Steroid

Steroid ring system: The parent ABCD steroid ring system (hydrocarbon framework) is shown with IUPAC-approved ring lettering and atom numbering.^[1]:1785f

A steroid is an organic compound with four rings arranged in a specific configuration. Examples include the dietary lipid cholesterol, the sex hormones estradiol and testosterone^[2]:10–19 and the anti-inflammatory drug dexamethasone.^[3] Steroids have two principal biological functions: certain steroids (such as cholesterol) are important components of cell membranes which alter membrane fluidity, and many steroids are signaling molecules which activate steroid hormone receptors.

The steroid core structure is composed of seventeen carbon atoms, bonded in four "fused" rings: three six-member cyclohexane rings (rings A, B and C in the first illustration) and one five-member cyclopentane ring (the D ring). Steroids vary by the functional groups attached to this four-ring core and by the oxidation state of the rings. Sterols are forms of steroids with a hydroxyl group at position three and a skeleton derived from cholestane.^{[4][1]:1785f [5]} They can also vary more markedly by changes to the ring structure (for example, ring scissions which produce secosteroids such as vitamin D₃).

Hundreds of steroids are found in plants, animals and fungi. All steroids are manufactured in cells from the sterols lanosterol (animals and fungi) or cycloartenol (plants). Lanosterol and cycloartenol are derived from the cyclization of the triterpene squalene.^[6]

Space-filling representation

Ball-and-stick representation

5α-dihydroprogesterone (5α-DHP), a steroid. The shape of the four rings of most steroids is illustrated (carbon atoms in black, oxygens in red and hydrogens in grey). The apolar "slab" of hydrocarbon in the middle (grey, black) and the polar groups at opposing ends (red) are common features of natural steroids. 5α-DHP is an endogenous steroid hormone and a biosynthetic intermediate.

Nomenclature

A gonane (steroid nucleus)

A gonane, the simplest steroid, is composed of seventeen carbon atoms in carbon-carbon bonds forming four fused rings in a three-dimensional shape. The three cyclohexane rings (A, B, and C in the first illustration) form the skeleton of a perhydro derivative of phenanthrene. The D ring has a cyclopentane structure. When the two methyl groups and eight carbon side chains (at C-17, as shown for cholesterol) are present, the steroid is said to have a cholestane framework. The two common 5α and 5β stereoisomeric forms of steroids exist because of differences in the side of the largely planar ring system where the hydrogen (H) atom at carbon-5 is attached, which results in a change in steroid A-ring conformation.

Examples of steroid structures are:

Testosterone, the principal male sex hormone and an anabolic steroid

Cholic acid, a bile acid, showing the carboxylic acid and additional hydroxyl groups often present

Dexamethasone, a synthetic corticosteroid drug

Lanosterol, the biosynthetic precursor to animal steroids. The number of carbons (30) indicates its triterpenoid classification.

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

Medrogestone, a synthetic drug with effects similar to progesterone

β-Sitosterol, a plant or phytosterol, with a fully branched hydrocarbon side chain at C-17 and an hydroxyl group at C-3

In addition to the ring scissions (cleavages), expansions and contractions (cleavage and reclosing to a larger or smaller rings)—all variations in the carbon-carbon bond framework—steroids can also vary:

• in the bond orders within the rings,
• in the number of methyl groups attached to the ring (and, when present, on the prominent side chain at C17),
• in the functional groups attached to the rings and side chain, and
• in the configuration of groups attached to the rings and chain.^[2]:2–9

For instance, sterols such as cholesterol and lanosterol have an hydroxyl group attached at position C-3, while testosterone and progesterone have a carbonyl (oxo substituent) at C-3; of these, lanosterol alone has two methyl groups at C-4 and cholesterol (with a C-5 to C-6 double bond) differs from testosterone and progesterone (which have a C-4 to C-5 double bond).

Cholesterol, a prototypical animal sterol. This structural lipid and key steroid biosynthetic precursor.[1]:1785f

5α-cholestane, a common steroid core

Steroid 5α and 5β stereoisomers[1]:1786f

Species distribution and function

The following are some common categories of steroids. In eukaryotes, steroids are found in fungi, animals, and plants. Fungal steroids include the ergosterols.

Animal steroids include compounds of vertebrate and insect origin, the latter including ecdysteroids such as ecdysterone (controlling molting in some species). Vertebrate examples include the steroid hormones and cholesterol; the latter is a structural component of cell membranes which helps determine the fluidity of cell membranes and is a principal constituent of plaque (implicated in atherosclerosis). Steroid hormones include:

• Sex hormones, which influence sex differences and support reproduction. These include androgens, estrogens, and progestagens.
• The corticosteroids, including most synthetic steroid drugs, with natural product classes the glucocorticoids (which regulate many aspects of metabolism and immune function) and the mineralocorticoids (which help maintain blood volume and control renal excretion of electrolytes)
• Anabolic steroids, natural and synthetic, which interact with androgen receptors to increase muscle and bone synthesis. In popular use, the term "steroids" often refers to anabolic steroids.

Plant steroids include steroidal alkaloids found in Solanaceae,^[7] the phytosterols, and the brassinosteroids (which include several plant hormones). In prokaryotes, biosynthetic pathways exist for the tetracyclic steroid framework (e.g. in mycobacteria)^[8] – where its origin from eukaryotes is conjectured^[9] – and the more-common pentacyclic triterpinoid hopanoid framework.^[10]

Types

Intact ring system

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

Cholecalciferol (vitamin D₃), an example of a 9,10-secosteroid

Cyclopamine, an example of a complex C-nor-D-homosteroid

The gonane (steroid nucleus) is the parent 17-carbon tetracyclic hydrocarbon molecule with no alkyl sidechains.^[11]

Cleaved, contracted, and expanded rings

Secosteroids (Latin seco, "to cut") are a subclass of steroidal compounds resulting, biosynthetically or conceptually, from scission (cleavage) of parent steroid rings (generally one of the four). Major secosteroid subclasses are defined by the steroid carbon atoms where this scission has taken place. For instance, the prototypical secosteroid cholecalciferol, vitamin D₃ (shown), is in the 9,10-secosteroid subclass and derives from the cleavage of carbon atoms C-9 and C-10 of the steroid B-ring; 5,6-secosteroids and 13,14-steroids are similar.^[12]

Norsteroids (nor-, L. norma; "normal" in chemistry, indicating carbon removal)^[13] and homosteroids (homo-, Greek homos; "same", indicating carbon addition) are structural subclasses of steroids formed from biosynthetic steps. The former involves enzymic ring expansion-contraction reactions, and the latter is accomplished (biomimetically) or (more frequently) through ring closures of acyclic precursors with more (or fewer) ring atoms than the parent steroid framework.^[14]

Combinations of these ring alterations are known in nature. For instance, ewes who graze on corn lily ingest cyclopamine (shown) and veratramine, two of a sub-family of steroids where the C- and D-rings are contracted and expanded respectively via a biosynthetic migration of the original C-13 atom. Ingestion of these C-nor-D-homosteroids results in birth defects in lambs: cyclopia from cyclopamine and leg deformity from veratramine.^[15] A further C-nor-D-homosteroid (nakiterpiosin) is excreted by Okinawan cyanobacteriosponges – Terpios hoshinota – leading to coral mortality from black coral disease.^[16] Nakiterpiosin-type steroids are active against the signaling pathway involving the smoothened and hedgehog proteins, a pathway which is hyperactive in a number of cancers.

Biological significance

Steroids and their metabolites often function as signalling molecules (the most notable examples are steroid hormones), and steroids and phospholipids are components of cell membranes. Steroids such as cholesterol decrease membrane fluidity.^[17] Similar to lipids, steroids are highly concentrated energy stores. However, they are not typically sources of energy; in mammals, they are normally metabolized and excreted.

Pharmacological action

Two classes of drugs target the mevalonate pathway: statins (used to reduce elevated cholesterol levels) and bisphosphonates (used to treat a number of bone-degenerative diseases).

Biosynthesis and metabolism

The hundreds of steroids found in animals, fungi, and plants are made from lanosterol (in animals and fungi; see examples above) or cycloartenol (in plants). Lanosterol and cycloartenol derive from cyclization of the triterpenoid squalene.^[6]

Simplification of the end of the steroid synthesis pathway, where the intermediates isopentenyl pyrophosphate (PP or IPP) and dimethylallyl pyrophosphate (DMAPP) form geranyl pyrophosphate (GPP), squalene and lanosterol (the first steroid in the pathway)

Steroid biosynthesis is an anabolic pathway which 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-infection drugs. Steroid metabolism in humans is also the target of cholesterol-lowering drugs, such as statins.

In humans and other animals the biosynthesis of steroids follows the mevalonate pathway, which uses acetyl-CoA as building blocks for dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP).^[18] In subsequent steps DMAPP and IPP join to form geranyl pyrophosphate (GPP), which synthesizes the steroid lanosterol. Modifications of lanosterol into other steroids are classified as steroidogenesis transformations.

Mevalonate pathway

Mevalonate pathway

The mevalonate, or HMG-CoA reductase pathway begins with acetyl-CoA and ends with dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP). DMAPP and IPP donate isoprene units, which are assembled and modified to form terpenes and isoprenoids^[19] (a large class of lipids, which include the carotenoids and form the largest class of plant natural products.^[20] Here, the isoprene units are joined to make squalene and folded into a set of rings to make lanosterol.^[21] Lanosterol can then be converted into other steroids, such as cholesterol and ergosterol.^[21][22]

Steroidogenesis

Human steroidogenesis, with the major classes of steroid hormones, individual steroids and enzymatic pathways. Changes in molecular structure from a precursor are highlighted in white.

Steroidogenesis is the biological process by which steroids are generated from cholesterol and changed into other steroids.^[23] The pathways of steroidogenesis differ among species. The major classes of steroid hormones, with prominent members and examples of related functions, are:

• Progestogens:
  • Progesterone, which regulates cyclical changes in the endometrium of the uterus and maintains a pregnancy
• Corticosteroids (corticoids):
  • Aldosterone, a mineralocorticoid which helps regulate blood pressure
  • Cortisol, a glucocorticoid whose functions include immunosuppression
• Androgens:
  • Testosterone, which contributes to the development and maintenance of male secondary sex characteristics
• Estrogens:
  • Estrogen, which contributes to the development and maintenance of female secondary sex characteristics

Human steroidogenesis occurs in a number of locations:

• Progestogens are the precursors of all other human steroids, and 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.^[24]
• Corticosteroids are produced in the adrenal cortex.
• Estrogen and progesterone are made primarily in the ovary and the placenta during pregnancy, and testosterone in the testes.
• Testosterone is also converted to estrogen to regulate the supply of each in females and males.
• Some neurons and glia in the central nervous system (CNS) express the enzymes required for the local synthesis of pregnane neurosteroids, de novo or from peripheral sources.

Alternative pathways

In plants and bacteria, the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates.^[19][25]

Catabolism and excretion

Steroids are primarily oxidized by cytochrome P450 oxidase enzymes, such as CYP3A4. These reactions introduce oxygen into the steroid ring, allowing the cholesterol to be broken up by other enzymes into bile acids.^[26] These acids can then be eliminated by secretion from the liver in bile.^[27] The expression of the oxidase gene can be upregulated by the steroid sensor PXR when there is a high blood concentration of steroids.^[28] Steroid hormones, lacking the side chain of cholesterol and bile acids, are typically hydroxylated at various ring positions or oxidized at the 17 position, conjugted with sulfate or glucuronic acid and excreted in the urine.^[29]

Isolation, structure determination, and methods of analysis

Steroid isolation, depending on context, is the isolation of chemical matter required for chemical structure elucidation, derivitzation or degradation chemistry, biological testing, and other research needs (generally milligrams to grams, but often more^[30] or the isolation of "analytical quantities" of the substance of interest (where the focus is on identifying and quantifying the substance (for example, in biological tissue or fluid). The amount isolated depends on the analytical method, but is generally less than one microgram.^[31] The methods of isolation to achieve the two scales of product are distinct, but include extraction, precipitation, adsorption, chromatography, and crystallization. In both cases, the isolated substance is purified to chemical homogeneity; combined separation and analytical methods, such as LC-MS, are chosen to be "orthogonal"—achieving their separations based on distinct modes of interaction between substance and isolating matrix—to detect a single species in the pure sample. Structure determination refers to the methods to determine the chemical structure of an isolated pure steroid, using an evolving array of chemical and physical methods which have included NMR and small-molecule crystallography.^[2]:10–19 Methods of analysis overlap both of the above areas, emphasizing analytical methods to determining if a steroid is present in a mixture and determining its quantity.^[31]

Chemical synthesis

Microbial catabolism of phytosterol sidechains yields C-19 steroids, a precursor to most steroid hormones, or C-22 steroids (a precursor to adrenocortical hormones).^[32][33]

The chemical conversion of sapogenins to steroids—e.g., via the Marker degradation—is a method of partial synthesis that is a long-established alternative to microbial transformation of phytosterols to steroids, and underpinned Syntex efforts using the Mexican barbasco trade (harvesting and marketing large tubers of wild-growing plants, e.g., yams) to produce early synthetic steroids.^[30]

Research awards

A number of Nobel Prizes have been awarded for steroid research, including:

• 1927 (Chemistry) Heinrich Otto Wieland – Constitution of bile acids and sterols and their connection to vitamins^[34]
• 1928 (Chemistry) Adolf Otto Reinhold Windaus – Constitution of sterols and their connection to vitamins^[35]
• 1939 (Chemistry) Adolf Butenandt and Leopold Ruzicka – Isolation and structural studies of steroid sex hormones, and related studies on higher terpenes^[36]
• 1950 (Physiology or Medicine) Edward Calvin Kendall, Tadeus Reichstein, and Philip Hench – Structure and biological effects of adrenal hormones^[37]
• 1965 (Chemistry) Robert Burns Woodward – In part, for the synthesis of cholesterol, cortisone, and lanosterol^[38]
• 1969 (Chemistry) Derek Barton and Odd Hassel – Development of the concept of conformation in chemistry, emphasizing the steroid nucleus^[39]
• 1975 (Chemistry) Vladimir Prelog – In part, for developing methods to determine the stereochemical course of cholesterol biosynthesis from mevalonic acid via squalene^[40]

See also

References

Further reading

External links

• G.P. Moss and the Working Party of the IUPAC-IUB JCBN. "The Nomenclature of Steroids". London, GBR: Queen Mary University of London. . Alternatively, see or , all web sources accessed 20 June 2015. [The content co-authors, the Working Party of the IUPAC-IUB JCBN, were P. Karlson (chairman), J.R. Bull, K. Engel, J. Fried^†, H.W. Kircher, K.L. Loening, G.P. Moss, G. Popják and M.R. Uskokovic.]
• Bowen RA (October 20, 2001). "Steroidogenesis". Pathophysiology of the Endocrine System. Colorado State University.