Lecture Notes on Structures and Biological Functions of Sterols

LECTURE NOTES ON STRUCTURES AND BIOLOGICAL FUNCTIONS OF STEROLS Ajilore B.S. (MBChB, PhD) 1 11/20/24  Sterols  Steroids are complex molecules containing 4 fused rings  Steroids...

LECTURE NOTES ON STRUCTURES AND BIOLOGICAL FUNCTIONS OF STEROLS Ajilore B.S. (MBChB, PhD) 1 11/20/24  Sterols  Steroids are complex molecules containing 4 fused rings  Steroids are often found in association with fat but may be separated from the fat, after the fat is saponified, since they occur in unsaponifiable residue  All of the steroids have a similar cyclic nucleus resembling phenanthrene (ring A, B and C) to which a cyclopentane ring (ring D) is attached.  It is designated as cyclopentano perhydro-phenanthrene nucleus  Other names for cyclopentano perhydro-phenanthrene ring are: Sterane ring or Gonane ring 2  When the hydrogen atom at position 3 on the ring is replaced by hydroxy group, we have a steroid alcohol called sterols.  Methyl side chains occur typically at positions 10 and 13 (constituting carbon atoms 19 and 18 respectively) and a side chain at position 17.  Sterols are therefore alcohols of gonane  They are amphipathic lipids synthesized from acetyl coenzyme A via HMG-CoA reductase pathway  Sterols occur naturally in eukaryotes including plants, animals and fungi. 3  Sterols of plants are called phytosterols and sterols of animals are called zoosterols.  The most important zoosterol is cholesterols.  Notable phytosterols include: campesterol, sitosterol and stigmasterol  Sterols play important role in the physiology of eukaryotic organisms  For example, cholesterol is an important part of animal cell membrane where it affects the cell membrane fluidity and serve as secondary messenger in developmental signaling. 11/20/24 4   In humans, corticosteroids e.g. cortisol acts as signalling compound  Sterols are common components of human skin oils  Phytosterols have been shown in clinical trials to block cholesterol absorption in human intestine, thereby helping to reduce cholesterol absorption in humans  At present, American Heart Association has recommended that supplemental plant sterols be taken by patients with hypercholesterolemia (but to be avoided in pregnant women and nursing mothers)  Some preliminary researches have shown that phytosterols may have anti-cancer effects 5 [email protected] Cholesterol Cholesterol is the most important sterol in human body. Its molecular formula is C27H45OH. It is biosynthesized by all animal cells and is an essential structural component of animal cell membrane 11/20/24 6  It possesses “cyclopentanoperhydrophenanthrene nucleus”.  It has an –OH group at C3.  It has an unsaturated double bond between C5 and C6.  It has two –CH3 groups at C10 and C13.  It has an eight carbon side chain attached to C17.  The name cholesterol is derived from the Greek word meaning solid bile.  It occurs as a white or faintly yellow, almost odourless, granules. 7   It is insoluble in water, sparingly soluble in alcohol and soluble in ether, chloroform, hot alcohol, ethyl acetate and vegetable oils.  It easily crystallises from such solutions in colourless, rhombic plates  It is not saponifiable.  Its melting point is 147 to 150o C.  Since it has an unsaturated bond, it can take up two halogen atoms. 8 11/20/24 [email protected]   Source: i. Exogenous: Dietary cholesterol, approximately 0.3 gm/day. Diet rich in cholesterol are butter, cream, milk, egg yolk, meat, etc. A hen’s egg weighing 2 oz gives 250 mg cholesterol ii. Endogenous: Synthesised in the body from acetyl CoA, approximately 1.0 gm/day  Cholesterol is found in largest amounts in normal human adult:  brain and nervous tissue 2 per cent,  in the liver about 0.3 per cent,  skin 0.3 per cent and  intestinal mucosa 0.2 per cent,  certain endocrine glands, viz. adrenal cortex contain some 10 per cent or more, corpus luteum is also rich in cholesterol. 9 11/20/24 [email protected]   The relatively high content of cholesterol in skin may be related to vit D formation by UV rays  and that in the adrenal gland and gonads to steroid hormone synthesis.  Cholesterol is present in blood and bile and is usually a major constituent of gallstones  Forms of cholesterol: Cholesterol occurs both in free form and in ester form, in which it is esterified with fatty acids at –OH group at C3 position. The ester form of cholesterol is also referred as bound form 10 [email protected]   The various fatty acids, which form cholesterol esters, are as follows: Esterification of cholesterol: Some cholesterol esters are formed in tissues by the transfer of acyl groups from acyl-CoA to cholesterol by acyl transferases. But most of the plasma cholesterol esters are produced in the plasma itself by the transfer of an acyl group (mostly unsaturated acyl group) from the β-position of lecithin to cholesterol with the help of the enzyme lecithin cholesterol acyl transferase (LCAT) 11 [email protected]  Norum’s disease: A genetic deficiency of LCAT produces Norum’s disease due to the failure of esterification of cholesterol at the cost of lecithin.  The disease is characterised by: Rise in free cholesterol ↑ Rise in lecithin in plasma ↑ and Fall in cholesterol ester, ↓ lysolecithin ↓ and α-lipoproteins ↓ in plasma. 11/20/24 12 [email protected]   Normal level of serum total cholesterol in an adult varies from 150 to 250 mg per cent.  About 40 to 50 mg% occurs as free cholesterol (approx 30% of total)  and 110-200 mg% as cholesterol esters (approximately 70%). Variations of cholesterol level: i. Age: Blood cholesterol level is low at birth (50-70% of the values in normal adults) and it gradually increases with age. After 55 years there is a tendency to decrease again ii. Sex and race: Sex and race have little effect, but in case of women, the level is increased just before and decreased during the menstrual period 13 [email protected] iii. Pregnancy: The level is also increased during pregnancy, when a progressive rise in free cholesterol and a fall in ‘ester’ fraction is observed. Other sterols of biological importance 7-Dehydrocholesterol It is an important sterol present in the skin. This differs from cholesterol only in having a second double bond, between C7 and C8 - -In man, 7-dehydrocholesterol may be obtained partly by synthesis from cholesterol in skin and/or intestinal wall. -In the epidermis of skin, UV rays of sunshine change 7- dehydrocholesterol (pre-cholecalciferol) to cholecalciferol (vitamin D3). 14 - Hence 7-dehydrocholesterol is called as provitamin D3. - This explains the value of sunshine in preventing rickets, a disease produced from vitamin D deficiency - 7-Dehydrocholesterol (Provitamin D3 15 [email protected] ii. Ergosterol -It is a plant sterol, first isolated from ergot, a fungus of rye and later from yeast and certain mushrooms. -Structurally this sterol has the same nucleus as 7- dehydrocholesterol but differs slightly in its side chain -When irradiated with UV rays (long wave 265 μm) ergosterol is changed to vitamin D 2 by the opening of the ring B of the sterol. - Hence ergosterol is called as Provitamin-D 2, over- irradiation may produce toxic products - 16 [email protected]. 17 iii. Stigmasterol and Sitosterol -They are plant sterols, occurring in higher plants. -They have no nutritional value for human beings -Sitosterol appears to decrease the intestinal absorption of both exogenous and endogenous cholesterol, thus lowering the blood cholesterol level. iv. Coprosterol (Coprostanol) -Occurs in feces as a result of the reduction of cholesterol (by hydrogenation of double bond). -This is brought about by bacterial action, double bond between C5 and C6 is saturated. v. Other important steroids of biomedical importance are bile acids, adrenocortical hormones, gonadal hormones, D vitamins, cardiac glycosides and some alkaloids 18