My road to Damascus: how I converted to the prohormone theory and the proprotein convertases.

My desire as a young endocrinologist to improve my clinical skills through a better knowledge of hormone chemistry led me to serendipitous discoveries and unexpected horizons. The first discovery, published in 1967, revealed that peptide hormones are derived from endoproteolytic cleavages of larger precursor polypeptides. It was the foundation of the prohormone theory. Initially thought to apply to a few hormones, the theory rapidly extended to many proteins, including neuropeptides, neurotrophins, growth and transcription factors, receptors, extracellular matrix proteins, bacterial toxins, and viral glycoproteins. Its endoproteolytic activation mechanism has become a fundamental cellular process, affecting many biological functions. It implied the existence of specific endoproteolytic enzymes. These proprotein convertases were discovered in 1990. They have been shown to play a wide range of important roles in health and disease. They have opened up novel therapeutic avenues. Inactivation of PCSK9 to reduce plasma cholesterol is currently the most promising. To make this good thing even better, I recently discovered in a French Canadian family a potent PCSK9 (Gln152His) mutation that significantly lowers plasma cholesterol and should confer cardiovascular longevity. The discovery helped me to complete the loop: "From the bedside to the bench and back to the bedside."

Detergent alkaline proteases: enzymatic properties, genes, and crystal structures.

Subtilisin-like serine proteases from bacilli have been used in various industrial fields worldwide, particularly in the production of laundry and automatic dishwashing detergents. They belong to family A of the subtilase superfamily, which is composed of three clans, namely, true subtilisins, high-alkaline proteases, and intracellular proteases. We succeeded in the large-scale production of a high-alkaline protease (M-protease) from alkaliphilic Bacillus clausii KSM-K16, and the enzyme has been introduced into compact heavy-duty laundry detergents. We have also succeeded in the industrial-scale production of a new alkaline protease, KP-43, which was originally resistant to chemical oxidants and to surfactants, produced by alkaliphilic Bacillus sp. strain KSM-KP43 and have incorporated it into laundry detergents. KP-43 and related proteases form a new clan, oxidatively stable proteases, in subtilase family A. In this review, we describe the enzymatic properties, gene sequences, and crystal structures of M-protease, KP-43, and related enzymes.