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Catalytic Site Atlas

CSA LITERATURE entry for 1auk

E.C. namecerebroside-sulfatase
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz)
CSA Homologues of 1auk1e1z,1e2s,1e33,1e3c,1n2k,1n2l,3ed4,
CSA Entries With UniProtID P15289
CSA Entries With EC Number
PDBe Entry 1auk
PDBSum Entry 1auk
MACiE Entry M0158

Literature Report

IntroductionSulphatases are an evolutionarily highly conserved gene family. They hydrolyse sulphate ester bonds in a wide variety of structurally different compounds ranging from complex glucosaminoglucans and glycolipids to sulphated hydroxysteroids and amino acids. Among the sulphatase family, lysosomal arylsulphatase A (ASA) has been most extensively studied.
The major physiological substrate of human ASA is a sphingolipid sulphate ester, cerebroside 3-sulphate, a major constituent of the myelin sheet. In vivo, the 3-sulphate group can be hydrolysed by ASA only if cerebroside 3-sulphate is complexed with the small activator protein saposin B solubilising the hydrophobic substrate.
MechansimASA requires the post-translational oxidation of a cysteine sidechain to an aldehyde, yielding a formylglycine (3 letter code FGL). This is reduced to a gem-diol by a hydroxide ion. One of the alcohol groups, activated by magnesium, is deprotonated by glutamate and then carries out a nucleophilic attack on the substrate. The sulphate ester bond is broken, and the negatively charged leaving group abstracts a proton from a histidine residue. Deprotonation of the non-nucleophilic alcohol group of formylglycine leads to the aldehyde being re-formed and the enzyme-substrate bond being broken, restoring the enzyme to its original state.

Catalytic Sites for 1auk

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
AspA281281macie:sideChainDeprotonates the gem-diol form of the nucleophilic residue to activate it.
HisA125125macie:sideChainActivates formylglycine to encourage the gem-diol form and protonates it.
HisA229229macie:sideChainProtonates the alcohol leaving group, deprotonates the water molecule which converts formylglycine to the gem-diol form.
LysA123123macie:sideChainWithdraws electron density from the sulphate oxygen atoms, leading to an increased electrophilicity of the sulphur centre.
SerA150150macie:sideChainWithdraws electron density from the sulphate oxygen atoms, leading to an increased electrophilicP08842ity of the sulphur centre.
LysA302302macie:sideChainWithdraws electron density from the sulphate oxygen atoms, leading to an increased electrophilicity of the sulphur centre.

Literature References

von B├╝low R
Crystal structure of an enzyme-substrate complex provides insight into the interaction between human arylsulfatase A and its substrates during catalysis.
J Mol Biol 2001 305 269-277
PubMed: 11124905
Ghosh D.
Human sulfatases: a structural perspective to catalysis.
Cell Mol Life Sci 2007 64 2013-2022
PubMed: 17558559
Lukatela G
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 1998 37 3654-3664
PubMed: 9521684