Assignment 1

Growth Hormone (GH)

Origin

    Growth hormone (GH) is a peptide pituitary hormone that plays a complex role in many biological processes in fish including growth promotion, energy mobilization, gonadal development, appetite, and social behaviors (Canosa et al., 2007). Additionally, GH enhances many aspects of immune functions including non-specific defences such as cytotoxic, phagocytic, hemolytic and lysozyme activities, and also activates immunoglobulin production (Yada, 2007). In humans, GH is a 191 amino acid single chain protein with a molecular weight of 22,124 daltons that is synthesized in the anterior pituitary by somatotropic cells (Kohler et al., 2008). Research centred around GH began in the early 20th century when Evans and Long first determined that the pituitary gland regulates growth through experimenting with a crude extract from bovine pituitary cells injected into rats which causes excess growth (Johnson & Sayles, 1929), while Evans and Li first isolated GH from bovine oxen in 1944 (Cohen, 2016). Human Growth Hormone (hGH) was extracted and purified in 1956-1957 by several researchers (Cohen, 2016). While the 3D structure of fish GH has not yet been identified, several sequences have been made, with striking similarities to hGH, and more studies are being carried out to better understand the complex interactions between the hormone and its receptor (Panicz et al., 2012). GH has also been found in extra-pituitary tissues in fish in both the brain and gonads (Canosa et al., 2007)

Structure

    The structure of GH in teleost fish is similar to humans - one study found many common characteristics, including a similar binding site, the growth hormone receptor (GHR) using two regions that are situated at opposite sites of molecule, and despite low sequence homology, the amino acid determinants binding sites of fish GH were similar to the human GH (Panicz, et al., 2012). HGH has two disulphide bridges, with 4 alpha helices arranged in anti-parallel distinctive manner, and is also known as somatotropin.

Fig. 1 Model of the human growth hormone.

(Chantalat et al., 1995)

    GH is coded by the gene GH1 in the 46.8 kb GH1 locus located on chromosome 17q24.2.

Here the disulphide bridges can be seen in the conformation of a four helical bundle protein (Cohen, 2016). This conformation is similar to other hormones such as prolactin and erythropoietin. Crystal structure analyses indicate the first two helices are parallel to each other and antiparallel to the remaining two helices, with long connecting loops between the first two helices and second two helices (de Vos, 1992). GH can also bind to the prolactin receptor (Cohen, 2016). There are no sites of glycosylation. The  cysteine  residues  involved  in  the disulfide bonds are highly conserved in all members of the family,  suggesting  an important role in biological  actions (Canosa et al., 2007).

Fig. 2 Human growth hormone chemical structure 

(National Center for Biotechnology Information (2021))

Function

    The functions of GH throughout the body are broad. Primarily, it is associated with stimulating growth - there are parallels associated with GH stimulating weight gain, but this may be related to GH also increasing appetite (Jönsson & Björnsson, 2002). GH also stimulates the production of the production of insulin-like growth factor 1 (IGF1) which also has growth-stimulating effects on all body tissues including bones, and GH promotes growth in all body organs with the exception of the brain (Sami, 2007). GH modulates glucose & free fatty acid levels in the blood, and helps modify calcium levels which also affect mineralization of bones and cartilage (Ahmad et al., 2003). 

    GH plays an important role in regulating homeostasis,  increases muscle mass and protein synthesis, and regulates some immune functions (Canosa et al., 2007). GH secretion is stronger in the childhood and adolescent age range than in adulthood, as at this life stage, organisms are continually undergoing growth, while sleep and nutritional influences also affect GH secretion (Cohen, 2016). 

    Growth Hormone-Releasing Hormone (GHRH) and somatostatin are hypothalamic polypeptides which play an important role in regulating GH. GHRH binds to its receptor on the anterior pituitary somatotrophic cells to stimulate the production of cAMP, which triggers GH synthesis and release from secretory granules (Cohen, 2016). Somatostatin, also called somatotropin release-inhibiting factor (SRIF) inhibits GH secretion. "Somatostatin is produced by neuroendocrine cells located in the ventromedial nucleus of the hypothalamus. Released somatostatin reaches the anterior pituitary gland through the hypothalamo-portal vascular network, where it inhibits the secre- tion of GH from the somatotroph cells" (Cohen, 2016). This functions as a negative feedback loop on GH release. 

    While there are many other hormonal interactions with GH, the study of GH actions and regulation is important in order to better understand the physiology of growth and development in animals. 

Works Cited

Ahmad, A. M., Thomas, J., Clewes, A., Hopkins, M. T., Guzder, R., Ibrahim, H., Durham, B. H., Vora, J. P., & Fraser, W. D. (2003). Effects of growth hormone replacement on parathyroid hormone sensitivity and bone mineral metabolism. The Journal of Clinical Endocrinology & Metabolism, 88(6), 2860–2868. https://doi.org/10.1210/jc.2002-021787 

Canosa, L. F., Chang, J. P., & Peter, R. E. (2007). Neuroendocrine control of growth                                          hormone in fish. General and Comparative Endocrinology, 151(1), 1–26. https://doi.org/10.1016/j.ygcen.2006.12.010 

Chantalat, L., Jones, N.D., Korber, F., Navaza, J., Pavlovsky, A.G. (1995) Protein Pept Lett 2: 333-340. THE CRYSTAL-STRUCTURE OF WILD-TYPE GROWTH-HORMONE AT 2.5 ANGSTROM RESOLUTION. https://www.rcsb.org/structure/1hgu

Cohen, L. E. (2016). Discovery of Growth Hormone and Synthesis of Recombinant Human Growth Hormone. In Growth hormone deficiency: Physiology and clinical management (pp. 1–7). Springer. 

de Vos AM, Ultsch M, Kossiakoff AA. Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science. 1992;255:306–12.

Johnson, G. E., & Sayles, E. D. (1929). The Effects of Daily Injections of Bovine Anterior Pituitary Extract upon the Developing Albino Rat. Physiological Zoology, 2(3), 285–301. http://www.jstor.org/stable/30151070

Jönsson, Elisabeth., & Björnsson, Björnthrandur. (2002). Physiological functions of growth hormone in fish with special reference to its influence on behaviour. Fisheries Science, 68(sup1), 742–748. https://doi.org/10.2331/fishsci.68.sup1_742 

Kohler, M., Püschel, K., Sakharov, D., Tonevitskiy, A., Schänzer, W., & Thevis, M. (2008). Detection of recombinant growth hormone in human plasma by a 2-D page method. ELECTROPHORESIS, 29(22), 4495–4502. https://doi.org/10.1002/elps.200800221 

National Center for Biotechnology Information (2021). PubChem Compound Summary for CID 126658, Human growth hormone (32-38). Retrieved October 27, 2021 from https://pubchem.ncbi.nlm.nih.gov/compound/Human-growth-hormone-_32-38.

Panicz, R., Sadowski, J., & Drozd, R. (2012). Genetic and structural characterization of the growth hormone gene and protein from tench, Tinca tinca. Fish physiology and biochemistry, 38(6), 1645–1653. https://doi.org/10.1007/s10695-012-9661-x

Peptide hormones and their receptors. The Medical Biochemistry Page. (2021, September 1). Retrieved October 27, 2021, from https://themedicalbiochemistrypage.org/peptide-hormones-and-their-receptors/#growthhormone. 

Sami AJ. Structure-function relation of somatotropin with reference to molecular modeling. Curr Protein Pept Sci. 2007 Jun;8(3):283-92. doi: 10.2174/138920307780831820. PMID: 17584122.

Yada, T. (2007). Growth hormone and fish immune system. General and Comparative Endocrinology, 152(2-3), 353–358. https://doi.org/10.1016/j.ygcen.2007.01.045