Parathyroid hormone (PTH) is an 84-amino acid containing protein that is secreted by the chief cells of the parathyroid gland. PTH is a single-chain polypeptide of 84 amino acids (molecular weight = 9300) with no cysteine residues and hence no disulfide bridges. A fragment of the intact hormone consisting of the first 34 amino acids at the N-terminal region of the molecule is sufficient for the peptide to exert its entire spectrum of characteristic biological effects; see Figure 1.
Fig1. Comparison of the gene intron/exon organization and the protein size and amino acid length of Pre-Pro-, Pro- for the secreted parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP). The gene for PTH and PTHrP are respectively found on chromosome 11p and 12p. In comparison to the gene for PTHrP which has 9 exons, the PTH gene has only 3 exons. The secreted and mature forms of PTH and PTHrP each have their own color. The secreted PTH has 84 amino acids, but, as indicated by cross-hatching, all the biological activity resides in the first 34 amino acids. Both the PTH and PTHrP bind to the same G-protein coupled receptor to generate their diverse biological responses. The secreted PTHrP has 141 amino acids; after residue 13 there is no sequence homology with PTH. However, the first 13 amino acids of PTH and PTHrP are virtually identical (see bottom of figure).
Because PTH is a secreted protein, it is biosynthesized as a larger precursor by the parathyroid gland. Two precursor species have been identified, including a prepro-PTH with 31 additional amino acids added onto the N-terminal region of PTH, representing the primary translation product of the mRNA in the ribosomal fraction of the parathyroid gland. This prepro-PTH then is secreted into the cisterna of the rough endoplasmic reticulum, where it is processed within seconds into a form known as pro-PTH. This occurs by the removal of the NH2-terminal methionyl residue and the next 24 amino acids (i.e., residues −30 through −7) after biosynthesis. By 20 min after synthesis, pro-PTH reaches the Golgi region where it is stored in vesicles and converted into PTH by removal of the N-terminal hexapeptide. PTH is stored in the secretory granule until it is released into circulation in response to a fall in the blood concentration of calcium.
The introduction of immunologic assay techniques has permitted the detection of circulating levels of PTH and its changing concentration in disease states. The half-life of the intact PTH molecule in normal human plasma is only 20 min. Several predominant C-terminal peptide species have been identified in human plasma. Conflicting views are held on the importance of these peripheral forms of circulating PTH. One view is that only the 9500 molecular weight material is biologically active, with the smaller species representing degradation products. The other view is that one of the smaller species may have biological importance, which is not yet understood.
