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LAP

Official Full Name
LAP
Background
Leucyl aminopeptidases are enzymes that preferentially catalyze the hydrolysis of leucine residues at the N-terminus of peptides and proteins. Other N-terminal residues can also be cleaved, however. LAPs have been found across superkingdoms. Identified LAPs include human LAP, bovine lens LAP, porcine LAP, Escherichia coli (E. coli) LAP (also known as PepA or XerB), and the solanaceous-specific acidic LAP (LAP-A) in tomato (Solanum lycopersicum).
Synonyms
Leucine Aminopeptidase# microsomal; 9054-63-1; leucine aminopeptidase; leucyl peptidase; peptidase S; cytosol aminopeptidase; cathepsin III; L-leucine aminopeptidase; leucinaminopeptidase; leucinamide aminopeptidase; FTBL proteins; proteinates FTBL; aminopeptidase II; aminopeptidase III; aminopeptidase I; EC 3.4.11.1; leucyl aminopeptidase; LAP

Catalog
ProductName
EC No.
CAS No.
Source
Price
CatalogNATE-1879
EC No.EC 3.4.11.1
CAS No.
SourcePorcine Kidney
CatalogEXWM-4007
EC No.EC 3.4.11.1
CAS No.9001-61-0
Source
CatalogNATE-0378
EC No.EC 3.4.11.1
CAS No.9054-63-1
SourcePorcine kidney
Related Reading

Leucyl aminopeptidases (EC 3.4.11.1), also called leucine aminopeptidase, LAPs, leucyl peptidase, leucinamide aminopeptidase, and so on, are prototypic dizinc peptidases preferentially catalyzing the hydrolysis of leucine residues at the N-terminus of peptides and proteins, while other N-terminal residues can also be cleaved simultaneously due to the broad specificity. LAPs are ubiquitously present in animals, plants, and prokaryotic cells and have different tissue-specific physiological roles in the processing or degradation of peptides. LAPs including human LAP, bovine lens LAP, porcine LAP, the solanaceous-specific acidic LAP (LAP-A) in tomato (Solanum lycopersicum), and Escherichia coli LAP (also known as PepA or XerB) have been identified.

Molecular Structure

LAP

It has been found that the active sites in PepA and bovine lens LAP are isostructural. The biochemistry of the PepA, bovine lens LAP, and LAP-A is also extremely similar, and the LAPs from these three species preferentially split N-terminal leucine, arginine, and methionine residues. All of these enzymes belong to metallopeptidases with the requirement of divalent metal cations for their enzymatic activity and are active in the presence of Mn2+, Mg2+ and Zn2+. These enzymes are also demonstrated to exhibit optimum activity at high pH and temperature. At pH of 8, the highest enzymatic activity is observed at 60 °C. These LAPs could also form hexamers in vivo. Six 55kDa enzymatically inactive LAP-A protomers have been demonstrated to come together to form the 353kDa bioactive LAP-A hexamer. Structures of both bovine lens LAP protomer and the constructed biologically active hexamer can be found in Protein Data Bank (PDB ID: 2J9A).

Mechanisms

In a suggested mechanism, the bicarbonate anion is bound to an arginine side chain (Arg-356 in PepA and Arg-336 in LAP) and is very near two catalytic zinc ions. Bicarbonate anion is anticipated to function as a general base that accepts a proton from the zinc-bridging water nucleophile and shuttles the proton to the leaving group. Therefore, the role of the bicarbonate ion as a general base in PepA and LAP is equivalent to the catalytic function of carboxylate side chains in the presumed mechanisms of other dizinc or monozinc peptidases. Additionally, the two zinc ions are related to the deprotonation of the nucleophile together with Lys-282, the polarization of the substrate carbonyl group and transition-state stabilization. The binding mode of transition-state analogue inhibitors to LAP that shows a symmetrical bridging of the two zinc ions by one of the gem-diol oxygens is thought to be derived from the attacking nucleophile, which is opposite to the possibility that the water nucleophile gets terminal coordination before the nucleophilic attack. The binding of the nucleophile with two metal ions is estimated to reduce its nucleophilicity. Furthermore, the type and charge of the coordinating ligands along with the dielectric constant and electrostatic potential of the protein environment will also have an impact on the pKa and nucleophilicity of water.

LAPFigure 1. Catalytic mechanisms of PepA and LAP. (Sträter N; et al. 1999)

Biological Functions

LAPs are often recognized as enzymes for cell maintenance with critical roles in the turnover of peptides. LAPs belong to members of the M1 or M17 peptidase families. In mammals, the M17 and M1 enzymes with LAP activity make contributions to the process of peptides for MHC I antigen presentation, the treatment of bioactive peptides (oxytocin, vasopressin, enkephalins), and vesicle trafficking to the plasma membrane. In microbes, the LAPs from M17 family take a role in proteolysis and exert the ability to bind with DNA, which enables LAPs to function as transcriptional repressors to control pyrimidine, alginate and cholera toxin biosynthesis, as well as regulate site-specific recombination events in plasmids and phages. LAPs are also implicated in defense, membrane transport of auxin receptors, and meiosis. LAP could indicate peptide digestion and leucine release, and represent amino acid absorption in the small intestine. Apart from being a housekeeping gene necessary for protein turnover, LAP-A has also been elucidated with a regulatory role in the immune response in tomato. LAP-A as a product of the octadecanoid pathway in some solanaceous plants, has been indicated to have a regulatory role in the late wound response of tomato, and is the first plant aminopeptidase shown to exert a regulatory function in signal transduction pathway. LAP can be also expressed in a variety of marine organisms to cope with the osmotic high salinity threat posing to the cells, during which LAP commences with the catalysis of proteins to release amino acids into the cell at the aim of balancing the high ion concentrations in the external environment.

Reference

  1. Sträter N, Sun L, Kantrowitz E R, Lipscomb W N. A bicarbonate ion as a general base in the mechanism of peptide hydrolysis by dizinc leucine aminopeptidase. PNAS, 1999, 96(20):11151–11155.

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