Cholesterol metabolism Sterol biosynthesis

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... 

Cholesterol metabolism and bile acid biosynthesis. At least seven cytochrome P-450 enzymes play critical roles in the conversion of acetate into sterols and bile acids. Key among these are CYP51A1, CYP7A1, CYP7B1, and CYP39A1. The roles of each of these enzymes are beyond the scope of this article, but some excellent reviews and texts are available on the topic. 

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. 

Figure 2.17 Suggested pathway of cholesterol metabolism in human brain based on the identification of metabolites in CSR The left hand branch constitutes the initial steps of the acidic pathway of bile acid biosynthesis. 26-Hydroxycholesterol may be synthesized in brain via a reaction catalyzed by CYP27A1 or imported into brain from the circulation (Heverin, Meaney, Liitjohann, et al. [60].) Thus, the ultimate product of this pathway 7a-hydroxy-3-oxocholest-4-en-26-oic may be derived from brain synthesized or imported sterols. The right-hand branch of the pathway represents the initial steps of the 24-hydroxylase pathway of bile acid biosynthesis. The initial enzyme CYP46A1 is uniquely expressed in nervous tissue (Lund, Guileyardo, and Russell [61]). (See color insert.)...

The interest of drugs interfering with cholesterol metabolism, is based on the assumption that high blood levels of this sterol are correlated with atherosclerosis. In fact, hypercholesterolaemia is considered a major risk factor for coronary heart disease. It is possible to act on cholesterol metabolism with drugs interfering either with cholesterol absorption and biosynthesis or with its catabolism and excretion. 

It is interesting that H and C are incorporated from L-[methyl- H, C]-methionine into cholesterol and 5a-cholest-7-en-3P-ol in normal and tumorous rats. The exact mechanism of this incorporation is obscure at present. There has been an increased interest in the biosynthesis and metabolism of cholesterol in brain tissue. This area has also been reviewed recently. The primary pathway of sterol biosynthesis in adult rat brain seems to be via A -intermediates. It is interesting that the conversion of squalene into sterols by microsomal fractions from brains of immature rats requires the lOOCKX) X g supernatant fraction from liver, the corresponding supernatant fraction from brain being inactive. ... 

Bjorkhem I, Boberg KM, Leitersdorf E (2001) Inborn Errors in bile acid biosynthesis and storage of sterols other than cholesterol. In Scriver C, Beaudet A, Sly W, Valle D (eds) The Metabolic Molecular Bases of Inherited Disease. McGraw-Hill, New York, pp 2961 -2964 and... 

The biosynthesis of cholesterol, related steroids, and phytosterols is dealt with in this section whereas the further metabolism of these classes and the remaining nonsteroidal triterpenoids are covered in the following two sections. Reviews have appeared on the biosynthesis of sterols and higher terpenoids, the in vivo metabolism of steroids in primates" and in plant tissue culture," and dietary feedback control of cholesterol synthesis." The latter contains a reasoned defence of the hypothesis that HMG-CoA reductase is controlled by alterations to its supporting microsomal membrane. Abstracts of a symposium on all aspects of steroid biosynthesis have appeared." ... 

Large amounts of C28 and C29 sterols occur in asteroids and other echinoderms but it seems that they cannot be synthesized from C27 sterols by transmethylation as is the case in plants (but not in other animals). This was confirmed with the starfish Laiaster leechii, which could convert MVA into A -cholesterol but could not alkylate this at C-24 or introduce a A -bond. Similarly the starfish Asterias rubens can only synthesize C27 sterols de novo, but here there is evidencethat a A -bond can be introduced into both cholesterol and A -cholesterol. This starfish can also synthesize A -sterols and there is some indication that cholesterol itself may be synthesized even though it was previously concluded that the family could not perform the final steps in this biosynthesis. This species also rapidly metabolized dietary steroids and such A -sterols could be converted into A -products, but it was considered unlikely that the organism had the ability to dealkylate C28 and C29 sterols. 

The resolution of synthetic presqualene and prephytoene alcohols via their etienic acid derivatives has been reported. This work confirmed that the active (-f-)-enantiomers in both series have the same absolute configuration [(li , 2/ , 3/ )]. It has been established, by use of Hn.m.r., that the proton (deuteron) introduced at C-3 during the cyclization of squalene to tetrahymanol by Tetrahymena pyriformis has the 3/8 configuration. Both antipodes of the trimethyldecalol (13) have been shown to be effective inhibitors of cholesterol biosynthesis in rat liver enzyme preparations and cultured mammalian cells. The accumulation of squalene 2,3-oxide and squalene 2,3 22,23-dioxide in the treated systems indicates that inhibition occurs at the cyclization stage. The inhibitor is metabolized to the diol (14). The results of other sterol inhibition... 

Excess cholesterol can also be metabolized to CE. ACAT is the ER enzyme that catalyzes the esterification of cellular sterols with fatty acids. In vivo, ACAT plays an important physiological role in intestinal absorption of dietary cholesterol, in intestinal and hepatic lipoprotein assembly, in transformation of macrophages into CE laden foam cells, and in control of the cellular free cholesterol pool that serves as substrate for bile acid and steroid hormone formation. ACAT is an allosteric enzyme, thought to be regulated by an ER cholesterol pool that is in equilibrium with the pool that regulates cholesterol biosynthesis. ACAT is activated more effectively by oxysterols than by cholesterol itself, likely due to differences in their solubility. As the fatty acyl donor, ACAT prefers endogenously synthesized, monounsaturated fatty acyl-CoA. 

Sterols are another class of compounds also involved in metabolic processes. They act as hormonal regulators of growth, respiration, eind reproduction in most marine oi anisms (Kanazawa and Teshima, 1971). Sterols, notably cholesterol, are also present in oi anisms as lipoproteins, probably a larger source of these compounds than as hormonal regulators. The presence of hydrocarbons in marine organisms is known, but their precise function is unclear. Farrington and Meyers (1975) review the present knowledge on biosynthesis of hydrocarbons by marine oi anisms. Alkenes appear to make up... 

Various aspects of steroid biosynthesis were included in a Royal Society Symposium. The published proceedings and other reviews have dealt with cyclase enzymes,water-soluble steroids and triterpenoids, the involvement of a 14(15)- or 8(14)-double bond and its reductionin cholesterol biosynthesis, biosynthesis of sterols, steroid metabolism in insects, pregnane steroids, cardenolides, and bufadienolides. ... 

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