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

Abstract

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.”