Steroid

A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary lipid cholesterol, the sex hormones estradiol and testosterone and the anti-inflammatory drug dexamethasone.

The core of steroids is composed of seventeen carbon atoms bonded together that take the form of four fused rings: three cyclohexane rings (designated as rings A, B and C in the figure to the right) and one cyclopentane ring (the D ring). The steroids vary by the functional groups attached to this four-ring core and by the oxidation state of the rings. Sterols are special forms of steroids, with a hydroxyl group at position-3 and a skeleton derived from cholestane.^[1]

Hundreds of distinct steroids are found in plants, animals and fungi. All steroids are made in cells either from the sterols lanosterol (animals and fungi, see below right) or from cycloartenol (plants). Both lanosterol and cycloartenol are derived from the cyclization of the triterpene squalene.^[2]

Nomenclature

Steroids are a class of organic compounds with a chemical structure that contains the core of gonane or a skeleton derived therefrom. Usually, methyl groups are present at the carbons C-10 and C-13 – an alkyl side-chain at carbon C-17 may also be present.

Gonane, see above, is the simplest possible steroid and is composed of seventeen carbon atoms, bonded together to form four fused rings. The three cyclohexane rings (designated as rings A, B, and C in the figure below) form the skeleton of phenanthrene; ring D has a cyclopentane structure. Hence, together they are called cyclopentaphenanthrene.^[3]

The more complex structure of cholic acid, a bile acid.

Commonly, steroids have a methyl group at the carbons C-10 and C-13 and an alkyl side chain at carbon C-17. Further, they vary by the configuration of the side chain, the number of additional methyl groups, and the functional groups attached to the rings. For example, sterols have a hydroxyl group attached at position C-3.

Some exemplary steroids with their structures:

The anabolic steroid testosterone, the principal male sex hormone.

Progesterone, a steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis.

Medrogestone, a synthetic drug with similar effects as progesterone.

β-Sitosterol, a phytosterol showing the hydroxyl group at C-3.

Types

Taxonomical/functional

Some of the common categories of steroids:

• Animal
  • Insect
    • Ecdysteroids such as ecdysterone that controls moulting
  • Vertebrate
    • Steroid hormones
      • Sex steroids are a subset of sex hormones that produce sex differences or support reproduction. They include androgens, estrogens, and progestagens.
      • Corticosteroids include glucocorticoids and mineralocorticoids. Glucocorticoids regulate many aspects of metabolism and immune function, whereas mineralocorticoids help maintain blood volume and control renal excretion of electrolytes. Most medical 'steroid' drugs are corticosteroids.
      • Anabolic steroids are a class of steroids that interact with androgen receptors to increase muscle and bone synthesis. There are natural and synthetic anabolic steroids. In popular language, the word "steroids" usually refers to anabolic steroids.
    • Cholesterol, which modulates the fluidity of cell membranes and is the principal constituent of the plaques implicated in atherosclerosis.
• Plant
  • Phytosterols
  • Brassinosteroids (includes several plant hormones)
  • Steroidal alkaloids found notably in Solanaceae
• Fungus
  • Ergosterols

Structural

It is also possible to classify steroids based upon their chemical composition. One example of how MeSH performs this classification is available at the Wikipedia MeSH catalog. Examples from this classification include:

Class	Examples	Number of carbon atoms
Cholestanes	cholesterol	27
Cholanes	cholic acid	24
Pregnanes	progesterone	21
Androstanes	testosterone	19
Estranes	estradiol	18

Gonane (or steroid nucleus) is the parent (17-carbon tetracyclic) hydrocarbon molecule without any alkyl sidechains.^[4]

Biological significance

Steroid and their metabolites are frequently used signalling molecules. The most notable examples are the steroid hormones.

Steroids along with phospholipids function as components of cell membranes. Steroids such as cholesterol decrease membrane fluidity.^[5]

Similar to lipids, steroids represent highly concentrated energy stores. However steroids are not typically used as sources of energy. In mammals, they are normally metabolized and excreted.

Pharmacological actions

A number of drugs target the mevalonate pathway:

• Statins (used for elevated cholesterol levels)
• Bisphosphonates (used in treatment of various bone-degenerative diseases)

Biosynthesis and metabolism

Steroid biosynthesis is an anabolic metabolic pathway that produces steroids from simple precursors. A unique biosynthetic pathway is followed in animals compared to many other organisms, making the pathway a common target for antibiotics and other anti-infective drugs. In addition, steroid metabolism in humans is the target of cholesterol-lowering drugs such as statins.

In humans and other animals, the biosynthesis of steroids follows the mevalonate pathway that uses acetyl-CoA as building-blocks to form dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP).^[6] In subsequent steps, DMAPP and IPP are joined to form geranyl pyrophosphate (GPP), which in turn is used to synthesize the steroid lanosterol. Further modifications of lanosterol into other steroids are classified steroidogenesis transformations.

Mevalonate pathway

The mevalonate pathway or HMG-CoA reductase pathway starts with acetyl-CoA and ends with dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP).

DMAPP and IPP in turn donate isoprene units, which are assembled and modified to form terpenes and isoprenoids,^[7] which are a large class of lipids that include the carotenoids, and form the largest class of plant natural products.^[8]

Here, the isoprene units are joined together to make squalene and then folded up and formed into a set of rings to make lanosterol.^[9] Lanosterol can then be converted into other steroids such as cholesterol and ergosterol.^[9][10]

Steroidogenesis

Steroidogenesis is the biological process by which steroids are generated from cholesterol and transformed into other steroids.^[11] The pathways of steroidogenesis differ between different species – as an example the pathways of human steroidogenesis are shown in this figure below: The major classes of steroid hormones and some prominent members of the human steroidogenesis are:

• Progestogens:
  • Progesterone
• Corticosteroids (Corticoids):
  • Aldosterone (Mineralocorticoids)
  • Cortisol (Glucocorticoids)
• Androgens:
  • Testosterone
• Estrogens:
  • Estrogen

Locations of human steroidogenesis:

• Progestogens serve as precursors to all other human steroids – thus all human tissues which produce steroids must first convert cholesterol to pregnenolone. This conversion is the rate-limiting step of steroid synthesis, which occurs inside the mitochondrion of the respective tissue.^[12]
• Corticosteroids are produced in the adrenal cortex.
• Estrogen and progesterone are made primarily in the ovary and in the placenta during pregnancy, and testosterone in the testes.
• Testosterone is also converted into estrogen to regulate the supply of each, in the bodies of both females and males.
• In addition, certain neurons and glia in the central nervous system (CNS) express the enzymes that are required for the local synthesis of pregnane neurosteroids, either de novo or from peripherally derived sources.

Regulation

Several key enzymes can be activated through DNA transcriptional regulation on activation of SREBP (Sterol Regulatory Element-Binding Protein-1 and -2).^{[citation needed]} This intracellular sensor detects low cholesterol levels and stimulates endogenous production by the HMG-CoA reductase pathway, as well as increasing lipoprotein uptake by up-regulating the LDL receptor.^{[citation needed]} Regulation of this pathway is also achieved by controlling the rate of translation of the mRNA, degradation of reductase and phosphorylation.^{[citation needed]}

Alternative pathways

In plants and bacteria, the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates.^[7][13]

Metabolism

Steroids are oxidized mainly by cytochrome P450 oxidase enzymes, such as CYP3A4. These reactions introduce oxygen into the steroid ring and allow the structure to be broken up by other enzymes, to form bile acids as final products.^[14] These bile acids can then be eliminated through secretion from the liver in the bile.^[15] The expression of this oxidase gene can be upregulated by the steroid sensor PXR when there is a high blood concentration of steroids.^[16]

Partial synthesis

Phytosterols, especially a mixture of soybean phytosterols, as starting materials can be converted into two kinds of steroid hormone intermediates through microbial transformation. Microbial catabolism of phytosterol sidechains yields either C-19 steroids, a precursor to most steroid hormones including sex hormones, or C-22 steroids, a precursor to adrenocortical hormones.

The chemical conversion of sapogenins to steroids — Marker degradation combined with Mexican barbasco trade — is a long established alternative to microbial transformation of phytosterols to steroids. It is however unsustainable since huge tubers of plants growing in the wild were harvested.^[17][18]

Determination of structure and methods of analysis

Methods of isolation

History

A number of Nobel Prizes have been awarded for research involving steroids. These prizes include:

• 1927 (Chemistry) Heinrich Otto Wieland – constitution of the bile acids, sterols, and their connection with the vitamins^[19]
• 1928 (Chemistry) Adolf Otto Reinhold Windaus – constitution of the sterols and their connection with the vitamins^[20]
• 1939 (Chemistry) Adolf Butenandt and Leopold Ruzicka – isolation and structural studiesof steroid sex hormones, and related studies on higher terpenes^[21]
• 1950 (Physiology or Medicine) Edward Kendall, Tadeus Reichstein, Philip Hench – on the structure and biological effects of adrenal hormones^[22]
• 1965 (Chemistry) Robert Burns Woodward, in part for the synthesis of cholesterol, cortisone, and lanosterol^[23]
• 1969 (Chemistry) Derek Barton, Odd Hassel, development of the concept of conformation and its application in chemistry, where a specific important emphasis was on the conformation of the "Steroid Nucleus"^[24]
• 1975 (Chemistry) Vladimir Prelog, in part for developing methods to determine the stereochemical course of cholesterol biosynthesis from mevalonic acid via squalene^[25]

See also

• Batrachotoxin
• Corticosteroid
• List of steroid abbreviations
• Sex steroid
• Steroid hormone
• Steroid hydroxylases
• Steroid sulfatase
• Steroidogenic acute regulatory protein

References

Further reading

• Lednicer D (2011). Steroid Chemistry at a Glance. Hoboken: Wiley. doi:10.1002/9780470973639. ISBN 978-0-470-66085-0. 
• Yoder RA, Johnston JN (December 2005). "A case study in biomimetic total synthesis: polyolefin carbocyclizations to terpenes and steroids". Chem. Rev. 105 (12): 4730–56. doi:10.1021/cr040623. PMC 2575671. PMID 16351060.  – review of the history of steroid synthesis, especially biomimetic

External links

• Moss GP; IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). "The Nomenclature of Steroids Home Page". Queen Mary University of London.  Cite uses deprecated parameters (help)
• Bowen RA (October 20, 2001). "Steroidogenesis". Pathophysiology of the Endocrine System. Colorado State University. 
• Heasley BH. "Modern Steroid Science". Steroid Blog. Google+. 

v t e Cholesterol and steroid metabolic intermediates Mevalonate pathway to HMG-CoA Acetyl-CoA Acetoacetyl-CoA HMG-CoA Ketone bodies Acetone Acetoacetic acid beta-Hydroxybutyric acid to DMAPP Mevalonic acid Phosphomevalonic acid 5-Diphosphomevalonic acid Isopentenyl pyrophosphate Dimethylallyl pyrophosphate Geranyl- Geranyl pyrophosphate Geranylgeranyl pyrophosphate Carotenoid Prephytoene diphosphate Phytoene Non-mevalonate pathway DOXP MEP CDP-ME CDP-MEP MEcPP HMB-PP IPP DMAPP To Cholesterol Farnesyl pyrophosphate Squalene 2,3-Oxidosqualene Lanosterol Lanosterol Lathosterol 7-Dehydrocholesterol Cholesterol Lanosterol Zymosterol 7-Dehydrodesmosterol Desmosterol Cholesterol From Cholesterol (to steroids) 22R-Hydroxycholesterol 20α,22R-Dihydroxycholesterol Steroid hormones Corticosteroids (C21 pregnane) Mineralocorticoids Pregnenolone Progesterone Cortodoxone Corticosterone Aldosterone Glucocorticoids Pregnenolone 17-Hydroxypregnenolone 17-Hydroxyprogesterone Cortisol Cortisol Cortisone Sex steroids Androgens (C19 androstane) DHEA Androstenedione/5-Androstenediol Testosterone Dihydrotestosterone DHEA sulfate Epitestosterone Estrogens (C18 estrane) Estetrol Estrone Estradiol Estriol Nonhuman Phytosterols Stigmasterol Brassicasterol Ergosterols Ergosterol Ergocalciferol M: MET mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon m (A16/C10), i (k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m) M: END anat/phys/devp/horm noco (d)/cong/tumr, sysi/epon proc, drug (A10/H1/H2/H3/H5) Biochemical families: carbohydrates alcohols glycoproteins glycosides lipids eicosanoids fatty acids / intermediates phospholipids sphingolipids steroids nucleic acids constituents / intermediates proteins Amino acids / intermediates tetrapyrroles / intermediates

v t e Metabolism (Catabolism, Anabolism) General Metabolic pathway Metabolic network Primary nutritional groups Energy metabolism Aerobic respiration Glycolysis → Pyruvate Decarboxylation → Citric acid cycle → Oxidative phosphorylation (Electron Transport Chain + ATP synthase) Anaerobic respiration Electron acceptors are other than oxygen Fermentation Glycolysis → Substrate-level phosphorylation ABE Ethanol Lactic acid Specific paths Protein metabolism Protein synthesis Catabolism Carbohydrate metabolism (Carbohydrate catabolism and anabolism) Human Glycolysis ⇄ Gluconeogenesis Glycogenolysis ⇄ Glycogenesis Pentose phosphate pathway Fructolysis Galactolysis Glycosylation N-linked O-linked Nonhuman Photosynthesis Anoxygenic photosynthesis Chemosynthesis Carbon fixation Xylose metabolism Lipid metabolism (Lipolysis, Lipogenesis) Fatty acid metabolism Fatty acid degradation (Beta oxidation) Fatty acid synthesis Other Steroid metabolism Sphingolipid metabolism Eicosanoid metabolism Ketosis Amino acid Amino acid synthesis Urea cycle Nucleotide metabolism Purine metabolism Nucleotide salvage Pyrimidine metabolism Other Metal metabolism Iron metabolism Ethanol metabolism M: MET mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon m (A16/C10), i (k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m) Biochemical families: carbohydrates alcohols glycoproteins glycosides lipids eicosanoids fatty acids / intermediates phospholipids sphingolipids steroids nucleic acids constituents / intermediates proteins Amino acids / intermediates tetrapyrroles / intermediates