7-dehydrocholesterol biosynthesis

Some medications may exert some effect on cholesterol biosynthesis and result in elevated concentrations of intermediate sterol levels. A known example is ingestion of haloperidol, which may result in elevated levels of 7-dehydrocholesterol [6]. 

Vitamin D is obtained in the diet or by photolysis of 7-dehydrocholesterol in skin exposed to sunlight. Calcitriol works in concert with parathyroid hormone in Ca2+ homeostasis, regulating [Ca2+] in the blood and the balance between Ca2+ deposition and Ca2+ mobilization from bone. Acting through nuclear receptors, calcitriol activates the synthesis of an intestinal Ca2+-binding protein essential for uptake of dietary Ca2+. Inadequate dietary vitamin D or defects in the biosynthesis of calcitriol result in serious diseases such as rickets, in which bones are weak and malformed (see Fig. 10-20b). 

In the biosynthesis of vitamin D substances, precursors include cholesterol (skin + ultraviolet radiation) in animals ergosterol (algae, yeast + ultraviolet radiation), Intermediates in the biosynthesis include preergocaldferol, tachysterol, and 7-dehydrocholesterol. Provitamins in very small quantities are generated in the leaves, seeds, and shoots of plants. In animals, the production site is the skin. Target tissues in animals are bone, intestine, kidney, and liver. Storage sites in animals are liver and skin. 

Vitamin D-active substances are required in the diets of growing children and pregnant women, but normal adults receiving sufficient doses of sunshine can manufacture sufficient amounts of these compounds to meet their needs. Active vitamin D compounds can by synthesized in such individuals from 7-dehydro-cholesterol (see Table 6.2), an intermediate in cholesterol biosynthesis. Dietary sources also include cholecalciferol, which is produced from 7-dehydrocholesterol and ergosterol (Table 6.2). 7-Dehydrocholesterol and ergosterol are often referred to as provitamins. 

The biosynthesis of vitamin D3 (8.24) involves the thermal [1,7]-sigmatropic rearrangement of pre-vitamin 8.23, which is obtained by conrotatory electrocyclic ring opening of 7-dehydrocholesterol (8.22) (Scheme 8.3). 

Cholesterol biosynthesis proceeds via the isoprenoids in a multistep pathway. The end product, cholesterol, and the intermediates of the pathway participate in diverse cellular functions. The isoprenoid units give rise to dolichol, CoQ, heme A, isopentenyl-tRNA, famesylated proteins, and vitamin D (in the presence of sunlight and 7-dehydrocholesterol). Dolichol is used in the synthesis of glycoproteins, CoQ in the mitochondrial electron transport chain, famesylation and geranylgeranylation by posttrans-lational lipid modification that is required for membrane association and function of proteins such as p2V and G-protein subunits. 

The cholesterol lowering agent AY-99 (l) has been studied extensively in the rat, pig, dog and cockerel.It Inhibits the conversion of 7-dehydrocholesterol to cholesterol and cholesterol levels in the serum, liver, adrenals, kidney and aorta are decreased while the precursor levels are increased. The compound has been used as a tool to study the course of cholesterol biosynthesis. Study of a series of structural analogs has allowed a definition of the structural requirements for this type of activity. ... 

The most abundant form of vitamin D is D3, called cholcalciferol. Vitamin D is not technically a vitamin, because it is not required in the diet. It arises from uv-photolysis of 7-dehydrocholesterol, an intermediate in cholesterol biosynthesis (see here). 

Table II also contains previously unpublished results of experiments In which medium was supplemented with AY-9944, a compound originally developed as a hypocholesterolemic agent due to Its Inhibition of the A -sterol reductase Involved In the conversion of 7-dehydrocholesterol to cholesterol In de novo sterol biosynthesis In mammals (44). In other biological sys ms (bramble suspension cells, algae an yeast), AY-9944 Inhibits A - to A -lsomerases and. In one case, a A -sterol reductase (45-47). When sitosterol-containing media was supplemented with...

Vitamin D is the sunshine vitamin . It was originally discovered as a crude mixture called vitamin Dj (no longer available as a supplement). Ergosterol, the plant equivalent of cholesterol, is converted to vitamin D2 by ultraviolet light. Vitamin D3 (cholecalciferol) is formed in the skin from 7-dehydrocholesterol (an intermediate in the cholesterol biosynthesis pathway) in the presence of ultraviolet light, which opens the B-ring of the steroid nucleus (Fig. 51.3). Cholecalciferol is successively hydroxylated first in the liver forming 25-hydroxycholecalciferol (25-HCC) and then in the kidney to form the most active form 1,25-dihydroxy cholecalciferol (1,25-DHCC), also known as calcitriol. 

Fig. 12.4 Biosynthesis of major vitamin D metabolites. In skin, 7-dehydrocholesterol undergoes light-induced rearrangement to vitamin D3 (cholecalciferol), via sequential retro-Diels-Alder reaction and [l,7]-sigmatropic shift. P450 2R1 and probably other enzymes catalyze vitamin D 25-hydroxylation to 250HD, which is bound to circulat-...

The best known compound in the triarylethanol series is the hypocholesterol-emic agent, triparanol (Mer. 29, XXXVI) [133, 134]. This drug effectively reduced serum cholesterol levels in patients with atherosclerotic diseases and in various states of hyperlipemia. As in the cases of the basic ethers XXI and XXXI, triparanol inhibited the biosynthesis of cholesterol mainly at the last step, by blocking the reduction of 24-dehydrocholesterol (desmosterol) to cholesterol. In the rat the plasma concentration of desmosterol is very low. Treatment of rats with triparanol led to an accumulation of desmosterol in the serum and in eight tissues [135]. Triparanol also caused desmosterol accumulation in man [136]. 

Cholecalciferol, traditionally and erroneously named vitamin D, represents a secosteroidal hormone inhumans. Biosynthesis of its activemetabolitela,25(OH)2D3 proceeds via cholesterol —> 7-dehydrocholesterol (liver) — cholecalciferol (irradiation... 

From cholesterol 4.18) biosynthesis leads through truncation of the side-chain and other modifications to mammalian steroid hormones, e.g. oestrone 4.22) [11, 33]. Vitamin D3 4.24) is obtainable by photochemically mediated electrocyclic ring-opening of 7-dehydrocholesterol 4.23), followed by a thermal 1,7-sigmatropic hydrogen shift (Scheme 4.7) [34, 35]. The ecdysone insect moulting... 

Defects of the biosynthesis of cholesterol were not included in the previous edition of this book, because they were practically non-existing . Since the mid-nineties it has been recognized that patients with the Smith-Lemli-Opitz syndrome lack the final enzyme of cholesterol biosynthesis, i.e. 7-de-hydrocholesterol reductase. Consequently the patients have hypocholestero-lemia and accumulate 7-dehydrocholesterol and 8-dehydrocholesterol in their plasma [12]. 

Fig. 30.1. The pathway of cholesterol biosynthesis. 30. i, Mevalonate kinase 30.2, 3 -hydroxysteroid dehydrogenase of the 4a-methylsterol-4-demethylase complex 30.3, 3 -hydroxysteroid-A, A -isomerase (sterol-A -isomerase) 30.4, 3/ -hydroxysteroid-A - reductase (desmosterol reductase) 30.5, 3 -hydroxysteroid-A -reductase (7-dehydrocholesterol reductase)...

Example 4.17 A vitamin D group characterizes the presence of a polycyclic 7-dehydrocholesterol frame. Biosynthesis starts with photochemically formed vitamin D3, and enzymatic hydroxylation produces a C(25)-OH derivative. The model compound in the synthesis of vitamin D is TM 4.14. Consider its ret-rosynthesis to easily available starting materials and then propose the synthesis. 

Cholecalciferol (vitamin D3) is formed by photolysis of 7-dehydrocholesterol, a precursor in cholesterol biosynthesis. As shown in Fig. 3.42, UV radiation opens the B ring. The precalciferol formed is then isomerized to vitamin D3 by a rearrangement of the double bond which is influenced by temperature. Side-products, such as lumi- and tachisterol, have no vitamin D activity. Cholecalciferol is converted into the active hormone, 1,25-dihydroxy-cholecalciferol, by hy-droxylation reactions in liver and kidney. 7-Dehydrocholesterol, the largest part of which is supplied by food intake and which accumulates in human skin, is transformed by UV light into vitamin D3. The occurrence and the physiological significance of the D vitamins are covered in Sect. 6.2.2. 

Plants synthesise a number of steroid substances from cycloartenol, including 4,4-drmethylsterols, 4-methylsterols and demethylsterols. Cycloartenol is a precursor of many other steroids that are aglycons of saponins, of steroidal glycoalkaloids and of other compounds. Lanosterol in animals is a precursor for the biosynthesis of the most important zoosterol cholesterol (3-114). An intermediate in the biosynthesis of cholesterol is 7-dehydrocholesterol, which is a precursor of vitamin D3 (see Section 5.3.1). Cholesterol in the body is used for the biosynthesis of steroid hormones and bile acids (3-126). 

Kandutsch and Russell (1960) have studied the kinetics of the incorporation of acetate by cell-free homogenates of preputial gland tumors and liver into various sterols and have come to the conclusion that the sequence, lanosterol, 24,25-dihydrolanosterol, 4a-methyl-J -cholestenol, J -cholestenol, 7-dehydrocholesterol, cholesterol, operates predominantly in the tumor tissue, and to some extent in the liver. In the latter tissue, the saturation of the double bond of desmosterol (24,25-dehydro-cholesterol) is thought to be the last step in the biosynthesis (Stokes and Fish, 1960). 

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