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Catalytic Site Atlas

CSA LITERATURE entry for 1lya

E.C. namecathepsin D
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz) 3.4.23.5
CSA Homologues of 1lyaThere are 311 Homologs
CSA Entries With UniProtID P07339
CSA Entries With EC Number 3.4.23.5
PDBe Entry 1lya
PDBSum Entry 1lya
MACiE Entry 1lya

Literature Report

IntroductionCathepsin D is an aspartic protease normally found in the lysosomes of higher eukaryotes. It is involved in the catabolism of cellular proteins and also in the selective processing of MHC II antigens, hormones and growth factors. The enzyme is able to cleave the amyloid precursor protein within senile plaques in the Alzheimer brain, and over-expression of the enzyme has been implicated in progressive breast cancer. High levels of cathepsin produced in the vicinity of the growing tumor may degrade the extracellular matrix and so promote the escape of cancer cells to the lymphatic and circulatory systems. Mature cathepsin D is found predominantly in a two-chain form due to a post-translational cleavage event.
MechansimCathepsin D is an aspartic peptidase with homology to other well-known mammalian aspartic proteases such as renin and pepsin. The active site contains two aspartate residues, Asp 33 and Asp 231, which carry out acid-base catalysis. The mechanism involves deprotonation of water by an ionised aspartate as this water molecule attacks the peptide carbonyl, and simultaneous protonation of the carbonyl oxygen by the other (protonated) aspartate. Collapse of the tetrahedral intermediate involves deprotonation of one of the OH groups and simultaneous protonation of the departing amine leaving group.
Reaction

Catalytic Sites for 1lya

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
AspA3397macie:sideChainActs as a general base to deprotonate attacking water molecule and/or tetrahedral intermediate and as a general acid to protonate substrate carbonyl and/or departing amine leaving group.
AspB231295macie:sideChainActs as a general base to deprotonate attacking water molecule and/or tetrahedral intermediate and as a general acid to protonate substrate carbonyl and/or departing amine leaving group.

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
AspC3397macie:sideChainActs as a general base to deprotonate attacking water molecule and/or tetrahedral intermediate and as a general acid to protonate substrate carbonyl and/or departing amine leaving group.
AspD231295macie:sideChainActs as a general base to deprotonate attacking water molecule and/or tetrahedral intermediate and as a general acid to protonate substrate carbonyl and/or departing amine leaving group.

Literature References

Notes:The exact sequence of proton transfers in the aspartic peptidase mechanism is not unequivocally established. Different literature sources assign opposite roles to the two aspartate residues while some suggest direct proton transfer between them partway through the mechanism. It is now thought that the mechanism is this: An LBHB (Low barrier hydrogen bond) and peptide dipoles hold the carboxyl groups of the Asps in coplanar conformation with a water molecule between them and hydrogen bonded to both. The resulting symmetrical 10-atom cyclised structure provides a scaffold to impart proximity, orientation and nucleophilicity to the water molecule. Once the substrate binds, a counterclockwise movement of electrons within the cycle occurs, the protons are moved clockwise and the water molecule attacks the carbonyl carbon atom of the amide bond. This generates a tetrahedral intermediate bound to a diprotonated form of the enzyme. The amide group of the tetrahedral intermediate attacks the nearby proton within the ring, causing a clockwise movement of electrons around the cycle, which moves two protons counterclockwise. A zwitterion intermediate is generated, bound to a monoprotonated form of the enzyme. Collapse of the zwitterion cleaves the scissile bond and destroys the coplanarity of the carboxyls. The form is then deprotonated, rehydrated and allowed to restructure the 10-atom cyclic structure with the LBHB.
Baldwin ET
Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design.
Proc Natl Acad Sci U S A 1993 90 6796-6800
PubMed: 8393577
Northrop DB.
Follow the protons: a low-barrier hydrogen bond unifies the mechanisms of the aspartic proteases.
Acc Chem Res 2001 34 790-797
PubMed: 11601963
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