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INTRODUCTION
Proteases (aka Peptidases or Proteolytic enzymes) catalyze the breakdown of protein peptide bonds. Proteolysis is an irreversible regulatory mechanism and are known to selectively cleave specific substrates Deregulated modifications in proteolytic actions underlie many diseases like cancer,neurodegenerative and cardiavascular disorders. With strong evidence of protease involvement in diseases,proteases play an important role in Drug development. MEROPS is a database that contains the classification and Nomenclature of proteolytic enzymes with their inhibitors. The database includes a collection of known cleavage sites in Substrates. The knowledge of cleavages in proteins,peptide and synthetic substrates is important for understanding the specificity and physiological roles of Proteolytic enzymes.
MEROPS
In 1993, Rawlings and Barret described a system in which individual peptidases were assigned to families and the families grouped into clans. The scheme was developed to provide the structure of the MEROPS database . The database was developed at Babraham University and moved to the wellcome Trust Sanger Institute in 2002 The database contains about more than 2000 peptidases and nearly 400 inhibitors. The peptidases and their inhibitors are classified into Families and Clans. The protein to which each peptidase or inhibitor belongs which has been fully characterized biochemically is chosen as a representative called Holotype
CLASSIFICATION OF PROTEASES
By the chemical mechanism of catalysis. E.g: Serine catalytic type, Aspartic and Threoninine catalytic types.
Proteolytic enzymes grouped by the type of reaction they catalyze E.g: Endopeptidases and Exopeptidases.
By molecular structure and Homology This depends on the availability of Data for Amino acid sequences and the 3D structures.
SERINE PEPTIDASES
Serine serves as the nucleophilic amino acid at the at the catalytic site f the enzyme.serine peptidase has an OH group that is able to act as a nucleophile attacking carbonyl Carbon of the peptide bond of the substrate. There are the trypsin like proteases which cleaves following a positively charged amino acid. And the Chymotrypsin-like which cleaves medium to large sized Hydrophobic amino acid such as Y, F and W.
Inhibition: Serine proteases are paired with serine protease inhibitors which turns off their activities when not needed.
Examples: Kallikrein is involved in blood coagulation and is inhibted by Antithrombin Neutrophyl elastase ,an enzyme of inflammatory cells that can cause damages to tissues is inhibited by Alpha-1 antityrpsin Bacterial serine proteases are inhibited by B lactams
ASPARTIC PEPTIDASES
These use aspartate residue for catalysis of their peptide substrates In generalthey have two(2)highly conserved aspartates in the active site. Members of this class include,Pepsins and Renins They are optimally active at acidic pH Inhibition: HIV - 1 retropepsin which is a drug target for HIV treatment ACE is a target for renin inhibitor in the treatment of hypertension. Pepstatin is a good inhibitor of aspartic proteases
METALLO PEPTIDASES
These are protease enzymes whose catalytic mechanism involves a metal. Most require Zinc but some cobalt The metal ion is coordinated to the protein via three ligands which vary with Histidine,Glutamate,Aspartate,Lysine and Arginine.
Inhibition:
Aminopeptidase N which plays a role in tumor invasion and metastatis is inhibited by Antineoplaston AS25,a metallo protease inhibitor. Generally metallo peptidases can be inhibited by chelating agents such as EDTA and Orthophenanthroline
CYSTEINE PEPTIDASES
Catalyzes hydrolyis of peptide bonds by deprotonation of the thiol in the enzymes active site by an adjacent amino acid with a basic side chain usually Histidine.
Inhibition:
THREONINE PEPTIDASE
Inhibition:
pfHsIV a threonine peptidase is claimed to be an attractive drug target for Malaria treatment Investigation is required to clarify its functional role in the parasite.
COMPOUND PEPTIDASE
More than one peptidase unit exist within the protein molecule.
An example is Polyserase 1 which is involved in tumor formation
Inhibition:
Proteolytic activities of Polyserase1 units which is involved in tumor formation is said to be inhibited by serine-protease inbibitors
Proteasomes:
Degradation of unneeded or damaged proteins by proteolysis ;
(a chemical reaction that breaks peptide bonds and catalysed by proteases enzymes).
(Ubiquitin-proteasome system)
Importance:
1. In the cell cycle control 2. Regulation of gene expression 3. In the response to oxidative stress
Protease Inhibitors:
1. Ritonavir (Norvir): anti-HIV Drug Inhibition of HIV Virus Infection (Prevent AIDS disease). Mechanism of Action: Inhibition of retroviral aspartyl protease Enzyme (retropepsin) that is important in the replication and assembly of the new virions.
SUMMARY
Therapies have been formulated to target and inhibit proteases that are disregulated,especially for tumor suppresssion Protease inhibitors have shown success in treatment of haematological malignancies and have therefore been tested as therapeutic agents in clinic for over 10 years. With a brief introduction to the classes of proteases in human,we have been able to show tha their disregulion can be implicated in many forms of cancer as well as neurological,pulmonary and cardiovascular diseases The MEROPS database aims to fulfil the need for an integrated source of information about the peptidases,their substrates and inhibitors
The database has hierarchical classification in which homoogous sets of peptidases and protein inhibitor are grouped into protein species,whch are grouped into families and further grouped into clans.
REFERENCES
Barret AJ,Rawlings ND. Species of peptidases. Biol. Chem 2007 Rawlings ND,Barret AJ, Merops.The peptidase database. Lopez-Otin C,Bond Js.Proteases:Multifunctional enzymes in life and diseases Orlowski RZ, Kuhn DJ. Proteosome inhibitors in cancer therapy http://www.wikidoc.org/index.php/File:1PSO.png