Steroids, Chemistry tutorial

Introduction:

The core of steroids is comprised of 20 carbon atoms bonded altogether which take the form of four fused rings: three cyclohexane rings and one cyclopentane ring (the D ring). The steroids differ by the functional groups linked to this four ring core and via the oxidation state of rings. Sterols are special forms of steroids having a hydroxyl group at position-3 and a skeleton derived from the cholestane.

Definition of Steroid:

A steroid is a kind of organic compound which includes a particular arrangement of four cycloalkane rings which are linked to one other. Illustrations of steroids comprise the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.

Hundreds of different steroids are found in animals, plants and fungi. All the steroids are made in cells either from the sterols lanosterol (that is, animals and fungi) or from cycloartenol (that is, plants). Both lanosterol and cycloartenol are derived from the cyclisation of the triterpene squalene.

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Fig: Definition of Steroid

The IUPAC suggested ring lettering (on left) and atom numbering (on right) of cholestane, a prototypical steroid skeleton. The four rings A-D form the gonane nucleus of the steroid.

The total number of carbons (30) points out its triterpenoid origin.

1800_Stick model of the steroid lanosterol.jpg

Fig: Stick model of the steroid lanosterol

Structure of Steroid:

Steroids are the class of organic compounds having a chemical structure which includes the core of gonane or a skeleton derived therefrom. Generally, methyl groups are present at the carbons C-10 and C-13. At carbon C-17 an alkyl side chain might as well be present.

1261_Structure of Steroid.jpg

Fig: Structure of Steroid

Gonane is the simplest likely steroid and is comprised of 17 carbon atoms; bonded altogether to form four fused rings. The three cyclohexane rings (that is, designated as rings A, B and C in the figure above right) make the skeleton of phenanthrene; ring D consists of a cyclopentane structure. Therefore, altogether they are termed as cyclopentaphenanthrene.

Generally, steroids encompass a methyl group at the carbons C-10 and C-13 and an alkyl side chain at carbon C-17. Moreover, they differ by the configuration of the side chain, the number of additional methyl groups and the functional groups linked to the rings. 

Classification of steroids:

I) Taxonomical/Functional Classification:

Some of the common groups of steroids:

1) Animal steroids:

a) Insect steroids: Such comprise Ecdysteroids like ecdysterone

b) Vertebrate steroids (that is, steroid hormones) 

Sex steroids are the subset of sex hormones which generate sex differences or support reproduction. They comprise estrogens, androgens and progestagens.

Corticosteroids comprise glucocorticoids and mineralocorticoids. Glucocorticoids control numerous features of metabolism and immune function, while mineralocorticoids assist in maintaining blood volume and control renal excretion of electrolytes. Most of the medical 'steroid' drugs are corticosteroids.

Anabolic steroids are the class of steroids which interact by androgen receptors to raise muscle and bone synthesis. There are natural and synthetic anabolic steroids. In well-liked language, the term 'steroids' generally refers to anabolic steroids.

Cholesterol that modulates the fluidity of cell membranes and is the main constituent of the plaques associated in atherosclerosis.

2) Plant steroids: Phytosterols and Brassinosteroids

3) Fungus steroids: Ergosterols

II) Structural Classification:

This is mainly based on the chemical composition of the steroids. Illustration from this categorization comprises:

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 (that is, 17-carbon tetracyclic) hydrocarbon molecule devoid of any alkyl side chains.

Metabolism of Steroid:

Steroids comprise estrogen, cortisol, progesterone and testosterone. Estrogen and progesterone are primarily made in the ovary and in the placenta throughout pregnancy and testosterone in the testes.

Testosterone is as well transformed to estrogen to control the supply of each, in the bodies of both males and females. Some of the neurons and glia in the central nervous system (CNS) express the enzymes which are needed for the local synthesis of pregnane neurosteroids, either de novo or by peripherally-derived sources. The rate-limiting step of steroid synthesis is the transformation of cholesterol to pregnenolone that takes place within the mitochondrion.   

Steroid metabolism is the entire set of chemical reactions in organisms which produce, modify, and use steroids. Such metabolic pathways comprise:

  • Steroid synthesis: the preparation of steroids from simpler precursors
  • Steroidogenesis: The interconversion of various kinds of steroids
  • Steroid degradation.

Steroid synthesis:

Steroid biosynthesis is the anabolic metabolic pathway which makes steroids from simple precursors. This pathway is taken out in different manners in animals than in most of the other organisms, making the pathway a general target for antibiotics and other anti-infective drugs. Moreover, steroid metabolism in humans is the target of cholesterol-lowering drugs like Statins.

It begins in the mevalonate pathway in humans, having Acetyl-CoA as building blocks that form DMAPP and IPP. In the given steps, DMAPP and IPP form lanosterol, the primary steroid.

920_Steroid synthesis.jpg

Fig: Steroid synthesis

The simplified version of latter portion of steroid synthesis pathway, where the intermediates isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) makes geranyl pyrophosphate (GPP), squalene and lastly, lanosterol, the primary steroid in the pathways. 

=> Mevalonate pathway:

The mevalonate pathway or HMG-CoA reductase pathway begins by and ends by the dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP). Some key enzymes can be activated via DNA transcriptional regulation on activation of SREBP (that is, Sterol Regulatory Element-Binding Protein-1 and -2). This intracellular sensor detects the low cholesterol levels and stimulates endogenous production through the HMG-CoA reductase pathway, and also increasing lipoprotein uptake through up-regulating the LDL receptor. Regulation of this pathway is as well accomplished via controlling the rate of translation of the mRNA, degradation of the reductase and phosphorylation.

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Fig: Mevalonate pathway

=> Pharmacology:

The number of drugs targets the mevalonate pathway:

  • Statins (employed for elevated cholesterol levels)
  • Bisphosphonates (employed in the treatment of different bone-degenerative diseases)

=> Plants and bacteria:

In plants and bacteria, the non-mevalonate pathway employs pyruvate and glyceraldehyde 3-phosphate as substrates.   

=> DMAPP to lanosterol:

Isopentenyl pyrophosphate and dimethylallyl pyrophosphate contribute isoprene units that are assembled and altered to form Terpenes and Isoprenoids that are a big class of lipids which comprise the carotenoids, and make the biggest class of plant natural products. 

Here, the isoprene units are linked altogether to form squalene and then folded up and formed to a set of rings to make lanosterol. Lanosterol can then be transformed to other steroids like cholesterol and ergosterol.

Steroidogenesis:

Steroidogenesis is the biological procedure through which steroids are produced from cholesterol and converted into other steroids. The pathways of Steroidogenesis differ between various species; however the pathways of human Steroidogenesis are illustrated in the figure shown below.

Lanosterol can then be transformed to other steroids like cholesterol and ergosterol. 

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Fig: Pathways of human Steroidogenesis

Products of Steroidogenesis comprise:

  • Androgens:  testosterone
  • Estrogens and progesterone
  • Corticoids: cortisol and aldosterone

Degradation and elimination of Steroids:

Steroids are mostly oxidized through cytochrome P450 oxidase enzymes, like CYP3A4. Such reactions introduce oxygen to the steroid ring and let the structure to be broken up by other enzymes, to make bile acids as final products. Such bile acids can then be removed via secretion from the liver in the bile. The expression of this oxidase gene can be up-regulated via the steroid sensor PXR whenever there is a high blood concentration of the steroids.

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