Cholesterol in mammals

The metabolism of cholesterol in mammals is extremely complex. A summary sketch (fig. 20.24) helps to draw the major metabolic interrelationships together. Cholesterol is biosynthesized from acetate largely in the liver (fig. 20.24a) or taken in through the diet (fig. 20.24b). From the intestine, dietary cholesterol is secreted into the plasma mainly as a component of chylomicrons. The triacylglycerol components of chylomicrons are quickly degraded by lipoprotein lipase, and the remnant particles are removed by the liver. Apoproteins and lipid components of the chylomicrons and remnants appear to exchange with HDL. Cholesterol made in the liver (fig. 20.24a) has several alternative fates. It can be (1) secreted into plasma as a component of VLDL,... 

Bile salts (or bile acids) are polar derivatives of cholesterol and constitute the major pathway for the excretion of cholesterol in mammals. In the liver, cholesterol is converted into the activated intermediate cholyl CoA which then reacts either with the amino group of glycine to form glycocholate (Fig. 3a), or with the amino group of taurine (H2N-CH2-CH2-S03", a derivative of cysteine) to form taurocholate (Fig. 3b). After synthesis in the liver, the bile salts glycocholate and taurocholate are stored and concentrated in the gall bladder, before release into the small intestine. Since they contain both polar and nonpolar... 

Fig. 20 Steps in the pathway from lanosterol to cholesterol in mammals.

Mevalonate, the 6-carbon product formed by HMG-CoA reductase, Is converted In several steps Into the 5-carbon Iso-prenold compound Isopentenyl pyrophosphate (IPP) and Its stereoisomer dimethylallyl pyrophosphate (DMPP). These reactions are catalyzed by cytosolic enzymes, as are the subsequent reactions In which six IPP units condense to yield squalene, a branched-chain 30-carbon Intermediate. Enzymes bound to the ER membrane catalyze the multiple reactions that convert squalene into cholesterol In mammals or into related sterols In other species. 

Steroid hormones are crucial signal molecules in mammals. (The details of their physiological effects are described in Chapter 34.) Their biosynthesis begins with the desmolase reaction, which converts cholesterol to preg-... 

Bark beetles primarily utilize isoprenoid derived pheromones [100,101] and have been the most studied regarding their biosynthesis [8,98]. Earlier work indicated that the isoprenoid pheromones could be produced by the beetle altering host derived isoprenoids however more recent work indicates that for the most part bark beetles are producing pheromones de novo. The production of isoprenoids follows a pathway outlined in Fig. 4 which is similar to the isoprenoid pathway as it occurs in cholesterol synthesis in mammals. Insects cannot synthesize cholesterol but can synthesize farnesyl pyrophosphate. Insects apparently do not have the ability to cyclize the longer chain isoprenoid compounds into steroids. The key enzymes in the early steps of the isoprenoid... 

The biosynthesis of pregnenelone (112) in mammals has been well documented [1] it is known to be produced from cholesterol (1) via its 20,22-dihydroxy derivative (121) (Scheme 19A). The origin of 112 has been investigated in the sponge Amphimedon compressa. At the present time it is not known whether cholesterol and its 20,22-dihydroxy derivative serve as precursors for this pregnane in A. compressa however a new pathway (Scheme 19B) has been found to operate [89]. This involves the conversion of 22-dehydro sterols (e.g. stigmasterol, 122) to pregnenelone. The mechanism is believed to... 

Recently, Voogt et al. [91] have reported on the d5-pathway in steroid metabolism of Asterias rubens. These workers established the existence of the d5-pathway (Scheme 20), analogous to the pathway found in mammals this conclusion was based on the observation that radiolabeled cholesterol (1) was converted to pregnenolone (112), 17a-hydroxypregnenolone (141), and androstenediol (142). Labeled pregnenolone was converted additionally to progesterone (129). Androstenediol (142) was the main metabolite of de-hydroepiandrosterone (143), a reaction catalyzed by 17/i-hydroxysteroid dehydrogenase (17/1-HSD). The metabolic conversion of androstenedione (131) to testosterone (132) is also mediated by 17/J-HSD and is related to... 

It is well known that the steroid hormones in mammals are biosynthesized from cholesterol. This compound is derived from the acetate-mevalonate pathway through the monoterpene geranyl pyrophosphate, which undergoes several enzymatic reactions to form the triterpene squalene. 

Prenylation (covalent attachment of an isoprenoid see Fig. 27-30) is a common mechanism by which proteins are anchored to the inner surface of cellular membranes in mammals (see Fig. 11-14). In some of these proteins the attached lipid is the 15-carbon farnesyl group others have the 20-carbon geranylgeranyl group. Different enzymes attach the two types of lipids. It is possible that prenylation reactions target proteins to different membranes, depending on which lipid is attached. Protein prenylation is another important role for the isoprene derivatives of the pathway to cholesterol. 

Sterols and Cholesterol. Natural sterols are crystalline C76 C1(1 steroid alcohols containing an aliphatic side chain at C17. Sterols were first isolated as lionsaponifiable fractions of lipids from various plant and animal sources and have been identified in almost all types of living organisms. By far, the most common sterol in vertebrates is cholesterol (8). Cholesterol serves two principal functions in mammals. First, cholesterol plays a role in the structure and function of biological membranes.. Secondly, cholesterol serves as a central intermediate in the biosynthesis of many biologically active steroids, including bile acids, corticosteroids, and sex hormones. 

The last sequence of reactions in the biosynthesis of choles-terol involves approximately 20 enzymatic steps, starting with lanosterol. In mammals the major route involves a series of double-bond reductions and demethylations (fig. 20.10). The sequence of reactions involves reduction of the A24 double bond, the oxidation and removal of the 14a methyl group followed by the oxidation and removal of the two methyl groups at position 4 in the sterol. The final reaction is a reduction of the A7 double bond in 7-dehydro-cholesterol. An alternative pathway from lanosterol to cholesterol also exists. The enzymes involved in the transformation of lanosterol to cholesterol are all located on the endoplasmic reticulum. 

Two pathways for the conversion of lanosterol to cholesterol. The major route in mammals proceeds through 7-dehy drocho l es terol. 

The major sterol found in mammals is the C27 compound cholesterol, which acts as a precursor for other steroid structures such as sex hormones and... 

The first pathogen-specific reaction is the S-adenosylmethio-nine-dependent side chain aklylation of lanosterol. This is pathogen specific since in cholesterol synthesis, a side chain alkylation does not take place. Secondly, the demethylation reactions at C - and C -positions of 24-methylene-dihydrolanosterol are pathogen-specific as well. In mammals demethylation reactions take place, but the substrate is not side chain alkylated, so the corresponding enzyme should possess different binding sites for the different substrates. 

Another target, that at first seems to be unfavorable since it is principally common for all organisms, is the enzyme HMG-CoA-reduc-tase which is the regulatory enzyme in terpenoid biosynthesis. Results from trials with naturally produced inhibitors for that enzyme, such as Compactine and Mevinoline, indicate that these compounds are able to lower the cholesterol content in mammals, but not markedly depress sterol synthesis in fungi U3). 

VL Meiner, S Cases, HM Myers, ER Sande, S Bellosta, M Schambelan, RE Pitas, J McGuire, J Herz, RV Farese Jr. Disruption of the acyl-CoAxholesterol acyltransferase gene in mice evidence suggesting multiple cholesterol esterification enzymes in mammals. Proc Natl Acad Sci (USA) 93 14041-14046, 1996. 

Because cholesterol contains an -OH group, it is amphipathic. It controls membrane fluidity in mammals by inhibiting the ordering of fatty acid side chains, but it is absent from bacterial plasma membranes. 

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