title: Proteases and the emerging role of protease inhibitors in prohormone processing.
abstract: Peptide hormones and neurotransmitters constitute a large class of neurohumoral agents that mediate cell-cell communication in neuroendocrine systems. Their biosynthesis requires proteolytic processing of inactive protein precursors into active neuropeptides. Elucidation of the proteolytic components required for prohormone processing is important for identifying key proteases that may control the production of neuropeptides. This article compares the subtilisin-like PC1/3 and PC2 processing enzymes identified through molecular biological approaches, and several candidate processing enzymes identified biochemically, including the 'proopiomelanocortin converting enzyme' (PCE) and the 'prohormone thiol protease' (PTP), as well as others of different classes (aspartyl, cysteine, metallo, and serine proteases). A role for PTP in cellular proenkephalin processing is suggested by blockade of forskolin-stimulated (Met)enkephalin production by Ep453 that is converted intracellularly to E-64c, a selective cysteine protease inhibitor that potently inhibits PTP. A possible role for endogenous protease inhibitors in prohormone processing represents a new aspect of cellular mechanisms that may regulate neuropeptide biosynthesis. Future studies of the enzymology and molecular biology of processing enzymes and endogenous protease inhibitors will be necessary to elucidate mechanisms of prohormone processing.
authors.affiliation: Department of Medicine, University of California, San Diego Medical Center 92103-8227.
authors.forename: V Y
authors.initials: VY
authors.lastname: Hook
authors.forename: A V
authors.initials: AV
authors.lastname: Azaryan
authors.forename: S R
authors.initials: SR
authors.lastname: Hwang
authors.forename: N
authors.initials: N
authors.lastname: Tezapsidis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000502:physiology; D010450:Endopeptidases / Q000502:physiology*; D006728:Hormones / Q000096:biosynthesis*; D006801:Humans; D008666:Metalloendopeptidases / Q000502:physiology; D008969:Molecular Sequence Data; D043484:Proprotein Convertases; D011480:Protease Inhibitors / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism*
chemical_list: D006728:Hormones; D011480:Protease Inhibitors; D011498:Protein Precursors; D010450:Endopeptidases; D043484:Proprotein Convertases; D003546:Cysteine Endopeptidases; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases