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Catalytic Site Atlas

CSA LITERATURE entry for 1lam

E.C. nameleucyl aminopeptidase
SpeciesBos taurus (Bovine)
E.C. Number (IntEnz)
CSA Homologues of 1lamThere are 12 Homologs
CSA Entries With UniProtID P00727
CSA Entries With EC Number
PDBe Entry 1lam
PDBSum Entry 1lam
MACiE Entry 1lam

Literature Report

IntroductionBovine lens leucine aminopeptidase (blLAP) is a widespread bizinc exopeptidase, whose function is to remove the N-terminal residue in a peptide chain. It plays a key role in the degradation and modification of proteins in the metabolism of mammals and has even been implicated in human HIV pathophysiology. blLAP has a hexameric structure, in which each monomer functions independently of the others. The active site (one per monomer) is sitting on the edge of two water channels: a large one for the substrate located below the two metal ions and a much smaller one located above Zn1.
MechansimBicarbonate ion acts as a general base to deprotonate a water molecule bound by the two active site zinc ions, creating a hydroxide nucleophile. Zinc1 (Zinc488) and a hydrogen bond from Lys262 polarises the carbonyl group of the substrate, to increase its electrophilicity. In concert with the bicarbonate ion deprotonating the water molecule, it nucleophilically attacks the polarised carbonyl group to form a tetrahedral gem-diolate intermediate. The negative charge is subsequently stabilised by the Lys262 and Zinc1. Collapse of the tetrahedral intermediate leads to protonation of the amine leaving group by the bicarbonate ion, which shuttles the proton from water to it. Arg336 provides a positively charged pocket for the bicarbonate ion.

Catalytic Sites for 1lam

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysA262294macie:sideChainActs to polarise the carbonyl side to chain to activate it to nucleophilic attack. Stabilises the gem-diolate intermediate via hydrogen bonding.
ArgA336368macie:sideChainForms a positive pocket for the bicarbonate ion.

Literature References

Sträter N
A bicarbonate ion as a general base in the mechanism of peptide hydrolysis by dizinc leucine aminopeptidase.
Proc Natl Acad Sci U S A 1999 96 11151-11155
PubMed: 10500145
Sträter N
Two-metal ion mechanism of bovine lens leucine aminopeptidase: active site solvent structure and binding mode of L-leucinal, a gem-diolate transition state analogue, by X-ray crystallography.
Biochemistry 1995 34 14792-14800
PubMed: 7578088