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Steroid

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This article is about a family of polycyclic hydrocarbons. For the performance-enhancing substance, see Anabolic steroid.
IUPAC-recommended ring-lettering (left) and atom-numbering (right) of cholestane, a prototypical steroid skeleton.[1] The four rings A-D form the gonane nucleus of the steroid.
Stick model of the steroid lanosterol. The total number of carbons (30) reflects its triterpenoid origin.

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 fat 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) or from cycloartenol (plants). Both lanosterol and cycloartenol are derived from the cyclization of the triterpene squalene.[2]

Structure

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.

The basic skeleton of a steroid, with standard stereo orientation. R is a side-chain at C-17.
Cholesterol. This steroid is the precursor to other steroids in the steroidogenesis.

Gonane 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]

Numbering of rings and of carbon atoms in gonane, the simplest possible steroid.
The structure of cholestane, one of the comparatively simpler steroids.
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.
An example of functional groups is the hydroxyl group at C-3 common to sterols.
β-Sitosterol, a phytosterol showing the hydroxyl group at C-3.

Classification

Taxonomical/functional

Some of the common categories of steroids:

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]

Biosynthesis

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.

Simplified version of latter part of steroid synthesis pathway, where the intermediates isopentenyl pyrophosphate (PP or IPP) and dimethylallyl pyrophosphate (DMAPP) form geranyl pyrophosphate (GPP), squalene and, finally, lanosterol, the first steroid in the pathways. Some intermediates are omitted for clarity.

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).[5] 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

Main article: Mevalonate pathway

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

Mevalonate pathway

Pharmacology

A number of drugs target the mevalonate pathway:

DMAPP to lanosterol

Isopentenyl pyrophosphate and dimethylallyl pyrophosphate donate isoprene units, which are assembled and modified to form terpenes and isoprenoids,[6] which are a large class of lipids that include the carotenoids, and form the largest class of plant natural products.[7]

Here, the isoprene units are joined together to make squalene and then folded up and formed into a set of rings to make lanosterol.[8] Lanosterol can then be converted into other steroids such as cholesterol and ergosterol.[8][9]

Steroidogenesis

"Steroidogenesis" redirects here. For other uses, see Steroidogenesis (disambiguation).

Steroidogenesis is the biological process by which steroids are generated from cholesterol and transformed into other steroids.[10] The pathways of steroidogenesis differ between different species – as an example the pathways of human steroidogenesis are shown in this figure below:

The human steroidogenesis, with the major classes of steroid hormones, individual steroids and enzymatic pathways. Note that changes in molecular structure compared to the respective precursor are highlighted with white circles.

The major classes of steroid hormones and some prominent members of the human steroidogenesis are:

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.[11]
  • 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). 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. Regulation of this pathway is also achieved by controlling the rate of translation of the mRNA, degradation of reductase and phosphorylation.

Alternative pathways

In plants and bacteria, the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates.[6][12]

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.[13] These bile acids can then be eliminated through secretion from the liver in the bile.[14] The expression of this oxidase gene can be upregulated by the steroid sensor PXR when there is a high blood concentration of steroids.[15]

See also

References

  1. ^ a b G. P. Moss (1989). "Nomenclature of Steroids (Recommendations 1989)". Pure & Appl. Chem. 61 (10): 1783–1822. doi:10.1351/pac198961101783. PDF "IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989". Eur. J. Biochem. 186 (3): 429–58. 1989. doi:10.1111/j.1432-1033.1989.tb15228.x. PMID 2606099. {{cite journal}}: Unknown parameter |month= ignored (help)
  2. ^ "Lanosterol biosynthesis". Recommendations on Biochemical & Organic Nomenclature, Symbols & Terminology. International Union Of Biochemistry And Molecular Biology.
  3. ^ CID 130801 from PubChem; 219-08-9 cyclopentaphenanthrene
  4. ^ Edgren RA, Stanczyk FZ (1999). "Nomenclature of the gonane progestins". Contraception. 60 (6): 313. doi:10.1016/S0010-7824(99)00101-8. PMID 10715364. {{cite journal}}: Unknown parameter |month= ignored (help)
  5. ^ Grochowski L, Xu H, White R (2006). "Methanocaldococcus jannaschii uses a modified mevalonate pathway for biosynthesis of isopentenyl diphosphate". J Bacteriol. 188 (9): 3192–8. doi:10.1128/JB.188.9.3192-3198.2006. PMC 1447442. PMID 16621811.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ a b Kuzuyama T, Seto H (2003). "Diversity of the biosynthesis of the isoprene units". Nat Prod Rep. 20 (2): 171–83. doi:10.1039/b109860h. PMID 12735695.
  7. ^ Dubey V, Bhalla R, Luthra R (2003). "An overview of the non-mevalonate pathway for terpenoid biosynthesis in plants" (PDF). J Biosci. 28 (5): 637–46. doi:10.1007/BF02703339. PMID 14517367.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ a b Schroepfer G (1981). "Sterol biosynthesis". Annu Rev Biochem. 50: 585–621. doi:10.1146/annurev.bi.50.070181.003101. PMID 7023367.
  9. ^ Lees N, Skaggs B, Kirsch D, Bard M (1995). "Cloning of the late genes in the ergosterol biosynthetic pathway of Saccharomyces cerevisiae—a review". Lipids. 30 (3): 221–6. doi:10.1007/BF02537824. PMID 7791529.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Hanukoglu I (1992). "Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis". J Steroid Biochem Mol Biol. 43 (8): 779–804. doi:10.1016/0960-0760(92)90307-5. PMID 22217824. {{cite journal}}: Unknown parameter |month= ignored (help)
  11. ^ Rossier MF (2006). "T channels and steroid biosynthesis: in search of a link with mitochondria". Cell Calcium. 40 (2): 155–64. doi:10.1016/j.ceca.2006.04.020. PMID 16759697.
  12. ^ Lichtenthaler H (1999). "The 1-Dideoxy-D-xylulose-5-phosphate pathway of isoprenoid biosynthesis in plants". Annu Rev Plant Physiol Plant Mol Biol. 50: 47–65. doi:10.1146/annurev.arplant.50.1.47. PMID 15012203.
  13. ^ Pikuleva IA (2006). "Cytochrome P450s and cholesterol homeostasis". Pharmacol. Ther. 112 (3): 761–73. doi:10.1016/j.pharmthera.2006.05.014. PMID 16872679.
  14. ^ Zollner G, Marschall HU, Wagner M, Trauner M (2006). "Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations". Mol. Pharm. 3 (3): 231–51. doi:10.1021/mp060010s. PMID 16749856.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Kliewer S, Goodwin B, Willson T (2002). "The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism". Endocr. Rev. 23 (5): 687–702. doi:10.1210/er.2001-0038. PMID 12372848.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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