Prohormone

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A prohormone is a committed precursor of a hormone consisting of peptide hormones synthesized together that has a minimal hormonal effect by itself because of its expression-suppressing structure, often created by protein folding and binding additional peptide chains to certain ends, that makes hormone receptor binding sites located on its peptide hormone chain segments inaccessible. [1] [2] Prohormones can travel the blood stream as a hormone in an inactivated form, ready to be activated later in the cell by post-translational modification. [1] [3]

Contents

The body naturally produces prohormones as a way to regulate hormone expression, making them an optimal storage and transportation unit for inactive hormones. Once prohormones are needed to be expressed, prohormone convertase, a protein, cleaves the prohormones and separates them into one or more active hormones. [4] Often in nature, this cleaving process happens immediately, and a prohormone is quickly converted to a set of one or more peptide hormones. [5]

Examples of natural, human prohormones include proinsulin and pro-opiomelanocortin, but the most widespread prohormones in use are synthetic and labeled as anabolic steroid precursors, used as ergogenic or anabolic agents for muscle growth. [6] A commonly consumed example of said precursors are androstenedione and androstenediol, both of which are currently banned substances in the United States. [6] [7] However, several illegal steroids, such as 1-testosterone, are still being produced legally under different chemical names, and the majority have not undergone clinical studies. [6] [8]

Structure

Prohormones vary considerably in length and design, as do peptide hormones, but their base structure is the same. [1] [9] They consist of one or more inactive peptide hormones or hormone chains attached to each other in a way that prevents hormone expression, often by making the chains’ binding ends inaccessible via folding and binding of other chains to said ends. [9] For hormonal expression to be induced, the binding ends of hormones but either bind to receptors in the cell membrane, or in the case of steroids, bind to steroid receptor proteins in the cell, both of which mediate hormone expression. [2]

Proinsulin molecule; schematic, topological drawing. B chain (orange), C-peptide (gray), and A chain (green). The C-peptide is seen to bind to the B and A chains and suppress hormonal expression. When cleavage occurs to produce insulin, the B and A chain are connected by disulfide bonds, while the C-peptide is cut out and discarded. Proinsuline schematic topological diagram.svg
Proinsulin molecule; schematic, topological drawing. B chain (orange), C-peptide (gray), and A chain (green). The C-peptide is seen to bind to the B and A chains and suppress hormonal expression. When cleavage occurs to produce insulin, the B and A chain are connected by disulfide bonds, while the C-peptide is cut out and discarded.

Some prohormones contain structures other than inactive peptide hormones for the purpose of keeping hormone expression suppressed. For example, proinsulin contains an extra non-hormonal chain called C-peptide that binds two insulin peptide chains together, designed to keep both chains inactive by binding to their ends, specifically, their C-domain junctions, which have been proposed to be their site of binding to hormone-expression receptors in the cell. [9] Despite the restrictions it enables, the C-peptide folds the proinsulin chains to make their junction ends accessible to be cleaved by prohormone convertases later, making the folding of the proinsulin chain containing C-peptide essential for the proper cleavage of proinsulin to successfully produce insulin. [10]

Function

Prohormones allow for transport and storage of usually-active proteins as inactive peptide chains, though they are much more commonly found in nature as a stable intermediate in the protein-synthesizing process of the cell. [11] Proinsulin, for example, is seen in nature as a brief precursor to insulin, as it is produced on the ribosomes of the cell, transported to the Golgi apparatus as proinsulin, then is converted to insulin immediately after reaching the Golgi apparatus. It is also primarily stored as insulin. [5]

However, other inactive proteins travel in their prohormone form, such as vitamin D, also known as calciferol, which can be produced by the human body via sunlight. [12]

The main regulator of prohormone to hormone conversion is prohormone convertase. Located in the Golgi apparatus, it uses endoproteolytic cleavage to separate peptide hormones from each other and removes extended amino acid residues that hinder the inactive peptides from being active proteins. [4] Because of this role, prohormone convertase is one of the deciding factors for regulation of hormone content in the body, as it has the ability to change an inactive protein with unsubstantial hormonal effect on the body, to a fully active protein with a meaningful hormonal effect. [4] [13]

For peptide hormones, the conversion process from prohormone to hormone (pro-protein to protein) typically occurs after being exported to the endoplasmic reticulum and often requires multiple processing enzymes. [14] Proamylin, which is cosecreted with proinsulin, requires the above three factors and an amidating monooxygenase to convert itself to an active hormone. [15] Some pro-protein precursors, such as preproinsulin, also go through this process, with the added step of removing a signal peptide by signal peptidases, to convert said precursors into prohormones. [14]

Uses

Prohormone supplements

The most everyday use of prohormones is as supplements for muscle growth via ergogenic and anabolic agents. [16] Prohormone supplements became popular from 1960 to 2001 and became used unregulated in Major League Baseball before select prohormones such as androstenedione and androstenediol became banned in the United States' Anabolic Steroid Control Act of 2004. [16] [17] Many prohormone supplements that were claimed to impart anabolic or ergogenic effects in men were banned for their poor side effects, commonly in supplements such as in 3β-hydroxy-5α-androst-1-en-17-one, commonly known as 1-testosterone, which are as follows: [16] [6]

Many prohormone supplements such as 1-testosterone were legal in the United States until reclassified as a Schedule III drug in 2005. [17] However, many illegal prohormones like 1-testosterone are currently being sold legally and marketed by brands such as “Advanced Muscle Science” as 1-androsterone, and are labeled to contain 1-androstenedione-3b-ol,17-one. [8] Only through a recent clinical study has it been shown that the 1-androsterone in the capsules being sold was identified using semi-quantitation and confirmed to be 1-testosterone. [8]

Research surrounding other prohormones and prohormone supplements is limited, so many side effects are unknown regarding both legal and illegal prohormone supplements. [16] [6]

See also

Related Research Articles

<span class="mw-page-title-main">Androgen</span> Any steroid hormone that promotes male characteristics

An androgen is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes the embryological development of the primary male sex organs, and the development of male secondary sex characteristics at puberty. Androgens are synthesized in the testes, the ovaries, and the adrenal glands.

<span class="mw-page-title-main">Proinsulin</span> Precursor protein in humans

Proinsulin is the prohormone precursor to insulin made in the beta cells of the Pancreatic Islets, specialized regions of the pancreas. In humans, proinsulin is encoded by the INS gene. The pancreatic islets only secrete between 1% and 3% of proinsulin intact. However, because proinsulin has a longer half life than insulin, it can account for anywhere from 5–30% of the insulin-like structures circulating in the blood. There are higher concentrations of proinsulin after meals and lower levels when a person is fasting. Additionally, while proinsulin and insulin have structural differences, proinsulin does demonstrate some affinity for the insulin receptor. Due to the relative similarities in structure, proinsulin can produce between 5% and 10% of the metabolic activity similarly induced by insulin.

An androgen prohormone, or proandrogen, is a prohormone of an anabolic-androgenic steroid (AAS). They can be prohormones of testosterone or of synthetic AAS, for example, nandrolone (19-nortestosterone). Dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and androstenedione may all be considered proandrogens of testosterone.

<span class="mw-page-title-main">Androstenedione</span> Endogenous weak androgen

Androstenedione, or 4-androstenedione, also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroepiandrosterone (DHEA). It is closely related to androstenediol (androst-5-ene-3β,17β-diol).

<span class="mw-page-title-main">Androsterone</span> Endogenous steroid hormone

Androsterone, or 3α-hydroxy-5α-androstan-17-one, is an endogenous steroid hormone, neurosteroid, and putative pheromone. It is a weak androgen with a potency that is approximately 1/7 that of testosterone. Androsterone is a metabolite of testosterone and dihydrotestosterone (DHT). In addition, it can be converted back into DHT via 3α-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase, bypassing conventional intermediates such as androstanedione and testosterone, and as such, can be considered to be a metabolic intermediate in its own right.

<span class="mw-page-title-main">Sex hormone-binding globulin</span> Human glycoprotein that binds to androgens and estrogens

Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it is called androgen-binding protein (ABP).

<span class="mw-page-title-main">Prasterone</span> Medical usage of the prasterone compound

Prasterone, also known as dehydroepiandrosterone (DHEA) and sold under the brand name Intrarosa among others, is a medication as well as over-the-counter dietary supplement which is used to correct DHEA deficiency due to adrenal insufficiency or old age, as a component of menopausal hormone therapy, to treat painful sexual intercourse due to vaginal atrophy, and to prepare the cervix for childbirth, among other uses. It is taken by mouth, by application to the skin, in through the vagina, or by injection into muscle.

<span class="mw-page-title-main">Androstenediol</span> Chemical compound

Androstenediol, or 5-androstenediol, also known as androst-5-ene-3β,17β-diol, is an endogenous weak androgen and estrogen steroid hormone and intermediate in the biosynthesis of testosterone from dehydroepiandrosterone (DHEA). It is closely related to androstenedione (androst-4-ene-3,17-dione).

Proprotein convertases (PPCs) are a family of proteins that activate other proteins. Many proteins are inactive when they are first synthesized, because they contain chains of amino acids that block their activity. Proprotein convertases remove those chains and activate the protein. The prototypical proprotein convertase is furin. Proprotein convertases have medical significance, because they are involved in many important biological processes, such as cholesterol synthesis. Compounds called proprotein convertase inhibitors can block their action, and block the target proteins from becoming active. Many proprotein convertases, especially furin and PACE4, are involved in pathological processes such as viral infection, inflammation, hypercholesterolemia, and cancer, and have been postulated as therapeutic targets for some of these diseases.

<span class="mw-page-title-main">Proprotein convertase 2</span> Protein-coding gene in the species Homo sapiens

Proprotein convertase 2 (PC2) also known as prohormone convertase 2 or neuroendocrine convertase 2 (NEC2) is a serine protease and proprotein convertase PC2, like proprotein convertase 1 (PC1), is an enzyme responsible for the first step in the maturation of many neuroendocrine peptides from their precursors, such as the conversion of proinsulin to insulin intermediates. To generate the bioactive form of insulin, a second step involving the removal of C-terminal basic residues is required; this step is mediated by carboxypeptidases E and/or D. PC2 plays only a minor role in the first step of insulin biosynthesis, but a greater role in the first step of glucagon biosynthesis compared to PC1. PC2 binds to the neuroendocrine protein named 7B2, and if this protein is not present, proPC2 cannot become enzymatically active. 7B2 accomplishes this by preventing the aggregation of proPC2 to inactivatable forms. The C-terminal domain of 7B2 also inhibits PC2 activity until it is cleaved into smaller inactive forms that lack carboxy-terminal basic residues. Thus, 7B2 is both an activator and an inhibitor of PC2. PC2 has been identified in a number of animals, including C. elegans.

Androstenediol may refer to:

<span class="mw-page-title-main">1-Androstenediol</span> Chemical compound

1-Androstenediol, or 5α-androst-1-ene-3β,17β-diol, also known as 4,5α-dihydro-δ1-4-androstenediol, is a prohormone of 1-testosterone (Δ1-DHT).

<span class="mw-page-title-main">1-Testosterone</span> Chemical compound

1-Testosterone, also known as δ1-dihydrotestosterone (δ1-DHT), as well as dihydroboldenone, is a synthetic anabolic–androgenic steroid (AAS) and a 5α-reduced derivative of boldenone (Δ1-testosterone). It differs from testosterone by having a 1(2)-double bond instead of a 4(5)-double bond in its A ring. It was legally sold online in the United States until 2005, when it was reclassified as a Schedule III drug.

<span class="mw-page-title-main">Methandriol</span> Chemical compound

Methandriol, also known as methylandrostenediol, is an androgen and anabolic steroid (AAS) medication which was developed by Organon and is used in both oral and injectable formulations. It is an orally active 17α-alkylated AAS and a derivative of the endogenous androgen prohormone androstenediol.

<span class="mw-page-title-main">1-Androstenedione</span> Chemical compound

1-Androstenedione, or 5α-androst-1-ene-3,17-dione, also known as 4,5α-dihydro-δ1-4-androstenedione, is a synthetic androgen and anabolic steroid. It is a 5α-reduced isomer of the endogenous steroid 4-androstenedione and acts as an androgen prohormone of 1-testosterone (4,5α-dihydro-δ1-testosterone), a derivative of dihydrotestosterone (DHT).

Androstenedione may refer to:

Androstenolone may refer to:

<span class="mw-page-title-main">1-Androsterone</span> Chemical compound

1-Androsterone is a synthetic, orally active anabolic-androgenic steroid (AAS). It is an androgen prohormone of 1-testosterone (dihydroboldenone), 1-androstenedione, and other 1-dehydrogenated androstanes. The drug has been sold on the Internet as a designer steroid and "dietary supplement". It is a positional isomer of dehydroepiandrosterone.

References

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  2. 1 2 "Control of Gene Expression in Eukaryotes". www.ndsu.edu. Retrieved 2021-12-10.
  3. ↑ Miller, Benjamin Frank; Claire Brackman Keane (1997). Miller-Keane Encyclopedia & dictionary of medicine, nursing & allied health (6th ed.). Philadelphia: Saunders. ISBN   0-7216-6278-1. OCLC   36465055.
  4. 1 2 3 Dhanvantari, Savita; Cawley, Niamh X.; Loh, Y. Peng (2004-01-01), "Prohormone Convertases", in Martini, Luciano (ed.), Encyclopedia of Endocrine Diseases, New York: Elsevier, pp. 84–90, ISBN   978-0-12-475570-3 , retrieved 2021-12-09
  5. 1 2 Alarcon, Cristina; Wicksteed, Barton; Rhodes, Christopher J. (2003-01-01), "Insulin Processing", in Henry, Helen L.; Norman, Anthony W. (eds.), Encyclopedia of Hormones, New York: Academic Press, pp. 359–368, doi:10.1016/b0-12-341103-3/00175-3, ISBN   978-0-12-341103-7 , retrieved 2021-12-09
  6. 1 2 3 4 5 Powers, Michael E. (2002). "The Safety and Efficacy of Anabolic Steroid Precursors: What is the Scientific Evidence?". Journal of Athletic Training. 37 (3): 300–305. ISSN   1062-6050. PMC   164360 . PMID   16558675.
  7. ↑ Pitts, Joseph R. (2014-12-18). "Text - H.R.4771 - 113th Congress (2013-2014): Designer Anabolic Steroid Control Act of 2014". www.congress.gov. Retrieved 2021-12-09.
  8. 1 2 3 Parr, Maria K.; Opfermann, Georg; Geyer, Hans; Westphal, Folker; Sönnichsen, Frank D.; Zapp, Josef; Kwiatkowska, Dorota; Schänzer, Wilhelm (2011-02-01). "Seized designer supplement named "1-Androsterone": identification as 3β-hydroxy-5α-androst-1-en-17-one and its urinary elimination". Steroids. 76 (6): 540–547. doi:10.1016/j.steroids.2011.02.001. ISSN   1878-5867. PMID   21310167. S2CID   4942690.
  9. 1 2 3 De Pablo, Flora; de la Rosa, Enrique (2011). "Proinsulin: from hormonal precursor to neuroprotective factor". Frontiers in Molecular Neuroscience. 4: 20. doi: 10.3389/fnmol.2011.00020 . ISSN   1662-5099. PMC   3171928 . PMID   21949502.
  10. ↑ Arunagiri, Anoop; Haataja, Leena; Pottekat, Anita; Pamenan, Fawnnie; Kim, Soohyun; Zeltser, Lori M; Paton, Adrienne W; Paton, James C; Tsai, Billy; Itkin-Ansari, Pamela; Kaufman, Randal J (2019-06-11). Gilmore, Reid; Malhotra, Vivek (eds.). "Proinsulin misfolding is an early event in the progression to type 2 diabetes". eLife. 8: e44532. doi: 10.7554/eLife.44532 . ISSN   2050-084X. PMC   6559786 . PMID   31184302.
  11. ↑ Goetze, Jens P (August 6, 2009). "Peptide hormones and their prohormones as biomarkers". Biomarkers in Medicine. 3 (4): 335–338. doi:10.2217/bmm.09.29. PMID   20477480 – via Future Medicine.
  12. ↑ Calcium, Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D. and; Ross, A. Catharine; Taylor, Christine L.; Yaktine, Ann L.; Valle, Heather B. Del (2011). Overview of Vitamin D. National Academies Press (US).
  13. ↑ Nillni, Eduardo A. (2007-09-01). "Regulation of Prohormone Convertases in Hypothalamic Neurons: Implications for ProThyrotropin-Releasing Hormone and Proopiomelanocortin". Endocrinology. 148 (9): 4191–4200. doi: 10.1210/en.2007-0173 . ISSN   0013-7227. PMID   17584972.
  14. 1 2 Alberts, Bruce; Alexander Johnson; Julian Lewis; Martin Raff; Keith Roberts; Peter Walter (2002). Molecular biology of the cell (4th ed.). New York: Garland Science. ISBN   0-8153-3218-1. OCLC   48122761.
  15. ↑ Yonemoto, I. T.; Kroon, G. J.; Dyson, H. J.; Balch, W. E.; Kelly, J. W. (August 19, 2008). "Amylin Proprotein Processing Generates Progressively More Amyloidogenic Peptides that Initially Sample the Helical State". Biochemistry. 47 (37): 9900–9910. doi:10.1021/bi800828u. PMC   2662778 . PMID   18710262 – via American Chemical Society.
  16. 1 2 3 4 Granados, Jorge; Gillum, Trevor L.; Christmas, Kevin M.; Kuennen, Matthew R. (2014-03-01). "Prohormone supplement 3β-hydroxy-5α-androst-1-en-17-one enhances resistance training gains but impairs user health". Journal of Applied Physiology. 116 (5): 560–569. doi:10.1152/japplphysiol.00616.2013. ISSN   8750-7587. PMID   24381122.
  17. 1 2 "Text - S.2195 - 108th Congress (2003-2004): Anabolic Steroid Control Act of 2004". www.congress.gov. 2004-10-22. Retrieved 2021-12-09.
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