Biosynthesis of peptide hormones derived from precursor sequences

Area of Science:

• Biochemistry
• Molecular Biology
• Endocrinology

Background:

• Hormone release is tightly regulated, with biosynthesis crucial for converting prohormones into active forms.
• Mammalian proteases, known as prohormone convertases (PCs), are responsible for this endoproteolytic processing.
• Seven PC members exist, with PC1/3 and PC2 vital for prohormone processing, and furin causing lethality in knock-out models.

Purpose of the Study:

• To explore the regulation of hormone biosynthesis and the role of prohormone convertases.
• To identify determinants of prohormone processing for novel drug target development.
• To investigate the structural basis of substrate-enzyme interactions in prohormone conversion.

Main Methods:

• Identification of mammalian subtilisin/kexin-like prohormone convertases (PCs).
• Chemical and recombinant synthesis for in vitro prohormone characterization.
• Structural analyses of prohormone systems (e.g., pro-oxytocin, prosomatostatin) and expressed protein ligation for semisynthesis.

Main Results:

• PCs exhibit high substrate specificity, recognizing basic residues.
• Tissue-specific co-localization and structural features of prohormones and PCs dictate conversion.
• Structural analyses revealed the importance of flexible turn/loop structures adjacent to cleavage sites.

Conclusions:

• Prohormone processing by PCs is complex and essential for hormone function.
• Understanding these interactions provides a basis for developing novel therapeutic strategies, including PC inhibitors for cancer treatment.