Steroid

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 twenty 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. At carbon C-17 an alkyl side chain may also be present.

The basic skeleton of a steroid, with standard stereo orientations. R is a side-chain.

Cholestane, a typical steroid

Numbering of carbon atoms in gonane

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 above right) form the skeleton of phenanthrene; ring D has a cyclopentane structure. Hence, together they are called cyclopentaphenanthrene.^[3]

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 the hydroxyl group at position C-3 in sterols.

Cholesterol

Cholic acid

Medrogestone

Classification

Taxonomical/Functional

Some of the common categories of steroids:

• Animal
  • Insect
    • Ecdysteroids such as ecdysterone
  • 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
• 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]

Biosynthesis

Simplified version of latter part of steroid synthesis pathway, where the intermediates isopentenyl pyrophosphate (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.

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).^[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

Mevalonate pathway

Main article: Mevalonate pathway

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

Pharmacology

A number of drugs target the mevalonate pathway:

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

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]

Human Steroidogenesis

Steroidogenesis

Steroidogenesis is the biological process by which steroids are generated from cholesterol and transformed into other steroids. The pathways of steroidogenesis differ between different species, but the pathways of human steroidogenesis are shown in the figure.

Products of steroidogenesis include:

• androgens
  • testosterone
• estrogens and progesterone
• corticoids
  • cortisol
  • aldosterone

Steroids include estrogen, cortisol, progesterone, and testosterone. 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. 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. The rate-limiting step of steroid synthesis is the conversion of cholesterol to pregnenolone, which occurs inside the mitochondrion.^[10]

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.^[11][6]

Metabolism

Steroids are oxidized mainly by cytochrome P450 oxidase enzymes, such as CYP3A4. These reactions introduce oxygen into the steroid ring and allows the structure to be broken up by other enzymes, to form bile acids as final products.^[12] These bile acids can then be eliminated through secretion from the liver in the bile.^[13] The expression of this oxidase gene can be upregulated by the steroid sensor PXR when there is a high blood concentration of steroids.^[14]

Use

Medical use

Main article: Steroid_use#Medical uses

Misuse

Main article: Steroid_use#Ergogenic_use_and_abuse

See also

pharmacology portal

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

References

1. ^ ^{a b} G. P. Moss (1989). "Nomenclature of Steroids (Recommendations 1989)". Pure & Appl. Chem. 61 (10): 1783–1822. doi:10.1351/pac198961101783. http://www.chem.qmul.ac.uk/iupac/steroid/.  PDF "IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989". Eur. J. Biochem. 186 (3): 429–58. December 1989. doi:10.1111/j.1432-1033.1989.tb15228.x. PMID 2606099. 
2. ^ "Lanosterol biosynthesis". Recommendations on Biochemical & Organic Nomenclature, Symbols & Terminology. International Union Of Biochemistry And Molecular Biology. http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/terp/lanost.html. 
3. ^ PubChem 130801; 219-08-9 cyclopentaphenanthrene
4. ^ Edgren RA, Stanczyk FZ (December 1999). "Nomenclature of the gonane progestins". Contraception 60 (6): 313. doi:10.1016/S0010-7824(99)00101-8. PMID 10715364. 
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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1447442. 
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". J Biosci 28 (5): 637–46. doi:10.1007/BF02703339. PMID 14517367. http://www.ias.ac.in/jbiosci/sep2003/637.pdf. 
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. 
10. ^ 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. 
11. ^ 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. 
12. ^ Pikuleva IA (2006). "Cytochrome P450s and cholesterol homeostasis". Pharmacol. Ther. 112 (3): 761–73. doi:10.1016/j.pharmthera.2006.05.014. PMID 16872679. 
13. ^ 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. 
14. ^ 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. 

External links

• Nomenclature of Steroids Home Page at Queen Mary University of London.
• Steroidogenesis