in the lysosomal degradation pathway of dermatan sulfate and heparan sulfate. These complex glycosaminoglycans have important roles in cell adhesion, growth, proliferation and repair, and their degradation and recycling in the lysosome is essential for cellular maintenance. A variety of disease-causing mutations have been identified throughout the IDS gene. However, understanding the molecular basis of the disease has been impaired by the lack of structural data. Here, we present the crystal structure of human IDS with a covalently bound sulfate ion in the active site. This structure provides essential insight into multiple mechanisms by which pathogenic mutations interfere with enzyme function, and a compelling explanation for severe Hunter syndrome phenotypes. Understanding the structural consequences of disease-associated mutations will facilitate the identification of patients that may benefit from specific tailored therapies.

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“…Clarity came from the analysis of several sulfatase crystal structures which support a role for fGly in covalent catalysis. 24 The first sulfatase structure, that of human ASB, was solved by Guss and co-workers in 1997, and one year later the structure of ASA was solved by von Figura and coworkers. 25,26 A third human sulfatase structure, that of steroid sulfatase (ASC, STS), was later reported by Ghosh and coworkers.…”

Section: Fgly Participates Directly In Sulfate Ester Hydrolysismentioning

confidence: 99%

Formylglycine, a Post-Translationally Generated Residue with Unique Catalytic Capabilities and Biotechnology Applications

2014

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Formylglycine (fGly) is a catalytically essential residue found almost exclusively in the active sites of type I sulfatases. Formed by post-translational oxidation of cysteine or serine side chains, this aldehyde-functionalized residue participates in a unique and highly efficient catalytic mechanism for sulfate ester hydrolysis. The enzymes that produce fGly, formylglycine-generating enzyme (FGE) and anaerobic sulfatase-maturating enzyme (anSME), are as unique and specialized as fGly itself. FGE especially is structurally and mechanistically distinct, and serves the sole function of activating type I sulfatase targets. This review summarizes the current state of knowledge regarding the mechanism by which fGly contributes to sulfate ester hydrolysis, the molecular details of fGly biogenesis by FGE and anSME, and finally, recent biotechnology applications of fGly beyond its natural catalytic function.

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Structure of sulfamidase provides insight into the molecular pathology of mucopolysaccharidosis IIIA

Cited by 34 publications

References 81 publications

Insights into the Mechanistic Basis of Plasmid-Mediated Colistin Resistance from Crystal Structures of the Catalytic Domain of MCR-1

Insights into the Mechanistic Basis of Plasmid-Mediated Colistin Resistance from Crystal Structures of the Catalytic Domain of MCR-1

Insights into Hunter syndrome from the structure of iduronate-2-sulfatase

Formylglycine, a Post-Translationally Generated Residue with Unique Catalytic Capabilities and Biotechnology Applications

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