Neuropeptide prohormone convertase

Like all neuropeptides, NT is synthesized as part of a larger precursor that also contains neuromedin N (NN), a 6 amino acid neurotensin-like peptide (Table 1). Pro-NT/NN is processed in the regulated secretory pathway of neuroendocrine cells by prohormone convertases PCI, PC2 and PC5-A that belong to a larger family of proprotein convertases. Due to differential cleavage specificity and tissue distribution of the convertases, pro-NT/NN processing gives rise to approximately a 1 1 and a 5 1 ratio of NT over NN content in the brain and gut, respectively. The peptides are stored in secretory vesicles and released from neuroendocrine cells in a Ca2+-dependent manner. NT and NN actions are terminated by desensitization of the... 

Further support for the occurrence and activity of neuropeptides in flatworms stems from the presence of enzymes necessary for the production of the mature peptides. For example, the first step in the generation of a mature neuropeptide is often the excision of a propeptide from a longer pre-propeptide. This is achieved by the activity of prohormone convertases, and a number of putative platyhelminth convertase-encoding cDNAs are represented within the EST databases. 

Brakch, N., Rist, B., Beck-Sickinger, A. G., et al. (1997) Role of prohormone convertases in pro-neuropeptide Y processing coexpression and in vitro kinetic investigations. Biochemistry 36, 16,309-16,320. 

Figure 3 Cysteine protease and subtilisin-like protease pathways for proneuropeptide processing. Distinct cysteine protease and subtilisin-like protease pathways have been demonstrated for pro-neuropeptide processing. Recent studies have identified secretory vesicle cathepsin L as an important processing enzyme for the production of the endogenous enkephalin opioid peptide. Preference of cathepsin L to cleave at the NH2-terminal side of dibasic residue processing sites yields peptide intermediates with NH2-terminal residues, which are removed by Arg/Lys aminopeptidase. The well-established subtilisin-like protease pathway involves several prohormone convertases (PC). PC1/3 and PC2 have been characterized as neuroendocrine processing proteases. The PC enzymes preferentially cleave at the COOH-terminal side of dibasic processing sites, which results in peptide intermediates with basic residue extensions at their COOH-termini that are removed by carboxypeptidase E/H.

Chemical biology defines the novel cathepsin L cysteine protease pathway combined with the prohormone convertase subtilisin-like pathway for neuropeptide production... 

LD, Devi LA. Neuropeptide processing profile in mice lacking prohormone convertase-1. Biochemistry 2005 44 4939-4948. 67. 

Pan H, Che FY, Peng B, Steiner DF, Pintar JE, Fricker LD. The role or prohormone convertase-2 in hypothalamic neuropeptide processing a quantitative neuropeptidomic study. J. Neurochem. 2006 98 1763-1777. 

---