Chapter 5 Biosynthesis of Pre-proparathyroid Hormone

Abstract

Publisher Summary This chapter discusses the biosynthesis of parathyroid hormone (PTH), a polypeptide of 84 amino acids whose principal physiological actions are to maintain calcium levels in the extracellular fluid and that is synthesized by way of two successive cleavages of NH 2 -terminal sequences from a larger precursor—namely, preproparathyroid hormone (pre-proPTH) of 115 amino acids. The earliest cleavage occurs predominantly cotranslationally in the rough endoplasmic reticulum (RER) and consists of the removal of an NH 2 -terminal leader sequence of 25 amino acids, thereby resulting in the formation of an intermediate precursor—namely, proparathyroid hormone (proPTH). The leader sequence of pre-proPTH appears to serve as a signal that functions in the establishment of a polyribosome-membrane junction through the attachment of the nascent polypeptide to a transport element, yet unidentified, located in the lipid bilayer of the RER. The growing polypeptide chain is then transferred in a unidirectional manner into the cisterna of the RER. The second cleavage occurs in the Golgi complex 12–15 minutes later by removal of an NH 2 -terminal sequence of six amino acids, thereby resulting in the formation of PTH. After release of the hormone from the gland into the circulation, a third highly specific cleavage occurs in liver and perhaps in kidney, thereby resulting in proteolysis of the polypeptide between residues 33 and 34 and several other sites toward the middle of the molecule. This chapter reviews the experimental evidence in support of the cellular biosynthetic pathway.