Chemistry and Biology of Bile Acids

View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Publications of the IAS Fellows REVIEW ARTICLES Chemistry and biology of bile acids Samrat Mukhopadhyay1,** and Uday Maitra1,2,* 1Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India 2Chemical Biology Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560 064, India **Present address: Chemical Dynamics Group, Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai 400 005, India cules having a powerful ability to transform lamellar arrays This review makes an attempt to combine the insights 1,2 gained into the biochemistry and physiology of bile acids of lipids into mixed micelles . with the elegant supramolecular systems designed from them. Bile acids are cholesterol-derived facial amphi- Historical perspectives philes responsible for the solubilization of cholesterol and fat through mixed micelle formation with phospho- Studies on the chemistry of compounds present in the bile lipids. An intriguing aspect of bile acids is that their had begun in the early nineteenth century3. Remarkable chemical structure has been postulated to correlate with experiments performed by Thenard and Berzelius led to vertebrate evolution. However, the etiology of molecular 4 evolution of bile acids is still poorly understood. There the identification of choleic acid and bilin . The isolation of nitrogen-free bile acid (cholic acid) was achieved by has been a steady progress in the studies aimed at elu- 4 cidating physiological functions and developing pharma- Demarcay . A crystalline sample of a bile acid was first 5 cological applications of bile acids. In recent years, bile prepared by Platner , but any structural insight was not acids and their analogues have been extensively utilized possible at that time. However, painstaking efforts were as supramolecular receptors for various types of guest taken by chemists, Strecker and Mylius to work out the molecules and ions. Under certain defined conditions, the molecular formulae of bile acids (both free and conjugated supramolecular association of bile acids and their deri- forms)6. Wieland and Sorage7 first demonstrated the forma- vatives leads to gel formation. Thus, modified bile acids tion of cholic acid–fatty acid complex (choleic acid). might find use in the design of futuristic materials. Wieland and Windaus performed detailed structural studies on bile acids8. After Bernal elucidated the cyclopentano- DESPITE having a history of more than a century, bile-acid perhydrophenanthrene structure of cholesterol by X-ray in science (cholanology) continues to have importance in bio- 1932, Rosenheim and King were able to propose the correct logy and medicine1–3. Bile salts are steroidal detergents, which structure of bile acids9. The current scientific phase of together with lipids/fats/cholesterol form mixed micelles bile acid research began in the 1950s. Isolation and char- in the intestine to enable fat digestion and absorption acterization of bile acids from different species, extensive through the intestinal wall1. They are biosynthesized from metabolic studies and detailed physico-chemical studies cholesterol in the liver and stored in the gall bladder were embarked upon during this period. (Figure 1). Bile is secreted through the bile duct into the intestine when food passes from the stomach to the duode- num. Most of the bile salts secreted into the upper region Chemical structure of bile acids of the small intestine are absorbed along with dietary lipids at the lower end of the small intestine. They are separated All bile acids consist of two connecting units, a rigid from the dietary lipid and returned (more than 85%) to the steroid nucleus and a short aliphatic side chain (Figure liver for re-circulation. This movement of bile salts is ter- 2)2. The steroid nucleus of bile acids has the saturated tetra- med as enterohepatic circulation (Figure 1 b). The most abun- cyclic hydrocarbon perhydrocyclopentanophenanthrene, dant bile salts in humans are cholate, chenodeoxycholate containing three six-member rings (A, B and C) and a five- and deoxycholate, and they are normally conjugated with member ring (D). In addition, there are angular methyl either glycine (75%) or taurine (25%). Conjugation increases groups at positions C-18 and C-19. In higher vertebrates, the the aqueous solubility of bile salts under physiological bile acid nucleus is curved (beaked) because the A and the conditions. The chemical structures of free and conjugated B rings are in a cis-fused configuration. Some bile acids in cholic acid (taurocholate and glycolate) are discussed later lower vertebrates, known as allo-bile acids, are flat because in the article. All primary bile acids appear to have three of an A/B trans-fusion (5a-stereochemistry). The side chain features in common: (i) they are the major end-products of structure determines the class of the compound (bile acids cholesterol metabolism, (ii) they are secreted into the bile or bile alcohols). There are four different types of bile alco- largely in a conjugated form, and (iii) these conjugates are hols (C27, C26, C25 and C24) and they occur in the less membrane-impermeable, water-soluble, amphiphilic mole- evolved forms of life. There are two major classes of bile acids depending on the length of the side chain: C27 and *For correspondence. (e-mail: [email protected]) C24 bile acids. In higher vertebrates, C24 bile acids consti- 1666 CURRENT SCIENCE, VOL. 87, NO. 12, 25 DECEMBER 2004 REVIEW ARTICLES a b Figure 1. a, Digestive system; b, Enterohepatic circulation. Me O a OH 24 b Me HO 12 O 12 C Me D 9 H 24 14 OH H 8 H 7 OH A B 3 OH HO 3 7 OH H OH d c Hydrophobic surface: b-face COOH Hydroxyl groups : a-face Figure 2. Structure of cholic acid. a, Chemical structure; b, Perspective structure; c, Cartoon representation (as introduced by Small); d, Space-filling model. tute a major part of the bile. They are conjugated to glycine a O or taurine to yield the conjugated form of bile acids (Fig- ure 3). Bile acids are facially amphipathic, i.e. they contain both hydrophobic (lipid soluble) and hydrophilic (polar) N COOH OH H faces. OH OH Chemical structure of bile acids and evolution O b In contrast to most of the small molecules found in verte- SO H brates, bile acids are strikingly diverse in a structural sense. N 3 OH H Bile acids from different species chemically differ in three OH respects: (i) side-chain structure, (ii) stereochemistry of the A/B ring fusion, and (iii) the distribution of the number, OH position and stereochemistry of hydroxyl groups in the 10 Figure 3. Structure of conjugated bile acids. a, Glycocholic acid; steroid nucleus. Several decades ago, Haslewood addressed b, Taurocholic acid. the issue of considering the bile acid structure as an aid to CURRENT SCIENCE, VOL. 87, NO. 12, 25 DECEMBER 2004 1667 REVIEW ARTICLES the understanding of the evolutionary processes. It has been Biosynthesis of bile acids noted that the bile acid structure shows a pattern of pro- gressive molecular development along the line of vertebrate Bile acids are synthesized from cholesterol involving a evolution. There is a clear evidence of evolution of bile number of complex steps in both the steroid nucleus and the 1,2 acids through the stages: C27 alcohols ® C27 acids ® C24 side chain (Scheme 1) . This biosynthesis involves at acids. Bile alcohols act as bile salt after conjugation with least five steps each on the nucleus and the side chain. sulphate (which increases water solubility), C27 acids are Since these steps may in principle occur in any order, conjugated with taurine and C24 acids exist in the bile as elucidation of individual steps of bile acid biosynthesis is taurine and glycine conjugates. It has been suggested that not straightforward. In the first step, believed to be the rate- the most evolved mammalian bile acids have a 5b-configu- limiting step, cholesterol is oxidized to 7a-hydroxychole- ration with hydroxyl groups at 3a, 7a and 12a. Names and sterol by cholesterol 7a-hydroxylase. 7a-Hydroxy cholesterol structures of bile acids in vertebrate bile are given in is then converted to the key intermediate cholest-7a- Chart 1 (approximately in the descending order of evolution). hydroxy-D4-3-one through the action of an isomerase and Bile alcohols are not discussed, although they are major a reductase. This unsaturated oxo derivative is the branching components in lower vertebrates. point for cholic and chenodeoxycholic acid biosynthesis. i ii HO OH O OH HO Cholesterol OH iii O OH iv i. 7a-Hydroxylation (rate limiting step) OH COOH 4 ii. Oxidation/isomerization to 3-oxo, -D COOH iii. 12a-Hydroxylation O OH iv. Side chain oxidation to C27 acid O OH v. Saturation to A/B cis v COOH OH vi. Reduction of 3-oxo to 7a-OH COOH OH vii. Oxidative cleavage of side chain O H (C27 acid to C24 acid) O H OH COOH vi OH HO OH COOH COOH HO OH vii OH COOH HO OH Chenodeoxycholic acid HO OH Cholic acid Scheme 1. Biosynthesis of bile acids from cholesterol. 1668 CURRENT SCIENCE, VOL. 87, NO. 12, 25 DECEMBER 2004 REVIEW ARTICLES COOH COOH COOH OH OH OH OH OH OH OH OH 3a, 7a-Dihydroxycoprostanic acid: 3a, 7a, 12a-Trihydroxycoprostanic acid: 3a, 7a, 12a-Trihydroxycholestanic acid: Rattites, alligator, Andean condor Hornbill, alligator, frog Iguana, frog COOH COOH COOH OH OH OH OH OH OH OH OH OH OH 3a, 7a, 16a-Trihydroxycoprost-24- 3a, 7a, 12a-Trihydroxy-25a-coprost-23-enic 3a, 7a, 12a, 24-Tetrahydroxycopro-stanic carboxylic acid: Andean condor acid: Toad acid (Varanic acid): Lizard OH COOH COOH COOH OH OH OH OH OH OH OH OH OH OH 3a, 7a, 12a, 22-Tetrahydroxycoprostanic 3a, 7a, 12a-Trihydroxycoprost-22-ene-24- 23R-hydroxycholic acid: acid: Turtle carboxylic acid: Toad Seal, snake OH COOH COOH COOH OH OH OH OH OH OH OH OH Bitocholic acid: Phocaecholic acid: 1a-Hydrohychenodeoxycholic acid: Snake Seal, walrus Australian marsupials OH COOH COOH COOH OH OH OH OH OH OH OH Allodeoxycholic acid: Allocholic acid: a-Muricholic acid: Rabbit Gigi fish Rat Contd… CURRENT SCIENCE, VOL.

Load more