Title: Biosynthesis of Peptide Hormones Derived from Precursor Sequences
Volume: 11
Issue: 20
Author(s): R. von Eggelkraut-Gottanka and A. G. Beck-Sickinger
Affiliation:
Keywords:
hormone biosynthesis, prohormone convertase, substrate specificity, recombinant expression, expressed protein ligation, chemical modification, secondary structure, inhibitor
Abstract: The release of hormones is subject to a complex and finely tuned regulation system. The biosynthesis plays a key role by specifically converting the prohormone precursor into its biological active product(s). A family of mammalian proteases could be identified to be responsible for the endoproteolytic processing. These subtilisin / kexin-like prohormone convertases (PC) recognize their substrates at single or pairs of basic residues with a high substrate specificity. The so far known seven members include PC1 / 3, PC2, furin / PACE, PACE4, PC4, PC5 / 6 and PC7 / SPC7 / LPC / PC8. PC1 / 3 and PC2 are the most important enzymes for the processing of prohormones, whereas furin is the only one that causes lethality in knock-out models. Tissuespecific co-localization of the prohormone and the PC as well as distinct characteristics of both, like the secondary structures, determine the possible conversion processes. Identification of such determinants implies a great potential for the development of novel drug targets. To obtain sufficient amounts for the in vitro characterization of prohormones, chemical and recombinant synthesis methods have been developed. Application of expressed protein ligation lead to the semisynthesis of the first chemically modified analogs of a full-length proneurohormone (pro-neuropeptide Y). Structural analyses mainly on peptides of the prooxytocin / neurophysin system and on prosomatostatin highlighted the importance of flexible turn or loop structures adjacent to the cleavage site for the specific substrate-enzyme active site interaction. Prohormones and their processing show multiple functions. Therapeutic application including PC inhibitors is very promising for the treatment of disorders like cancer.
