STEROIDS, BILE ACIDS, STEROID HORMONES

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1 STEROIDS, BILE ACIDS, STEROID HORMONES Vitamins D Steroids form an important group of compounds based on the fundamental saturated tetracyclic hydrocarbon : cyclopentanoperhydrophenanthrene (sterane). The prefix perhydro refers to the fact that all the necessary hydrogen atoms have been added to the compound to make it fully saturated Conformation For two-ring system, the structures of cis - and trans-fused rings look like this: There are four rings in a steroid skeleton and hence there are three fusion points. A/B, B/C and C/D rings share two carbons each (fusion). When there are directed on the same side, it is called cis. When the tow hydrogens are oriented opposite to each other with the ring system thought to as forming a plane, the ring fusion is called trans. 1

2 Natural steroids have two methyl groups Two methyl groups attached to C-10 and C-13 lie above the plane of the molecule and are customarily the points of reference for the describing the spatial orientation of other substituents in the steroid nucleus. The methyl groups are attached at points of ring junction and are called angular methyl groups. Other groups on the same side of the steroid plane as the angular methyl groups are said to be β substitutents Groups below the plane of the steroid ring system are said to be α substituents The main sterol found in the membranes of eukaryotic cells is cholesterol. The polar head in this lipids is the hydroxyl in carbon C3. CHOLESTEROL FACTS synthesized from acetyl CoA and eliminated as bile acids precursor of all other steroids in the body product of animal metabolism - in foods of animal origin amphipathic lipid (hydrophobic and hydrophilic portions) storage form is cholesterol ester found in most tissues. hydrophilic HO O R-C-O Cholesterol ester (1 st ring only) R = fatty acid hydrocarbon chain 2

3 Cholesterol One of the most widely occuring steroids, was first isolated in Contains 8 chiral C atoms, this means that 2 8 or 256 stereoisomers are possible, but only one of them is cholesterol. Contains 27 carbons Biosynthesis of Cholesterol The process has five major steps: 1. Acetyl-CoAs are converted to 3-hydroxy-3-methylglutaryl- CoA (HMG-CoA) 2. HMG-CoA is converted to mevalonate 3. Mevalonate is converted to the isoprene based molecule, isopentenyl pyrophosphate (IPP), with the concomitant loss of CO 2 4. IPP is converted to squalene 5. Squalene is converted to cholesterol. Overview of cholesterol synthesis Bile Acids Synthesis and Utilization The end products of cholesterol utilization are the bile acids, synthesized in the liver. Synthesis of bile acids is one of the predominant mechanisms for the excretion of excess cholesterol. However, the excretion of cholesterol in the form of bile acids is insufficient to compensate for an excess dietary intake of cholesterol. 3

4 Bile SYNTHESIS OF BILE ACIDS Bile is a complex solution of salts and protein, containing micelles composed of cholesterol, phospholipids and bile salts. The composition of these micelles is critical, as imbalance may lead to crystallization of cholesterol in the gallbladder, leading to the formation of gallstones. Bile acids are synthesized from cholesterol in the liver, stored in the gallbladder, and secreted through the common bile duct. alpha-hydroxylation of 7-carbon is the key step in bile-acid synthesis. This hydroxylation destines the product to become a bile-acid. Lose 3 carbons of the alpha-side: This is also common to all bile acids. Then the terminal carbon is oxidized to an acid (hence bile acid). Bile acid synthesis Synthesis of bile salts Reaction is catalyzed by 7ahydroxylase. An α hydoxyl group is formed at position 7 of cholesterol. This reaction is inhibited by bile salts, and is the rate-limiting step in bile salt synthesis. Cholesterol + NADPH + O 2 7-hydroxycholesterol + NADP + The initial reaction, 7α-hydroxylase, in the conversion of cholesterol to bile acids. Rate-determining step 7α-hydroxylase Repressed (decreased synthesis) by bile salts Induced (increased synthesis) by cholesterol 4

5 Bile acids Bile acids Grups OH localized at: CHOLATE: The major bile acid. It has three OH-groups in the rings, and a carboxyl group at the end of the side chain. DEOXYCHOLATE: The minor bile acid. It is missing one of the OHgroups (at the 12 carbon) C-3 C-7 C-12 Primary bile acids: cholic acid OH OH OH chenodeoxycholic acid OH OH H Secondary bile acids: deoxycholic acid OH H OH lithocholic acid OH H H Primary bile acids. The most abundant bile acids in human bile are chenodeoxycholic acid (45%) and cholic acid (31%). These are referred to as the primary bile acids. Primary bile acids Secondary bile acids Within the intestines the primary bile acids are converted by bacteria into the secondary bile acids, identified as deoxycholate (from cholate) and lithocholate (from chenodeoxycholate). 5

6 Bile acids are excreted in conjugated form, as taurocholic acid and glycocholic acid Clinical Significance of Bile Acid Synthesis Bile acids perform four physiologically significant functions: 1. Their synthesis and subsequent excretion in the feces represent the only significant mechanism for the elimination of excess cholesterol. 2. Bile acids and phospholipids solubilize cholesterol in the bile, thereby preventing the precipitation of cholesterol in the gallbladder. 3. They facilitate the digestion of dietary triacylglycerols by acting as emulsifying agents that render fats accessible to pancreatic lipases. 4. They facilitate the intestinal absorption of fat-soluble vitamins. Bile acids are conjugated with glycine or taurine before being secreted into bile, where the ratio of glycine to taurine-conjugated acid is about 3:1 BILE-ACID FUNCTIONS Emulsification of triacylglycerols ( Emulsification is a physical, not a chemical process). Promote absorption of fat-soluble vitamins. Maintain cholesterol homeostasis by promoting excretion of cholesterol Action of bile salts in emulsifying fats in the intestine The hydrophobic surface of the bile salt molecule associates with triacylglycerol, and a number of these complex aggregate to form a micelle, with the polar surface of the bile salt facing outward. This allows association with pancreatic lipase, whose action liberates free fatty acids in a much smaller micelle, which can be absorbed through the intestinal mucosa 6

7 Circulation of bile acids Bile acids are carried from the liver through these ducts to the gallbladder, where they are stored for future use. The ultimate fate of bile acids is secretion into the intestine, where they aid in the emulsification of dietary lipids. In the gut the glycine and taurine residues are removed and the bile acids are either excreted (only a small percentage) or reabsorbed by the gut and returned to the liver. This process of secretion from the liver to the gallbladder, to the intestines and finally reabsorbtion is termed the enterohepatic circulation. Steroid hormone production takes up a tiny fraction of the total body cholesterol, but is important because of the physiological function of the hormones. Steroid hormones Steroid hormones are grouped into five categories: - progestins, - glucocorticoids, - mineralocorticoids, - androgens, - estrogens. All contain the four-ring structure of the steroid nucleus and are remarkably similar in structure, considering the enormous differences in their physiological effects. They mediate a wide variety of vital physiological functions. 7

8 Groups of steroid hormones 1. Progestins regulate events during pregnancy, progesterone is the major hormone involved in sustaining pregnancy 2. Glucocorticoids affect basal metabolism, host defense mechanisms, blood pressure, response to stress, promote gluconeogenesis and supress inflammation reactions (cortisol, corticosterone) 3. Mineralocorticoids affect electrolyte balance and ion transport, regulate ion balance by promoting reabsorption in the kidney of Na +, Cl -, HCO 3 - (aldosterone) 4. Androgens promote male sexual differentiation, spermatogenesis, and maintain male characteristics (androstenedione, testosterone), 5. Estrogens female sex hormones, stimulate the development of tissues involved in reproduction, support femal characteristics (estrone, estradiol) SYNTHESIS OF STEROID HORMONES CHOLESTEROL > PREGNENOLONE CHOLESTEROL > PREGNENOLONE Removal of 6 of the side-chain carbons. This step is common to all steroid hormone synthesis. This step occurs on the mitochondrial membrane. This leaves a C21 compound, pregnenolone, which may accurately be described as the mother of all steroids (the C21 steroid carbon skeleton is given the name pregnane). activated to turn on pathways Cholesterol Pregnenolone Progesterone Progesterone 21-hydroxylase 11-Deoxycortisone Aldosterone Progesterone 21-hydroxylase 11-Deoxycortisol Cortisol General pathways for the synthesis of aldosterone and cortisol in the adrenal cortex 8

9 Functions of Hormones Derived from Cholesterol Product Progesterone Glucocorticoids (cortisol) (produced in adrenal cortex) (catabolic steroid) Mineralocorticoids (aldosterone) (produced in adrenal glands) Functions prepares uterus lining for implantation of ovum promote gluconeogenesis; favor breakdown of fat and protein (fuel mobilization); anti-inflammatory maintains blood volume and blood pressure by increasing sodium reabsorption by kidney Product Functions of Hormones Derived from Cholesterol cont. Androgens (strongest = testosterone) (produced in testes primarily but weak androgens in adrenal cortex) (anabolic steroid) Estrogen (produced in ovaries primarily but also in adipose cells of males and females) Vitamin D (not a steroid hormone) (produced in the skin in response to UV light and processed to active form in kidney) Functions development of male secondary sex characteristics; prevents bone resorption development of female secondary sex characteristics; prevents bone resorption intestinal calcium absorption; promotes bone formation; prevents phosphate loss by kidneys Vitamin D Vitamin D is a steroid prohormone, by various metabolic changes in the body it gives rise to a hormone known as calcitriol, which play a central role in calcium and phosphate metabolism. D Vitamins are generated from the provitamins ergosterol and 7-dehydrocholesterol by the action of sunlight. Ergosterol occurs in plants and 7-dehydrocholesterol in animals. UV light from sunlight cleaves the B ring of both compounds. Ergocalciferol (vitamin D 2 ) is formed in plants. Cholecalciferol (vitamin D 3 ) is formed in exposed skin. 9

10 Formation of provitamin D (7-dehydrocholesterol) A specific transport protein called the vitamin D-binding protein binds vitamin D 3 and moves its from the skin or intestine to the liver, where it undergoes 25-hydroxylation Photobiosynthesis of vitamin D 3 and its metabolism The product (1α,25-dihydroxyD 3 ) is the most potent vitamin D metabolite. Its production is regulated by its own concentration, parathyroid hormone, and serum phosphate. 25-HydroxyD 3 can also be hydroxylated at the 24 position. The level of the product 24,25-dihydroxyD 3 is reciprocally related to the level of 1,25-dihydroxyD 3 in serum. Deficiency of vitamin D causes rickets and osteomalacia. 10