1auk Citations

Crystal structure of human arylsulfatase A: the aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis.

Biochemistry 37 3654-64 (1998)
Cited: 9 times
EuropePMC logo PMID: 9521684

Abstract

Human lysosomal arylsulfatase A (ASA) is a prototype member of the sulfatase family. These enzymes require the posttranslational oxidation of the -CH2SH group of a conserved cysteine to an aldehyde, yielding a formylglycine. Without this modification sulfatases are catalytically inactive, as revealed by a lysosomal storage disorder known as multiple sulfatase deficiency. The 2.1 A resolution X-ray crystal structure shows an ASA homooctamer composed of a tetramer of dimers, (alpha 2)4. The alpha/beta fold of the monomer has significant structural analogy to another hydrolytic enzyme, the alkaline phosphatase, and superposition of these two structures shows that the active centers are located in largely identical positions. The functionally essential formylglycine is located in a positively charged pocket and acts as ligand to an octahedrally coordinated metal ion interpreted as Mg2+. The electron density at the formylglycine suggests the presence of a 2-fold disordered aldehyde group with the possible contribution of an aldehyde hydrate, -CH(OH)2, with gem-hydroxyl groups. In the proposed catalytic mechanism, the aldehyde accepts a water molecule to form a hydrate. One of the two hydroxyl groups hydrolyzes the substrate sulfate ester via a transesterification step, resulting in a covalent intermediate. The second hydroxyl serves to eliminate sulfate under inversion of configuration through C-O cleavage and reformation of the aldehyde. This study provides the structural basis for understanding a novel mechanism of ester hydrolysis and explains the functional importance of the unusually modified amino acid.

Reviews - 1auk mentioned but not cited (1)

  1. Divergence and convergence in enzyme evolution. Galperin MY, Koonin EV. J. Biol. Chem. 287 21-28 (2012)

Articles - 1auk mentioned but not cited (8)

  1. Predicting protein function from structure: unique structural features of proteases. Stawiski EW, Baucom AE, Lohr SC, Gregoret LM. Proc. Natl. Acad. Sci. U.S.A. 97 3954-3958 (2000)
  2. A novel N-terminal domain may dictate the glucose response of Mondo proteins. McFerrin LG, Atchley WR. PLoS ONE 7 e34803 (2012)
  3. Heparin/heparan sulfate N-sulfamidase from Flavobacterium heparinum: structural and biochemical investigation of catalytic nitrogen-sulfur bond cleavage. Myette JR, Soundararajan V, Behr J, Shriver Z, Raman R, Sasisekharan R. J. Biol. Chem. 284 35189-35200 (2009)
  4. Mapping the mutual information network of enzymatic families in the protein structure to unveil functional features. Aguilar D, Oliva B, Marino Buslje C. PLoS ONE 7 e41430 (2012)
  5. Cooperative Electrostatic Interactions Drive Functional Evolution in the Alkaline Phosphatase Superfamily. Barrozo A, Duarte F, Bauer P, Carvalho AT, Kamerlin SC. J. Am. Chem. Soc. 137 9061-9076 (2015)
  6. Structure of sulfamidase provides insight into the molecular pathology of mucopolysaccharidosis IIIA. Sidhu NS, Schreiber K, Pröpper K, Becker S, Usón I, Sheldrick GM, Gärtner J, Krätzner R, Steinfeld R. Acta Crystallogr. D Biol. Crystallogr. 70 1321-1335 (2014)
  7. Impact of genetic variation on three dimensional structure and function of proteins. Bhattacharya R, Rose PW, Burley SK, Prlić A. PLoS ONE 12 e0171355 (2017)
  8. Abstract Protein structure prediction for novel mutations in Arylsulfatase-A gene. Divya M, Jain SJMN, Phadke S, Kishore R, Kamate M, Gupta N, Dalal A. Mol Cytogenet 7 P62-P62 (2014)