STK31003 Mevalonate Pathways - Terpenes Steroids (2) PDF

Vertebrate hormonal steroids This large group can be divided into two major families, mainly on the basis of their physiological function or their glandular origin : the sexual hormones and the corticosteroids.  Sexual Hormone  The biosynthetic pathway to sex hormones in male and femal...

Vertebrate hormonal steroids This large group can be divided into two major families, mainly on the basis of their physiological function or their glandular origin : the sexual hormones and the corticosteroids.  Sexual Hormone  The biosynthetic pathway to sex hormones in male and female gonadal tissue includes the production of the androgens  androstenedione and dehydroepiandrosterone.  Testes and ovaries contain an additional enzyme, a 17-hydroxysteroid dehydrogenase, that enables androgens to be converted to testosterone  Sexual hormones This important group can be divided into estrogens, progestagens, and androgens. Estrogens : They are C18 steroids generally with a phenolic function at C-3 (the first ring A being aromatic), without methyl group at C-10, and with always an oxygenated function at C-17. 17-estradiol is the model molecule.  Sexual hormones Progestagens : They are C21 steroids with a en-4-one-3 group and a ketone function at C-20. Progesterone is the model molecule.  Sexual hormones  Androgens : They are C19 steroids. The major androgen is testosterone which is a 17-hydroxysteroid with a en-4-one-3 group.  Testosterone (an Androgens) - Stimulates sperm production; promotes sex drive; responsible for development of male secondary sexual characteristics;  Estrogen (mostly Estradiol) -Promotes follicular growth; responsible for development of female secondary sexual characteristics; stimulates growth of uterus and breasts; promotes epiphyseal plate closure  Progesterone (an Progestagens) - Prepares uterus for implantation and gestation, furthers breast development  Estrogen peaks just before ovulation (some is produced by the corpus luteum)  Progesterone is produced by cells of the corpus luteum in the 2nd half of the cycle  Progesterone remains high in pregnancy, preventing further ovulation during embryonic development  If fertilization does not occur, progesterone rapidly falls to low levels; this causes menstruation Hormones: The pituitary gland (a small area Hormones: The dominant follicle in the ovary at the base of the brain that makes hormones) produces more and more estrogen as it grows produces a hormone called follicle stimulating larger. When estrogen levels are high enough, hormone (FSH). FSH tells the ovaries to they send a signal to the brain. The brain then prepare an egg for ovulation (release of an causes a dramatic increase in luteinizing egg from the ovary). The dominant follicle hormone (LH). This spike is what causes the produces estrogen as it grows which peaks release of the egg to occur. Estrogen levels just before ovulation happens. drop right after ovulation.  Steroids of the Adrenal Cortex  The adrenal cortex is responsible for production of 3 major classes of steroid hormones: glucocorticoids, which regulate carbohydrate metabolism; mineralocorticoids, which regulate the body levels of sodium and potassium; and androgens, whose actions are similar to that of steroids produced by the male gonads.  Adrenal insufficiency is known as Addison disease, and in the absence of steroid hormone replacement therapy can rapidly cause death (in 1-2 weeks). The adrenal cortex is composed of 3 main tissue regions: zona glomerulosa, zona fasciculata, and zona reticularis. Although the pathway to pregnenolone synthesis is the same in all zones of the cortex, the zones are histologically and enzymatically distinct, with the exact steroid hormone product dependent on the enzymes present in the cells of each zone. ou a  Corticosteroids  These compounds are formed in the adrenal cortex and are C21 steroids with three or more oxygen atoms. They have all a en-4-one-3 group and an oxygenated function at C-20.  The major corticosteroids in vertebrates are cortisol which has an hydroxyl group at C-11, C-17, and C-21 and aldosterone which has only one hydroxyl group at C-11 and one aldehyde function at C-18.  Steroid -adrenal cortex  aldosterone Increases Na+ reabsorption and K+ secretion  cortisol Increases blood glucose (best in adapting to stress) by mobilizing protein and fat  androgens (esp. dehydroepiandrosterone) responsible for growth spurt at puberty and initiates sex drive  Steroid -adrenal cortex Steroids of this groups and related compounds which contain carbonyl at C11 will provide similar properties as cortison and are widely used in the treatment of asthma and inflammatory. g Cortisone Pregnenolone: produced directly from cholesterol, the precusor molecule for all C18, C19 and C21 steroids Progesterone: a progestin, produced directly from pregnenolone and secreted from the corpus luteum, responsible for changes associated with luteral phase of the menstrual cycle, differentiation factor for mammary glands Aldosterone: the principal mineralocorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na+ uptake Testosterone: an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics, produced from progesterone Estradiol: an estrogen, principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics Cortisol: dominant glucocorticoid in humans, synthesized from progesterone in the zona fasciculata of the adrenal cortex, involved in stress adaptation, elevates blood pressure and Na+ uptake, numerous effects on the immune system  STEROL Sterols may be found either as free sterols, acylated (sterol esters), alkylated (steryl alkyl ethers), sulfated (cholesterol sulfate), or linked to a glycoside moiety (steryl glycosides) which can be itself acylated (acylated sterol glycosides).  Sterols Sterols form an important group among the steroids. Unsaturated steroids with most of the skeleton of cholestane containing a 3-hydroxyl group and an aliphatic side chain of 8 or more carbon atoms attached to position 17 form the group of sterols.  Sterols  They are lipids resistant to saponification and are found in an appreciable quantity in all animal and vegetal tissues.  These unsaponifiable lipids may include one or more of a variety of molecules belonging to 3- hydroxysteroids, they are C27-C30 crystalline alcohols (in Greek, stereos, solid).  These lipids can be classed as triterpenes as they derive from squalene which gives directly by cyclization, unsaturation and 3-hydroxylation, lanosterol in animals or cycloartenol in plants  resists sterols with this te process STEROL  In the tissues of vertebrates, the main sterol is the C27 alcohol cholesterol (Greek, chole, bile), particularly abundant in adrenals (10%, w/w), nervous tissues (2%,w/w), liver (0.2%,w/w) and gall stones.  The vertebrate brain is the most cholesterol-rich organ , containing roughly 25% of the total free cholesterol present in the whole body Sterols 5-cholestane  Sterols  In late-step synthesis of cholesterol, discrete oxidoreductive and/or demethylation reactions occur, which start with the common precursor lanosterol.  Lanosterol is also found as a major constituent of the unsaponifiable portion of wool fat (lanoline).  Animal tissues contain in addition to cholesterol small amounts of 7-dehydrocholesterol which, on UV irradiation, is converted to vitamin D3 (cholecalciferol)  Sterols  Most phytosterols are compounds having 28 to 30 carbon atoms and one or two carbon-carbon double bonds, typically one in the sterol nucleus and sometimes a second in the alkyl side chain.  Allphytosterols were shown to derive in plants from cycloartenol and in fungi from lanosterol, both direct products of the cyclization of squalene.  Sterols  More than 200 different types of phytosterols have been reported in plant species.  Representatives of these sterols are campesterol, stigmasterol (in soybean oil) and - sitosterol which is present in all plant lipids and is used for steroid synthesis.  An important sterol from yeast and ergot is the C28 compound ergosterol (mycosterol). Upon irradiation, this sterol gives rise to vitamin D2 (calciferol).  Sterols  Phytosterols account for a substantial portion of total dietary sterols in vertebrates but they are excluded from the body. Accumulation of other sterol than cholesterol is prevented at the level of the intestinal epithelium concurrently with a facilitation of biliary excretion of phytosterols  Phytosterols produce a wide spectrum of biological activities in animals and humans. They are considered efficient cholesterol-lowering agents  In addition, they produce a wide spectrum of therapeutic effects including anti-tumor properties  VITAMIN D  Vitamin D2 and Vitamin D3  Both play the same role in the body, but vitamins D2 and D3 have slightly different molecular structures.  The main difference is that vitamin D2 comes from plants, whereas D3 comes from animals, including human.  Vitamin D sterol  Vitamin D is a steroid hormone that functions to regulate specific gene expression following interaction with its intracellular receptor.  The biologically active form of the hormone is 1,25-dihydroxy vitamin D3 (also termed calcitriol).  Calcitriol functions primarily to regulate calcium and phosphorous homeostasis. O of Vitamin D3 is synthesized in the skin upon UVB exposure. The UVB exposure of provitamin D3 (7-dehydrocholesterol) in the skin breaks the B-ring to form previtamin D3, which undergoes thermally induced rearrangement to vitamin D3. Vitamin D3 is transported to the liver where it is hydroxylated at C-25 by the enzyme 25-hydroxylase producing 25OHD3, which is the major circulating form in vertebrates. The 25OHD3 is hydroxylated a second time at C-1 in the kidneys to the active metabolite 1,25(OH)2D3 Happen In ev  Ergosterol Vitamin D2 7-Dehydrocholesterol Vitamin D3  Vitamin D  Active calcitriol is derived from ergosterol (produced in plants) and from 7- dehydrocholesterol (produced in the skin).  Ergocalciferol (vitamin D2) is formed by uv irradiation of ergosterol.  In the skin 7-dehydrocholesterol is converted to cholecalciferol (vitamin D3) following uv irradiation.  Vitamin D  Vitamin D2 (egrocalciferol) and D3 (cholecalciferol) are processed to D2- calcitriol and D3-calcitriol, respectively, by the same enzymatic pathways in the body.  Cholecalciferol (or egrocalciferol) are absorbed from the intestine and transported to the liver bound to a specific vitamin D-binding protein.  Vitamin D  In the liver cholecalciferol is hydroxylated at the 25 position by a specific D3-25-hydroxylase generating 25-hydroxy-D3 [25-(OH)D3] which is the major circulating form of vitamin D.  Conversion of 25-(OH)D3 to its biologically active form, calcitriol, occurs through the activity of a specific D3-1-hydroxylase present in the proximal convoluted tubules of the kidneys, and in bone and placenta.  25-(OH)D3 can also be hydroxylated at the 24 position by a specific D3-24-hydroxylase in the kidneys, intestine, placenta and cartilage. 25-hydroxyvitamin D3 1,25-dihydroxyvitamin D3 Clinical Significance of Vitamin D Deficiency  As a result of the addition of vitamin D to milk, deficiencies in this vitamin are rare.  The main symptom of vitamin D deficiency in children is rickets and in adults is osteomalacia.  Rickets is characterized improper mineralization during the development of the bones resulting in soft bones.  Osteomalacia is characterized by demineralization of previously formed bone leading to increased softness and susceptibility to fracture.  CAROTENOIDS C40  Carotenoids are a class of natural fat- soluble pigments found principally in plants, algae, and photosynthetic bacteria, where they play a critical role in the photosynthetic process.  They also occur in some non- photosynthetic bacteria, yeasts, and molds, where they may carry out a protective function against damage by light and oxygen.  CAROTENOIDS  Carotenoids are beneficial antioxidants that can protect from disease and enhance immune system.  Provitamin A carotenoids can be converted into vitamin A, which is essential for growth, immune system function, and eye health.  CAROTENOIDS  Carotenoids are antioxidants, lowering inflammation in the body. Carotenoid anti-inflammatory properties have been associated with improving cardiovascular health. Reducing inflammation helps to protect against heart disease and prevents arterial walls from being blocked.  Antioxidants protect cells from free radicals, or substances that destroy or damage cell membranes. Increasing carotenoids via your diet can increase the amount of antioxidants and protective cells in your body. This is significant when battling cancer and may be able to prevent cancer growth.  CAROTENOIDS  Although animals appear to be incapable of synthesizing carotenoids, many animals incorporate carotenoids from their diet.  Within animals, carotenoids provide bright coloration, serve as antioxidants, and can be a source for vitamin A activity  CAROTENOIDS  Carotenoids are responsible for many of the red, orange, and yellow hues of plant leaves, fruits, and flowers, as well as the colors of some birds, insects, fish, and crustaceans.  Some familiar examples of carotenoid coloration are the oranges of carrots and citrus fruits, the reds of peppers and tomatoes, and the pinks of flamingoes and salmon.  Some 600 different carotenoids are known to occur naturally and new carotenoids continue to be identified  CAROTENOIDS  Carotenoids are defined by their chemical structure. The majority carotenoids are derived from a 40-carbon polyene chain, which could be considered the backbone of the molecule. This chain may be terminated by cyclic end-groups (rings) and may be complemented with oxygen- containing functional groups.  The hydrocarbon carotenoids are known as carotenes, while oxygenated derivatives of these hydrocarbons are known as xanthophylls. has oxygen ator  Beta-carotene, the principal carotenoid in carrots, is a familiar carotene, while lutein, the major yellow pigment of marigold petals, is a common xanthophyll dimerization Carotenoids  CAROTENOIDS  In human beings, carotenoids can serve several important functions. The most widely studied and well-understood nutritional role for carotenoids is their provitamin A activity.  Deficiency of vitamin A is a major cause of premature death in developing nations, particularly among children.  Vitamin A, which has many vital systemic functions in humans, can be produced within the body from certain carotenoids, notably beta- carotene. Some common examples of carotenoids  CAROTENOIDS  Dietary beta-carotene is obtained from a number of fruits and vegetables, such as carrots, spinach, peaches, apricots, and sweet potatoes.  Other provitamin A carotenoids include alpha-carotene (found in carrots, pumpkin, and red and yellow peppers) and cryptoxanthin (from oranges, tangerines, peaches, nectarines, and papayas).  CAROTENOIDS  Carotenoids also play an important potential role in human health by acting as biological antioxidants, protecting cells and tissues from the damaging effects of free radicals and singlet oxygen.  Lycopene, the hydrocarbon carotenoid that gives tomatoes their red color, is particularly effective at quenching the destructive potential of singlet oxygen  CAROTENOIDS Lutein and zeaxanthin, xanthophylls found in corn and in leafy greens such as kale and spinach, are believed to function as protective antioxidants in the macular region of the human retina  CAROTENOIDS  Astaxanthin, a xanthophyll found in salmon, shrimp, and other seafoods, is another naturally occurring xanthophyll with potent antioxidant properties.  Other health benefits of carotenoids that may be related to their antioxidative potential include enhancement of immune system function, protection from sunburn, and inhibition of the development of certain types of cancers.