proprotein convertases
The proprotein convertases (PCs) are a seven-member family of endoproteases that activate proproteins by cleavage at basic motifs. Expression patterns for individual PCs vary widely, and all cells express several members. The list of substrates activated by PCs has grown to include neuropeptides, peptide hormones, growth and differentiation factors, receptors, enzymes, adhesion molecules, blood coagulation factors, plasma proteins, viral coat proteins, and bacterial toxins.
The discovery of mammalian subtilases, proprotein convertases (PCs) or subtilisin-like proprotein convertases (SPCs), in 1990 was a result of sustained efforts in searching for enzyme/s responsible for maturation of inactive protein precursors.
Since then, seven PCs have so far been discovered that cleave at the carboxy-terminal of a basic amino acid characterized by the consensus sequence Arg/Lys/His-X-X/Lys/Arg-Arg downward arrow, where X denotes any amino acid other than Cys.
Two additional PCs subtypes, called subtilisin kexin isozyme 1 (SKI-1) or site 1 protease (S1P) and neural apoptosis regulated convertase 1 (NARC-1), also known as PCSK9, that cleave at the carboxy terminus of nonbasic amino acids were discovered later.
Numerous studies revealed various important functional roles of PCs in health and diseases such as tumorigenesis, diabetes, viral infections, bacterial pathogenesis, atherosclerosis, and neurodegenarative diseases such as Alzheimer’s.
Owing to these findings, PCs became a promising frontier for treatment of diverse pathologies. Thus modulation of PC activity with designed inhibitors is an attractive proposition not only for intervention of diseases, but also for biochemical characterization of these enzymes.
Various physiological and bioengineered proteins as well as small molecules such as peptide, peptidomimetic, and nonpeptide compounds as inhibitors of PCs have been described in the literature.
Among the strategies used for design of PC inhibitors, the most successful is the one based on bioengineered serpin proteins, of which the best example is alpha1-PDX, the double mutant variant of alpha1-antitrypsin (from A(355)IPM(358) to R(355)IPR(358)).
Others include small peptide inhibitors with C-terminal carboxyl function modified with a potent neucleophile or those containing pseudo or isosteric peptide bond at the scissile site of a suitable peptide substrate.
Among nonpeptide PC inhibitors, the number is very limited. So far, these include 20-carbon atoms containing alicyclic diterpenes of andrographolide family and heterocyclic compounds that are ligands of Zn2+ and Cu2+ ions.
Overall, these molecules display only a modest enzyme inhibition; however, they may serve as important lead structures for further development of more potent and specific nonpeptide PC inhibitors as potential therapeutic agents.
Many PC inhibitors display their functional properties in proliferation, fertilization, tumorigenesis, obesity, embryogenesis, or diabetes via their inhibitory action on PC activities.
PCs and cadherins (CDHs)
Cadherins are a family of intercellular adhesion receptors. Produced as inactive precursors, they become functional adhesion molecules after proteolytic cleavage by subtilisin-like pro-protein convertases (PCs).
Owing to their activation and assembly into multiprotein adhesion complexes at sites of cell contacts, adhesion-competent cadherins are prerequisite for tissue integrity.
Intercellular junctions not only provide mechanical linkage, but in addition are potent modulators of signalling cascades. This infers a biological role to intercellular adhesion complexes that is significantly more complex and powerful.
Pathology
It has become clear that the PC family plays a crucial role in a variety of physiological processes and is involved in the pathology of diseases such as cancer, viral infection, and Alzheimer’s disease.
See also
PCSKs
- PCSK1
- PCSK9
autosomal dominant hypercholesterolemia
References
Basak A. Inhibitors of proprotein convertases. J Mol Med. 2005 Nov;83(11):844-55. PMID: #16215768#
Chretien M. Endoproteolysis in health and diseases—implications of proprotein convertases (PCs). J Mol Med. 2005 Nov;83(11):842-3. PMID: #16151759#
Seidah NG, Prat A. Precursor convertases in the secretory pathway, cytosol and extracellular milieu. Essays Biochem. 2002;38:79-94. PMID: #12463163#
Muller EJ, Caldelari R, Posthaus H. Role of subtilisin-like convertases in cadherin processing or the conundrum to stall cadherin function by convertase inhibitors in cancer therapy. J Mol Histol. 2004 Mar;35(3):263-75. PMID: #15339046#
Taylor NA, Van De Ven WJ, Creemers JW. Curbing activation: proprotein convertases in homeostasis and pathology. FASEB J. 2003 Jul;17(10):1215-27. PMID: #12832286#
Seidah NG, Prat A. Precursor convertases in the secretory pathway, cytosol and extracellular milieu. Essays Biochem. 2002;38:79-94. PMID: #12463163#