Proprotein convertase

= Discovery of Prohormone Convertases =

The phenomenon of prohormone conversion was discovered by Donald F. Steiner while examining the biosynthesis of insulin [Steiner DF, Cunningham D, Spigelman L, Aten B 1967 Insulin biosynthesis: evidence for a precursor. Science (New York, NY 157:697-700] in 1967. At the same time, while conducting chemical sequencing of β-lipotrophic hormone (βLPH) with sheep pituitary glands Dr. Michel Chretien determined that the sequence of another hormone, Melanocyte-stimulating hormone ( βMSH) [Chretien M, Li CH 1967 Isolation, purification, and characterization of gamma-lipotropic hormone from sheep pituitary glands. Canadian journal of biochemistry 45:1163-1174] . This was the chemical evidence, at the level of primary protein sequence that peptide hormones could be found within larger protein molecules. The identity of the responsible enzymes was not clear for decades. In 1984, David Julius, working in the laboratory of Jeremy Thorner, identified the product of the Kex2 gene as responsible for processing of the alpha factor mating pheromone. Robert Fuller, working with Thorner, identified the partial sequence of the Kex2-homologous Furin gene in 1989. In 1990 human Kex2-homologous genes were cloned by the Steiner group, Nabil Seidah and co-workers, Wim J.M. van de Ven and co-workers, Yukio Ikehara and co-workers, Randal Kaufman and co-workers, Gary Thomas and co-workers, and Kazuhisa Nakayama and co-workers.

Biochemical and Structural Characterization of Kex2-Related Prohormone Convertases

Kex2 was first purified and characterized by Charles Brenner and Robert Fuller in 1992. The Kex2 crystal structure was solved by a group led by Dagmar Ringe, Robert Fuller and Gregory Petsko. That of Furin was determined by a group led by Manual Than and Wolfram Bode. The key features of Kex2 and Furin are a subtilisin-related catalytic domain, a specificity pocket that requires the amino acid amino terminal to the scissile bond to be arginine for rapid acylation, and a P-domain carboxy-terminal to the subtilisin domain, which is required for biosynthesis.

PCSK subtypes

To date there are 9 PCSKs with varying functions and tissue distributions [Seidah NG, Chretien M. Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides. Brain research 1999;848:45-62.] . Often, due to similar times of discovery from different groups the same PCSKs have aquired multiple names. In an attempt to alleviate confusion, there is a trend towards using the PCSK prefix with the appropriate number suffix [Martin Fugere, Robert Day, Cutting back on pro-protein convertases: the latest approaches to pharmacological inhibition, Trends in Pharmacological SciencesVolume 26, Issue 6, , June 2005, Pages 294-301.] .


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