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Parathyroid hormone (PTH) is secreted by the parathyroid glands as a polypeptide containing 84 amino acids.

In 1925, Collip prepared hot hydrochloric acid extracts of the parathyroid glands, an approach which he correctly deduced was needed to free the active substance from other gland stromal components and render it soluble. The author showed that these acid extracts of the parathyroid gland would completely relieve the tetany that followed parathyroidectomy, and established the parathyroids as an endocrine gland which secreted hormone (PTH) 1.

Structural Characteristics
Amino acid composition: Bovine parathyroid hormone has been isolated in homogeneous form from a trichloroacetic acid precipitate of defatted parathyroid glands. Disc gel electrophoresis of the purified hormone revealed a single electrophoretic band, and Edman amino terminal analysis showed a single amino acid, PTH-alanine. The purified hormone consisted of 84 amino acids.The amino acid composition of the isolated hormone, determined by a combination of timed acid hydrolysis and total enzymatic digestion, is as follows: Lys9, His4, Arg5, Trpl, Tyr1, Phe2, Leu8, ILe3, Met2, Val8, Ala7, Pro2, Gly4, Glu6, Gln5, Ser8, Asp6, Asn3. Cystine and threonine are absent 2.

Mode of Action
PTH acts on the PTH/PTHrP receptor (P1R), a class II G protein-coupled receptor which stimulates the adenylyl cyclase/cAMP and phospholipase C/inositol phosphate (IP) signaling pathways. Peptide deletion studies have shown that the N-terminal residues of PTH play a crucial role in P1R activation 3 and cross-linking and receptor mutagenesis studies have revealed that the N-terminal residues of PTH interact with the portion of the P1R that contains the extracellular loops and extracellular ends of the transmembrane helices (the juxtamembrane or J domain) 4.

Peptide Analogs
Parathyroid Hormone (PTH)-(1-14) and -(1-11) Analogs Conformationally Constrained by a -Aminoisobutyric Acid Mediate Full Agonist Responses via the Juxtamembrane Region of the PTH-1 Receptor: The N-terminal portion of parathyroid hormone is critical for PTH-1 receptor (P1R) activation and has been postulated to be a-helical when bound to the receptor. In a study it was investigated whether substitution of the sterically hindered and helix-promoting amino acid a -aminoisobutyric acid (Aib) in N-terminal PTH oligopeptides would improve the capacity of the peptide to activate the P1R. Analysis of the effects of individual Aib substitutions at each position in [Ala3,12,Gln10,Har11,Trp14]PTH(1-14)NH2 ([M]PTH(1-14)) on cAMP-stimulating potency in HKRK-B28 cells revealed that Aib at most positions diminished potency; however, Aib at positions 1 and 3 enhanced potency. Thus [Aib1,3,M]PTH(1-14) was ~100-fold more potent than [M]PTH(1-14), ~100,000-fold more potent than native PTH(1-14), and 2-fold more potent than PTH(1-34). The shorter peptide, [Aib1,3,M]PTH(1-11), was also fully efficacious and 1,000-fold more potent than [M]PTH(1-11). In cAMP stimulation assays performed in COS-7 cells expressing P1R-delNt, a receptor that lacks most of the N-terminal extracellular domain, [Aib1,3,M]PTH(1-14) was 50-fold more potent than [M]PTH(1-14) and 1,000-fold more potent than PTH(1-34). [Aib1,3,M]PTH(1-14), but not PTH(1-34), inhibited the binding of 125I-[Aib1,3 ,Nle8 ,Gln10 ,Har11 ,Ala12 ,Trp14 ,Arg19 ,Tyr21]PTH(1-21)NH2 to hP1R-delNt. The Aib1,3 substitutions in otherwise unmodified PTH(1-34) enhanced potency and binding affinity on hP1R-delNt, but they had no effect for this peptide on hP1R-WT. Circular dichroism spectroscopy demonstrated that the Aib-1,3 substitutions increased helicity in all peptides tested, including PTH(1-34). Thus it has been suggested that the N-terminal residues of PTH are intrinsically disordered but become conformationally constrained, possibly as an a -helix, upon interaction with the activation domain of the PTH-1 receptor 5.

PTH, its fragments and their analogs for the treatment of osteoporosis: The susceptibility to traumatic fracturing of osteopenic bones, and the spontaneous fracturing of osteoporotic bones by normal body movements caused by the microstructural deterioration and loss of bone, are currently treated with antiresorptive drugs, such as the bisphosphonates, calcitonin, estrogens, and selective estrogen receptor modulators. These antiresorptive agents target osteoclasts and, as their name indicates, reduce or stop bone resorption. They cannot directly stimulate bone formation, increase bone mass above normal values in ovariectomized rat models, or improve microstructure. However, there is a family of agents - the PTH and some of its fragments and their analogs - which directly stimulate bone growth and improve microstructure independently from impairing osteoclasts. These drugs are about to make their clinical debut in treating patients with osteoporosis and, probably not too far in the future, for accelerating fracture healing. They stimulate osteoblast accumulation and bone formation in three ways via signals from the type 1 PTH/PTH-related protein (PTHR1) receptors on proliferatively inactive preosteoblasts, osteoblasts, osteocytes and bone-lining cells. The receptor signals shut down the proliferative machinery in preosteoblasts and push their maturation to osteoblasts, cause the osteoblastic cells to make and secrete several factors that stimulate the extensive proliferation of osteoprogenitors without PTHRI receptors, stimulate the reversion of bone-lining cells to osteoblasts, and extend osteoblast lifespan and productivity by preventing them from suicidally initiating apoptosis 6.


1. Collip JB (1925). The extraction of a parathyroid hormone which will prevent or control parathyroid tetany and which regulates the level of blood calcium. Journal of Biological Chemistry, 63:395-438.
2. Brewer HB Jr, Ronan R (1970). Bovine Parathyroid Hormone: Amino Acid Sequence. Proceedings of the National Academy of Sciences, 67(4):1862-1869.
3. Takasu H, Gardella TJ, Luck MD, Potts JT, Jr and Bringhurst FR (1999). Amino-Terminal Modifications of Human Parathyroid Hormone (PTH) Selectively Alter Phospholipase C Signaling via the Type 1 PTH Receptor:  Implications for Design of Signal-Specific PTH Ligands. Biochemistry, 38:13453-13460. 
4. Hoare SRJ, Gardella TJ, and Usdin TB (2001). Evaluating the Signal Transduction Mechanism of the Parathyroid Hormone 1 Receptor. J. Biol. Chem., 276:7741-7753.
5. Shimizu N, Guo J, Gardella TJ (2001). Parathyroid Hormone (PTH)-(1-14) and -(1-11) Analogs Conformationally Constrained by a -Aminoisobutyric Acid Mediate Full Agonist Responses via the Juxtamembrane Region of the PTH-1 Receptor. J. Biol. Chem., 276 (52):49003-49012.
6. Whitfield JF, Morley P, Willick GE (2002). Parathyroid hormone, its fragments and their analogs for the treatment of osteoporosis. Treat Endocrinol., 1(3):175-190.

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