One group of enzymes could have a positive impact on health, from cholesterol to osteoporosis - IRCM's Dr. Nabil G. Seidah and his team publish six articles on PCSK enzymes

MONTREAL, Feb. 16 /CNW Telbec/ - Recent studies conducted at the Institut de recherches cliniques de Montréal (IRCM) on a group of PCSK enzymes could have a positive impact on health, from cholesterol to osteoporosis. A team led by Dr. Nabil G. Seidah, Director of the Biochemical Neuroendocrinology research unit, has published six articles in prestigious scientific journals over the past four months, all shedding light on novel functions of certain PCSK enzymes.

PCSK enzymes belong to the proprotein convertase family, responsible for the conversion of an inactive protein into its active state. The latest projects led by Dr. Seidah and his team focused on five of the nine PCSK enzymes, which are implicated in diseases such as cardiovascular and neuroendocrine disorders, cancer, and viral infections.

PCSK9 could help lower bad cholesterol levels
A member of the proprotein convertase family, PCSK9 plays a key role in the regulation of cholesterol. It is involved in causing familial hypercholesterolemia, a genetic disorder characterized by high total cholesterol levels in the blood, specifically very high levels of LDL (low-density lipoprotein) or bad cholesterol, which can lead to the early onset of cardiovascular diseases. PCSK9 is thus a target for the treatment of dyslipidemia, which results from an abnormal concentration of lipids (fat) in the blood. It is believed that inhibition of PCSK9 function could lower LDL-cholesterol levels, and such treatments are currently undergoing early phase clinical trials.

"Members of my team, led by Dr. Annik Prat and Dr. Anna Roubtsova, discovered that PCSK9 also regulates fatty acids," explains Dr. Seidah. "They investigated its role in the metabolism of body fat, and found that PCSK9 is pivotal in regulating cholesterol and fat metabolism: it maintains high circulating cholesterol levels, but it also limits fat generation."

In another study, the researchers uncovered further data on PCSK9's mechanism of action and functional structure. Their data showed that a part of PCSK9 inhibits its own function, and that acidic pH levels affect the degradation of bad cholesterol receptors.

In a third study, the team discovered that two other PCSK enzymes, Furin (PCSK3) and PC5/6 (PCSK5), reduce the level of active PCSK9. "They were able to demonstrate how enzymes of the PCSK family communicate with one another and found that liver-derived Furin cuts PCSK9 and inactivates it," adds Dr. Seidah. "This provided genetic evidence for the mechanism behind the functioning of a mutant gene found in some human hypercholesterolemic patients."

An important enzyme for osteoporosis, especially for women after menopause
The eighth member of the family (PCSK8), known as SKI-1/S1P, is critical in the intracellular pathway leading to the synthesis of cholesterol and fatty acids. Researchers discovered a new function of the enzyme in the regulation of bone formation. They demonstrated that mineralization - the process by which the body uses minerals to build bone structure - was blocked by inhibitors of SKI-1/S1P.

"The team found that SKI-1/S1P also regulates the activation of a membrane-bound transcription factor required for bone formation, which could have an impact on osteoporosis," says Dr. Seidah. "This could be especially important for women after menopause, as they are most likely to develop bone disease."

A better understanding of an enzyme implicated in various cancers
PC7 (or PCSK7) is the most ancient and highly-conserved basic amino acid-specific member of the proprotein convertase family. The team of researchers, led by Estelle Rousselet, shed light on how PC7 functions within cells, and was able to define its intracellular trafficking pathways. "We identified a mechanism for PC7's unique ability to activate the precursor of epidermal growth factor, which is involved in various cancers, tumour growth, and the maintenance of stem cells," concludes Dr. Seidah.

FUNDING AND SUPPORT
These research projects have been supported, in whole or in part, by the Canadian Institutes of Health Research (CIHR), the Canada Research Chair program, the Strauss Foundation, FWO Vlaanderen, the National Institutes of Health, and a Bristol-Myers Squibb collaborative research grant.

REFERENCES
Benjannet S, Saavedra YG, Hamelin J, Asselin MC, Essalmani R, Pasquato A, Lemaire P, Duke G, Miao B, Duclos F, Parker R, Mayer G, and Seidah NG (2010). Effects of the prosegment and pH on the activity of PCSK9: evidence for additional processing events. The Journal of Biological Chemistry 285: 40965-40978. (http://www.jbc.org/content/285/52/40965.abstract?sid=f2dbe014-c339-4acb-ac09-55a385fa9182)

Essalmani R, Susan-Resiga D, Chamberland A, Abifadel M, Creemers JW, Boileau C, Seidah NG, and Prat A. (2011). In vivo evidence that Furin from hepatocytes inactivates PCSK9. The Journal of Biological Chemistry [in press]. (http://www.jbc.org/content/286/6/4257.abstract?sid=f2dbe014-c339-4acb-ac09-55a385fa9182)

Gorski JP, Huffman NT, Chittur S, Midura RJ, Black C, Oxford J, and Seidah NG (2010). Inhibition of proprotein convertase SKI-1 blocks transcription of key extracellular matrix genes regulating osteoblastic mineralization. The Journal of Biological Chemistry 286: 1836-1849. (http://www.jbc.org/content/286/3/1836.abstract?sid=f2dbe014-c339-4acb-ac09-55a385fa9182)

Roubtsova A, Munkonda MN, Awan Z, Marcinkiewicz J, Chamberland A, Lazure C, Cianflone K, Seidah NG, and Prat A (2011). Circulating Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Regulates VLDLR Protein and Triglyceride Accumulation in Visceral Adipose Tissue. Arteriosclerosis, Thrombosis, and Vascular Biology [in press]. (http://atvb.ahajournals.org/cgi/content/abstract/ATVBAHA.110.220988v1?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=Circulating+Proprotein+Convertase+Subtilisin%2FKexin+9+%28PCSK9%29+Regulates+VLDLR+Pro&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT)

Rousselet E, Benjannet S, Hamelin J, Canuel M, and Seidah NG (2011a) The Proprotein Convertase PC7: unique zymogen activation and trafficking pathways. The Journal of Biological Chemistry 286: 2728-2738. (http://www.jbc.org/content/286/4/2728.abstract?sid=f2dbe014-c339-4acb-ac09-55a385fa9182)

Rousselet E, Benjannet S, Marcinkiewicz E, Asselin MC, Lazure C, and Seidah NG (2011b). The proprotein convertase PC7 enhances the activation of the EGF receptor pathway through processing of the EGF precursor. The Journal of Biological Chemistry [in press]. (http://www.jbc.org/content/early/2011/01/05/jbc.M110.189936.abstract?sid=f2dbe014-c339-4acb-ac09-55a385fa9182)

ABOUT DR. NABIL G. SEIDAH
Nabil G. Seidah obtained his PhD in chemistry from Georgetown University in Washington, D.C. He is a Full IRCM Research Professor and Director of the institute's Biochemical Neuroendocrinology research unit. Dr. Seidah is also Full researcher in the Department of Medicine, with an accreditation in Biochemistry, at the Université de Montréal. In addition, he is associate member of the Department of Medicine's Division of Experimental Medicine at McGill University. Dr. Seidah holds a Canada Research Chair in Precursor Proteolysis.

ABOUT THE INSTITUT DE RECHERCHES CLINIQUES DE MONTRÉAL (IRCM)
Founded in 1967, the IRCM (www.ircm.qc.ca) is currently comprised of 34 research units in various fields, namely immunity and viral infections, cardiovascular and metabolic diseases, cancer, neurobiology and development, systems biology and medicinal chemistry. It also houses three specialized research clinics, as well as eight core facilities and two research platforms with state-of-the-art equipment. The IRCM employs 425 people and is an independent institution affiliated with the Université de Montréal. The IRCM clinic is associated to the Centre hospitalier de l'Université de Montréal (CHUM). The IRCM also maintains a long-standing association with McGill University.

SOURCE Institut de recherches cliniques de Montréal

For further information:

and to schedule an interview with Dr. Seidah, please contact:

Julie Langelier, Chargée de communication (IRCM) julie.langelier@ircm.qc.ca     514-987-5555
Lucette Thériault, Directrice des communications (IRCM)    lucette.theriault@ircm.qc.ca   514-987-5535

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