Oxygenated derivatives of cholesterol

The identity of the multiple signals which regulate HMG-CoA reductase levels has yet to be established. One of these appears to be a sterol or sterol derivative. The second appears to be mevalonate or one of its metabolites [141]. Leading candidates for the sterol signal(s) are oxygenated derivatives of cholesterol. These are present in the circulation and many are potent suppressors of HMG-CoA reductase levels [175-177]. A candidate for the regulatory metabolite of mevalonate is isopentenyl adenine. Compactin added to baby hamster kidney-21 cells completely inhibits both DNA synthesis and cell proliferation [178]. Added mevalonolactone relieved this inhibition, but added sterols did not. Isopentenyl adenine also relieved compactin inhibition, and did so 100-200 times more effectively than did mevalonolactone [178]. 

Oxysterols are defined as oxygenated derivatives of cholest-5-en-3(3-ol (cholesterol) (Figure 18.1) or precursors of CHOL that may be formed directly by autoxidation or by the action of a specific monooxygenase, or that may be secondary to enzymatic or nonenzymatic lipid peroxidation (Guardiola et al., 1996 Schroepfer, 2000 Bjorkhem and Diczfalusy, 2002). These OS may be formed in the human body by endogenous free-radical attack on CHOL or by enzymatic processes, mainly in the biosynthesis of bile acids and steroid hormones. In addition, OS may be formed exogenously by autoxidation of CHOL in foods. The nomenclature and abbreviations of OS are presented in Table 18.1. It should be emphasized at this point that the OS that occur in... 

Choiesteroi oxygenated Atheroma formation arterial damage Atherosclerosis derivatives of cholesterol noncholesterol steroids... 

Inhibitors of HMG-CoA reductase activity (for example compac-tin240), or compounds that lower the levels of the enzyme (including a number of oxygenated cholesterol derivatives,241- 24 la such as 25-liy-droxycholesterol), not only decrease the formation of polyprenyl diphosphate, but also affect the formation of cholesterol and the polyprenyl side-chains of coenzyme Q. Consequently, prolonged treatment with such compounds may cause side effects, for example, changes in membrane fluidity (see also, Section III,5), decreased activity of membrane enzymes,1214,2,3 and inactivation of membrane transport systems,246 and, therefore, indirectly prevent glvcosvlation of proteins. 

Reactivity of carbon-centered radicals may remain high even in crystalline state of the matrix when the access of oxygen towards unpaired electrons is not hindered by the sterical arrangement of surrounding molecules. This is, e.g., the case of peroxyl radicals formed during irradiation of cholesterol [60]. Oxygen reacts with alkyl radicals derived from cholesterol already at 125 K which is far below the melting point of the matrix (423 K). Two peroxyl radicals of cholesterol were observed (Scheme). 

Fig. 22.1. (A) Enzymatic cycle of cholesterol oxidase which catalyzes the oxidation of cholesterol by oxygen. The enzyme s naturally fluorescent FAD active site is first reduced by a cholesterol substrate molecule, generating a non-fluorescent FADH2, which is then oxidized by oxygen. (B) Structure of FAD, the active site of cholesterol oxidase. (C) A portion of the fluorescence intensity time trace of a single cholesterol oxidase molecule. Each on-off cycle of emission corresponds to an enzymatic turnover. (D) Distribution of emission on-times derived from (C). The solid line is the convolution of two exponential functions with rate constants fci[S] = 2.5 s and fc2 = 15.3 s, reflecting the existence of an intermediate, ES, the enzyme-substrate complex, as shown in the kinetic scheme in the inset. From ref. [15]...

Angina occurs when atherosclerotic plaques obstruct coronary blood flow, therefore decreasing the oxygen supply to myocardial tissues. Atherosclerotic plaques are composed of cholesterol and foam cells (derivatives of macrophages) enclosed within a fibrous capsule. Thrombus formation occurs within the plaque, and as erosion of the endothelium occurs, the thrombus extends into the arterial lumen. Coronary blood flow may become occluded depending on... 

The squalestatins, e.g. 6.28, also known as the zaragozic adds, have attracted considerable interest as inhibitors of squalene synthase and hence of cholesterol biosynthesis and lipid deposition in the circulatory system. They are also inhibitors of farnesyl protein transferase and thus they may have other potentially useful biological applications. They are formed by Phoma spedes and also by Setosphaeria khartoumensis. The squalestatins are characterized by a dioxabicyclo-octane core bearing three carboxyl groups and two polyketide chains, one of which is attached as an ester. The biosynthetic incorporation of succinic acid into part of the bicyclo-octane, together with its oxygenation pattern, indicate that it may be derived via oxaloacetic acid. Both the polyketide chains have several pendant methyl groups attached to them, which arise from methionine, whilst benzoic add ads as a starter unit for one of the chains. These complex structures are thus the summation of several biosynthetic pathways. 

As silyl derivatives of oxygen-containing compounds are those most frequently used, we shall cite some examples of their application. Experimental results [83] indicate the expediency of using the trimethylsilyl ether of cholesterol and not the methyl ether, as the former yields more symmetrical chromatographic zones. VandenHeuvel et al. 

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