In this article we will discuss about the process of biosynthesis of steroids, explained with the help of suitable diagrams.
Biosynthesis of Cholesterol:
The main steps of the biosynthesis of cholesterol are diagrammatically represented in figure 5-22. The first reaction consists of the condensation of 2 molecules of acetyl-coA. It is the reverse of the reaction which takes place during the last turn of the helix in β-oxidation.
Then a third molecule of acetyl-coA binds to the acetoacetyl-coenzyme A thus formed which gives β-hydroxy-β-methyl-glutaryl coenzyme A (HMG coA). This binding of an acetyl-coenzyme A to a carbonyl group is similar to the reaction permitting the entry of acetyl-coenzyme A in the Krebs cycle by condensation on oxaloacetic acid.
The reduction of the acid group (engaged in a thioester linkage) to alcohol, catalyzed by HMG coA reductase, gives mevalonic acid. It must be noted that all the carbon atoms of cholesterol originate from acetyl- coenzyme A.
A pyrophosphate group will then bind to the primary alcohol group of mevalonic acid. Mevalonyl-pyrophosphate will react with a third molecule of ATP; this reaction gives an unstable compound which decomposes spontaneously, losing the tertiary alcohol group and the free carbonyl group.
An isoprene derivative with 5 carbon atoms is formed, isopentenyl-pyrophosphate which can be isomerized to dimethyl-allyl-pyrophosphale. The condensation of 2 fragments in C5 gives geranyl-pyrophosphate (C10), and after the binding of a third fragment in C5, farnesyl-pyrophosphate (C15) is obtained. The dimerization of the latter leads to squalene (C30).
In vertebrates, the cyclization of squalene by squalene-oxidocyclase takes place by a series of reactions requiring molecular oxygen and a reducing coenzyme like NADPH, and leads to lanosterol. The passage from lanosterol to cholesterol lakes place through several parallel pathways. The most important intermediates are desmosterol and 7-dehydrocholesterol, immediate precursors of cholesterol.
The isoprene derivatives with 5 carbon atoms are the precursors of dolichols, of the side chain of ubiquinone and vitamin K, of the isopentenyl group of some tRNAs.
In vertebrates, the biosynthesis of cholesterol is microsomal. It is regulated by a feedback inhibition mechanism by a metabolite of cholesterol (most probably the 25 hydroxycholesterol) acting on the HMG coA reductase. This feedback inhibition is never total to always permit the synthesis of polyisoprenoids important for other metabolisms, like the dolichols.
The liver is one of the principal sites of synthesis. Cholesterol is then carried to other organs in the form of lipoproteins. It enters the cells by binding of the lipoprotein to a specific receptor. In physiological conditions the exogenous input of hepatic cholesterol to various tissues is sufficient to inhibit endogenous synthesis in these tissues.
In plants, the cyclization of squalene takes place similarly as in vertebrates except for the last step. One obtains cycloartenol, precursor of other sterols. Cycloartenol-oxidocyclase also requires O2 and a reducing coenzyme. A part of sterols are glycosylated in presence of UDP-glucose, before being incorporated into the membranes.
In plants, there are two synthesis sites. Chloroplastic synthesis leads to squalene and permits the formation of terpenes, carotenoids, xantophylls, polyisoprene chains of plastoquinones, vitamins K and E. In cytosol, on the contrary, the synthesized squalene is cyclized, yielding the various plant sterols. There is apparently no feedback inhibition mechanism in these organisms.
Insects are capable of synthesizing squalene, but they cannot cyclize it. They use the sterols (animal or plant) present in their food and are capable of metabolizing them to cholesterol, precursor of hormonal derivatives like ecdysone.
Procaryotes also synthesize squalene. Squalcne-hopene cyclase which carries out the cyclization is an enzyme which does not require oxygen.
Biosynthesis of Bile Acids:
The transformation of cholesterol into bile acids takes place by two distinct processes. The shortening of the side chain first requires the oxidation of one of the terminal methyl groups with formation of a carboxyl.
A process of β-oxidation of branched fatty acids gives a derivative with 24 carbon atoms, possessing a carboxylic group ending the side chain. At the same time hydroxyls (in a conformation) are introduced on the carbons 7 or 12. The transformation of the alcohol group 3βof cholesterol into 3 α takes place by oxidation of alcohol to ketone and then reduction to a new alcohol group (see fig. 5-23).
Formation of Other Steroids:
As shown by the diagram of figure 5-23, cholesterol is the starting point of the synthesis of various steroids:
1. Progesterone is secreted by the corpus luteum, the placenta and the cortex of the adrenal gland, and acts mainly in the uterus to permit implantation and gestation;
2. Aldosterone, a hormone secreted by the adrenal cortex, which permits the reabsorption of sodium (and secondarily of chlorine and water) in the kidney, hence its name, mineralocorticosteroid;
3. Cortisol and cortisone, also secreted by the adrenal cortex, sometimes called glucocorticosteroids, because they stimulate protein catabolism and neoglucogenesis in the liver (they are therefore hyperglycemic). They also act on conjunctive and limphoid tissues by depressing membrane permeability and opposing the inflammatory processes (which explains their use in therapeutics).
The synthesis of cortisol (and therefore of cortisone) is stimulated by the corticotropic hormone of the anterior lobe of the pituitary gland or ACTH (Adreno Cortico Tropic Hormone);
1. Testosterone, secreted mainly by the testicles, is responsible for the various male sexual characters;
2. Estrogenic hormones (estradiol and estrone), responsible for the various female sexual characters, synthesized mainly in the ovary and placenta, and characterized — from the structural point of view — by a phenolic ring.
It may be observed that it is relatively easy to pass (in few steps) from progesterone to other hormones having very different physiological properties; in other words, in this family of steroid hormones, small structures modifications correspond to large differences in biological activity.
We mentioned that the synthesis of Cortisol and cortisone by the adrenal glands is influenced by ACTH, a hormone of anterior lobe of the pituitary gland; we must indicate that the secretory activities of ovaries and testicles are also controlled by the hormones of the anterior lobe of the pituitary gland called gonadotropins, like FSH (Follicule Stimulating Hormone) and LH (Luteinizing Hormone), for example.
Moreover, this anterior lobe also secretes other stimulines, like the growth hormone or somatotropic hormone, and thyrotropic hormone (TSH), which stimulates the synthesis of thyroid hormones by the thyroid gland.
Chemists sometimes classify the steroid hormones according to the number of carbon atoms contained in their molecules and thus distinguish:
1. C18 hormones (estradiol, estrone);
2. C19 hormones (testosterone);
3. C21 hormones (progesterone and most of the hormones secreted by the cortical part of adrenal glands, the mineralocorticoids like aldosterone as well as the glucocorticoids like Cortisol and cortisone).
Vitamins D are formed by the opening of the B cycle due to ultraviolet light, either from ergosterol (vitamin D2), or from 7-dehydro-cholesterol (which gives vitamin D3).