The proprotein convertases and their implication in sterol and/or lipid metabolism

  title={The proprotein convertases and their implication in sterol and/or lipid metabolism},
  author={Nabil G. Seidah and Abdel M Khatib and Annik Prat},
  booktitle={Biological chemistry},
Abstract The proprotein convertases represent a family of nine proteinases, comprising seven basic amino acid-specific subtilisin-like serine proteinases related to yeast kexin, known as PC1/3, PC2, furin, PC4, PC5/6, PACE4 and PC7, and two other subtilases that cleave at non-basic residues, called SKI-1/S1P and NARC-1/PCSK9. The present review concentrates on the regulatory role played by some of these convertases in cholesterol and lipid metabolism. Thus, PC5/6, PACE4 and Furin upregulate… 

Figures from this paper

The proprotein convertases are potential targets in the treatment of dyslipidemia
A PCSK9 inhibitor in combination with statins offers a most promising therapeutic target to treat cardiovascular disorders including dyslipidemias and hypercholesterolemia phenotypes.
The activation and physiological functions of the proprotein convertases.
What lies ahead for the proprotein convertases?
  • N. Seidah
  • Biology
    Annals of the New York Academy of Sciences
  • 2011
In vivo studies demonstrated that PCs play major roles in health and disease states by regulating body axis and polarity determinants and the members SKI‐1/S1P and PCSK9 do not require a basic residue at the cleavage site and play major role in the regulation of cholesterol/lipid homeostasis.
Proprotein convertases in high-density lipoprotein metabolism
An integrative model in which PCSKMembers regulate HDL metabolism through various molecular mechanisms and metabolic processes and genetic variation in some PCSK members may affect the efficiency of reverse cholesterol transport is proposed.
The biology and therapeutic targeting of the proprotein convertases
The physiological functions and pathological implications of the proprotein convertases are summarized, proposed strategies to control some of their activities are discussed, and their therapeutic application and validation in selected disease states are discussed.
Proprotein convertase subtilisin kexin type 9 and high-density lipoprotein metabolism: experimental animal models and clinical evidence.
Proprotein Convertase Subtilisin/Kexin-Type 9 and Lipid Metabolism.
Plasma levels of cholesterol, especially low-density lipoprotein cholesterol (LDL-C), are positively correlated with the risk of cardiovascular disease and many proteins have been identified as interacting with PCSK9, regulating plasma cholesterol levels.
PCSK9 as a therapeutic target of dyslipidemia
Approaches proposed to reduce the levels of PCSK9 and/or its activity include the use of antisense oligonucleotides either as soluble phosphorothioates or locked nucleic acids and lipidoid nanoparticles embedded with small interfering RNAs.
The Proprotein Convertase SKI-1/S1P
This study has identified a smaller C-terminal fragment St-2 generated closer to the transmembrane domain of SKI-1 and its fragments, and site-directed mutagenesis revealed the critical amino acid involved in this novel process.
The Proprotein Convertase (PC) PCSK9 Is Inactivated by Furin and/or PC5/6A
It is proposed that PCSK9 levels are finely regulated by the basic amino acid convertases furin and PC5/6A, thereby regulating the levels of circulating LDL cholesterol.


Biosynthesis and Cellular Trafficking of the Convertase SKI-1/S1P
Results revealed that Arg130 and Arg134 are critical for the autocatalytic primary processing of the prosegment and for the subsequent efficient exit of SKI-1 from the endoplasmic reticulum.
Precursor convertases in the secretory pathway, cytosol and extracellular milieu.
It was recognized that the metalloendopeptidase N-arginine dibasic convertase (NRDc; nardilysin), which cleaves at the N-terminus side of basic residues in dibAsic pairs, is localized both in the cytosol and at the cell surface or in the extracellular milieu.
Development of Protein-based Inhibitors of the Proprotein of Convertase SKI-1/S1P
Transient transfections data showed that the R134E prosegment mutant or the α1-AT reactive site loop variants RRVL358, RRYL358 and RRIL358 are the best specific cellular inhibitors of SKI-1.
The Subtilisin/Kexin Family of Precursor Convertases: Emphasis on PC1, PC2/7B2, POMC and the Novel Enzyme SKI‐1
The phenotypic consequences of the absence of genetic expression of either PC1 or PC2 are now explored using knockout mice and in human patients suffering from obesity and diabetes.
Curbing activation: proprotein convertases in homeostasis and pathology
The major lesson learned from studies using PC inhibitors is that specific PC‐substrate pairs do exist, but that there is substantial redundancy for the majority of substrates.
Statins Upregulate PCSK9, the Gene Encoding the Proprotein Convertase Neural Apoptosis-Regulated Convertase-1 Implicated in Familial Hypercholesterolemia
It was found that NARC-1 expression was strongly induced by statins in a dose-dependent manner and that this induction was efficiently reversed by mevalonate, and PCSK9 regulation is typical of that of the genes implicated in lipoprotein metabolism.
The cysteine-rich domain of the secreted proprotein convertases PC5A and PACE4 functions as a cell surface anchor and interacts with tissue inhibitors of metalloproteinases.
The CRD of PC5A and PACE4 functions as a cell surface anchor favoring the processing of their cognate surface-anchored substrates, including endothelial lipase.
The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation
The properties of a proteinase K-like subtilase, neural apoptosis-regulated convertase 1 (NARC-1), representing the ninth member of the secretory subtilases family, are described, suggesting that NARC- 1 is implicated in the differentiation of cortical neurons.
The Prosegments of Furin and PC7 as Potent Inhibitors of Proprotein Convertases
It is demonstrated for the first time that PC prosegments, expressed ex vivo as independent domains, can act in trans to inhibit precursor maturation by intracellular PCs.