Cholesterol sterol biosynthesis

A recent and surprising finding in sponge sterol biosynthesis is the observation that certain 24-alkyl sterols can be transformed to cholesterol [46,48, 50]. This is particularly unusual, as this pathway operates in organisms which are also... 

There is a single report of the dealkylation of a sterol side-chain in the whelk Buccinum undatum [52]. This organism also transformed 3H-lanosterol (33) to cholesterol (1), thus indicating its capability for de novo sterol biosynthesis. 

In green plants, which contain little or no cholesterol, cydoartenol is the key intermediate in sterol biosynthesis.161-1623 As indicated in Fig. 22-6, step c, cydoartenol can be formed if the proton at C-9 is shifted (as a hydride ion) to displace the methyl group from C-8. A proton is lost from the adjacent methyl group to close the cyclopropane ring. There are still other ways in which squalene is cyclized,162/163/1633 including some that incorporate nitrogen atoms and form alkaloids.1631 One pathway leads to the hop-anoids. These triterpene derivatives function in bacterial membranes, probably much as cholesterol does in our membranes. The three-dimensional structure of a bacterial hopene synthase is known.164 1643 Like glucoamylase (Fig. 2-29) and farnesyl transferase, the enzyme has an (a,a)6-barrel structure in one domain and a somewhat similar barrel in a second domain. 

Radioactive carbon dioxide was detected in the breath of rats and men almost immediately after the administration, either orally or by injection, of (RS)-[5-14C]MVA,36 and up to 6.5% of the administered dose was exhaled within 100 minutes. Since the carbon dioxide was not derived from the unnatural S-enantiometer of MVA, or from degradation of cholesterol biosynthesized from the additive MVA, the observations support the hypothesis that there exists a metabolic shunt of intermediates of sterol biosynthesis which, although derived from MVA, do not lead to sterol formation. The significance of this shunt is that its occurrence could explain some of the human hypercholesterolaemias. The authors claim that MVA has no metabolic fate (hitherto known) except the biosynthesis of terpenoids is quite... 

High serum cholesterol levels are an important risk factor for coronary heart disease and an effective way of reducing serum cholesterol is to inhibit sterol biosynthesis. The "statins" work by inhibiting 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase), a major regulatory enzyme in the cholesterol biosynthetic pathway which catalyses the rate-limiting conversion of HMG CoA to mevalonic acid. 

Arthropod Sterols.—The absence of sterol biosynthesis has been observed in further examples from the class ArachnidaT The conversion of /5-sitosterol back to cholesterol was demonstrated in bees and in locusts/ where it was shown that fucosterol, but not 24-methylenecholesterol, was probably a precursor of desmosterol and cholesterol. Some interconversions of pregnane, andros-tane, and oestrane steroids have been examined in the cricket.The stages in the oxidation of the side-chain of ecdysone hormones have been studied in several species. In Calliphora, the sequence of oxidation seems to be hydroxylation at C-25, C-22,and C-20 i.e. (115)— (116)— (117)— (118). The last step, conversion... 

Patients with familial hypercholesterolaemia exhibit lower levels of plasma cholesterol after an operation for portacaval anastomosis, and it has now been shown in rats that such an operation causes an increase in HMG-CoA reductase and cholesterol 7a -hydroxylase activities. Many transplantable human and rodent hepatomas do not control the rate of sterol biosynthesis and HMG-CoA reductase levels in response to dietary cholesterol as normal liver cells do. However, certain hepatoma cells have now been found that, although lacking feedback regulation of choles-terologenesis in vivo, retain their regulatory ability in vitro It thus appears that malignant transformation is not necessarily linked to the loss of regulation by the cell of HMG-CoA reductase activity or sterol synthesis. 

In considering the mechanism of action of azoles on sterol biosynthesis in powdery mildew (see figure 4), we should discuss a variation in the biosynthetic sequence to the end-product. The occurrence of obtusifoliol and 24-methylenedihydrolanosterol following azole treatment confirms that the oxidative removal of the C-14-methyl group by the cytochrome P-450 system is also inhibited. The fact that side chain alkylation is performed prior to this step in powdery mildew seems worthy of note, reflecting as it does a principal difference to cholesterol biosynthesis in mammals. 

Very early in the investigation of sterol biosynthesis it was estabUshed that acetate was the primary precursor. In 1942 Bloch and Rittenberg found that deutero-acetate could be converted to cholesterol in the intact animal in high yields [7]. This was in accord with the earlier observation of Sonderhoff and Thomas that the nonsaponifi-able lipids from yeast (primarily sterol) were heavily labeled by the same substrate [8]. Degradation of the sterol molecule in the laboratories of both Bloch and Popjak showed that all of the carbon atoms of cholesterol were derived from acetate and that the labeling pattern of methyl and carboxyl carbons originating from acetate indicated that the molecule was isoprenoid in nature [9]. It was apparent then that sterols have as their fundamental building block, acetate, a molecule that resides at the center of intermediary metabolism. 

In addition to cholesterol and 5a-cholest-7-en-3y8-ol, many C2g and C29 conventional sterols are present in Echinodermata. These sterols are probably derived from the diet. However, echinoderms are able to synthesize sterols. Thus, [ C]mevalonic acid was incorporated into squalene, lanosterol and desmosterol by the sea urchin. Echinus esculentus [87]. The ability of ophiurpids to synthesize sterol from [ C]acetate has also been demonstrated [88]. Sterol biosynthesis by a holothuroid was first investigated by Numura [89], and sterol biosynthesis from [ C]acetate in sea cucumbers has also been reported [90]. 

London, M., Bakht, O. London, E. Cholesterol precursors stabihze ordinary and ceramide-rich ordered hpid domains (hpid rafts) to different degrees. Imphcations for the Bloch hypothesis and sterol biosynthesis disorders. J Biol Chem 281 (2006) 21903-13. 

Lack of De Novo Sterol Biosynthesis in Nematodes. The dietary requirement tor sterol results from the lack ofde novo sterol biosynthesis in nematodes. Species In which radiolabeled acetate or mevalonate are not converted to radiolabeled sterol Include T. aceti (14, 15), Caenorhabditls (15) and the animal parasites AscarTs (l6), Dirof aria immitis (17), and Brugia pahangi (17). On occasion, radiolabeled sterols Identified by thin-layer cRromatography have been detected from nematodes incubated with radiolabeled acetate in the lone case in which such compounds were further characterized by gas-liquid chromatography, the radiolabeled components possessed retention times much earlier than cholesterol (16). 

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...

Many of the enzymes in the sterol biosynthesis pathway have selective-inhibitors (Fig. 3). These include some extremely important classes of drugs such as Statins , used to treat high cholesterol, bisphosphonates, used to treat osteoporosis, allylamines (e.g., terbinafine) and azoles used to treat fungal infections, and morpholines which are used as fungicidal agrochemicals. 

Steroids are derived from the same squalene precursor and have an oxygen-dependent biosynthetic pathway beginning with the formation of the first intermediate, 2,3-oxidosqualene (for details, see Sect. 5.1). Sterols, also known as steroid alcohols, are a subclass of steroids and may be found either as fi ee sterols, acylated, alkylated, sulfated, or linked to a glycoside moiety which can be itself acylated. Sterol biosynthesis is nearly ubiquitous among eukaryotes but almost completely absent in prokaryotes. As a result, the presence of diverse steranes (saturated four-cycle skeleton) in ancient rocks has been considered as evidence for over 2.7 billion years of eukaryotic evolution. Cholesterol is the most well-known sterol found in animal cell membranes (for establishing proper membrane permeability and fluidity) and red blood cells. 

Whether some procaryotes contain sterols and others do not has, of course, an important bearing on evolutionary relationships. One may ask, for example, whether Methylococcus and related methanotrophs were ancestral to a line of aerobic bacteria which then abandoned the sterol pathway or whether in another independently evolving branch of aerobes sterol biosynthesis was never invented. These issues are of interest not only by themselves but also because they bear on the matter of how the wide evolutionary gap between procaryotes and eucaryotic cells was bridged. As pointed out earlier, the possession of the sterol molecule is a universal feature of eucaryotic forms of life. For eucaryotes, phylogenetic relationships are much more certain than they are for procaryotic cells so that one can speak with some confidence of eucaryotes that are primitive and those that are more advanced. In the present context it is therefore significant that the red algae, supposedly the most primitive extant eucaryotes, not only contain sterols in substantial amounts but also that in these cells the biosynthetic pathway is modern, i.e. fully developed. Cholesterol or related cholestane derivatives are the dominant sterols in all members of the order Rhodophytae so far examined. ... 

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