Steroid


A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes which alter membrane fluidity; and as signaling molecules. Hundreds of steroids are found in plants, animals and fungi. All steroids are manufactured in cells from the sterols lanosterol or cycloartenol. Lanosterol and cycloartenol are derived from the cyclization of the triterpene squalene.
The steroid core structure is typically composed of seventeen carbon atoms, bonded in four "fused" rings: three six-member cyclohexane rings and one five-member cyclopentane 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 hydroxy group at position three and a skeleton derived from cholestane. Steroids can also be more radically modified, such as by changes to the ring structure, for example, cutting one of the rings. Cutting Ring B produces secosteroids one of which is vitamin D3.
Examples include the lipid cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.

Nomenclature

, also known as steran or cyclopentanoperhydrophenanthrene, the simplest steroid and the nucleus of all steroids and sterols, is composed of seventeen carbon atoms in carbon-carbon bonds forming four fused rings in a three-dimensional shape. The three cyclohexane rings 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 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 atom at carbon-5 is attached, which results in a change in steroid A-ring conformation. Isomerisation at the C-21 side chain produces a parallel series of compounds, referred to as isosteroids.
Examples of steroid structures are:
In addition to the ring scissions, expansions and contractions —all variations in the carbon-carbon bond framework—steroids can also vary:
For instance, sterols such as cholesterol and lanosterol have a hydroxyl group attached at position C-3, while testosterone and progesterone have a carbonyl at C-3; of these, lanosterol alone has two methyl groups at C-4 and cholesterol differs from testosterone and progesterone.

Species distribution and function

In eukaryotes, steroids are found in fungi, animals, and plants.

Fungal steroids

Fungal steroids include the ergosterols, which are involved in maintaining the integrity of the fungal cellular membrane. Various antifungal drugs, such as amphotericin B and azole antifungals, utilize this information to kill pathogenic fungi. Fungi can alter their ergosterol content to develop resistance to drugs that target ergosterol. Ergosterol is analogous to the cholesterol found in the cellular membranes of animals, or the phytosterols found in the cellular membranes of plants. All mushrooms contain large quantities of ergosterol, in the range of tens to hundreds of milligrams per 100 grams of dry weight. Oxygen is necessary for the synthesis of ergosterol in fungi. Ergosterol is responsible for the vitamin D content found in mushrooms; ergosterol is chemically converted into provitamin D2 by exposure to ultraviolet light. Provitamin D2 spontaneously forms vitamin D2. However, not all fungi utilize ergosterol in their cellular membranes; for example, the pathogenic fungal species Pneumocystis jirovecii does not, which has important clinical implications. Using the fungus Saccharomyces cerevisiae as an example, other major steroids include ergosta‐5,7,22,24‐tetraen‐3β‐ol, zymosterol, and lanosterol. S. cerevisiae utilizes 5,6‐dihydroergosterol in place of ergosterol in its cell membrane.

Animal steroids

Animal steroids include compounds of vertebrate and insect origin, the latter including ecdysteroids such as ecdysterone. 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. Steroid hormones include:
Plant steroids include steroidal alkaloids found in Solanaceae and Melanthiaceae, cardiac glycosides, the phytosterols and the brassinosteroids.

Prokaryotes

In prokaryotes, biosynthetic pathways exist for the tetracyclic steroid framework – where its origin from eukaryotes is conjectured – and the more-common pentacyclic triterpinoid hopanoid framework.

Types

By function

The major classes of steroid hormones, with prominent members and examples of related functions, are:
Additional classes of steroids include:
As well as the following class of secosteroids :

Intact ring system

Steroids can be classified based on their chemical composition. One example of how MeSH performs this classification is available at. Examples of this classification include:
, an example of a 9,10-secosteroid
, an example of a complex C-nor-D-homosteroid
ClassExampleNumber of carbon atoms
CholestanesCholesterol27
CholanesCholic acid24
PregnanesProgesterone21
AndrostanesTestosterone19
EstranesEstradiol18

The gonane is the parent 17-carbon tetracyclic hydrocarbon molecule with no alkyl sidechains.

Cleaved, contracted, and expanded rings

Secosteroids are a subclass of steroidal compounds resulting, biosynthetically or conceptually, from scission of parent steroid rings. Major secosteroid subclasses are defined by the steroid carbon atoms where this scission has taken place. For instance, the prototypical secosteroid cholecalciferol, vitamin D3, 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.
Norsteroids and homosteroids are structural subclasses of steroids formed from biosynthetic steps. The former involves enzymic ring expansion-contraction reactions, and the latter is accomplished or through ring closures of acyclic precursors with more ring atoms than the parent steroid framework.
Combinations of these ring alterations are known in nature. For instance, ewes who graze on corn lily ingest cyclopamine 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. A further C-nor-D-homosteroid is excreted by Okinawan cyanobacteriosponges. e.g., Terpios hoshinota, leading to coral mortality from black coral disease. 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, and steroids and phospholipids are components of cell membranes. Steroids such as cholesterol decrease membrane fluidity.
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.
Steroids play critical roles in a number of disorders, including malignancies like prostate cancer, where steroid production inside and outside the tumour promotes cancer cell aggressiveness.

Biosynthesis and metabolism

The hundreds of steroids found in animals, fungi, and plants are made from lanosterol or cycloartenol. Lanosterol and cycloartenol derive from cyclization of the triterpenoid squalene.
Steroid biosynthesis is an anabolic pathway which produces steroids from simple precursors. A unique biosynthetic pathway is followed in animals, 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 and isopentenyl pyrophosphate. In subsequent steps DMAPP and IPP join to form geranyl pyrophosphate, which synthesizes the steroid lanosterol. Modifications of lanosterol into other steroids are classified as steroidogenesis transformations.

Mevalonate pathway

The mevalonate pathway begins with acetyl-CoA and ends with dimethylallyl pyrophosphate and isopentenyl pyrophosphate.
DMAPP and IPP donate isoprene units, which are assembled and modified to form terpenes and isoprenoids, which are used to reduce elevated cholesterol levels, and bisphosphonates, which are used to treat a number of bone-degenerative diseases.

Steroidogenesis

Steroidogenesis is the biological process by which steroids are generated from cholesterol and changed into other steroids. The pathways of steroidogenesis differ among species. The major classes of steroid hormones, as noted above, are the Progestogen, Corticosteroids, Androgens, and Estrogens. Human steroidogenesis of these classes occurs in a number of locations:
In plants and bacteria, the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates.
During diseases pathways otherwise not significant in healthy humans can become utilized. For example, in one form of congenital adrenal hyperplasia a deficiency in the 21-hydroxylase enzymatic pathway leads to an excess of 17α-Hydroxyprogesterone – this pathological excess of 17-OHP in turn may be converted to dihydrotestosterone through among others 17,20 Lyase, 5α-Reductase and 3α-Hydroxysteroid dehydrogenase.

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. These acids can then be eliminated by secretion from the liver in bile. The expression of the oxidase gene can be upregulated by the steroid sensor PXR when there is a high blood concentration of steroids. Steroid hormones, lacking the side chain of cholesterol and bile acids, are typically hydroxylated at various ring positions or oxidized at the 17 position, conjugated with sulfate or glucuronic acid and excreted in the urine.

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. The amount isolated depends on the analytical method, but is generally less than one microgram. 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. 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.

Chemical synthesis

Microbial catabolism of phytosterol side chains yields C-19 steroids, C-22 steroids, and 17-ketosteroids. The addition and modification of functional groups is key when producing the wide variety of medications available within this chemical classification. These modifications are performed using conventional organic synthesis and/or biotransformation techniques.

Precursors

Semisynthesis

The semisynthesis of steroids often begins from precursors such as cholesterol, phytosterols, or sapogenins. The efforts of Syntex, a company involved in the Mexican barbasco trade, used Dioscorea mexicana to produce the sapogenin diosgenin in the early days of the synthetic steroid pharmaceutical industry.

Total synthesis

Some steroidal hormones are economically obtained only by total synthesis from petrochemicals. For example, the pharmaceutical Norgestrel begins from Methoxy-1-tetralone, a petrochemical derived from phenol.

Research awards

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