The biosynthesis of squalene from acetate in man.
The biosynthesis of cholesterol in the liver and intestinal cells is a process that creates the essential lipid from acetyl CoA subunits. Much interaction and regulation exists between this endogenous synthesis process and the absorption of dietary cholesterol in the small intestine. As less cholesterol is consumed, synthesis increases in order to meet the body’s demands for the nutrient, while an increase in consumption results in the downregulation of the endogenous process (2). Canonically, the synthesis pathway is divided into three distinct segments: the synthesis of activated isoprene subunits, the condensation of these isoprene molecules to form squalene, and squalene’s cyclization into cholesterol (3) The cholesterol synthesis pathway, as divided into the three main steps listed above, is shown below (Fig. 4).
Biosynthesis of cholesterol generally takes ..
Figure 3. Chemical structures for reduction reaction of 3-hydroxy-3-methylglutaryl-CoA, better known as HMG-CoA, into mevalonate as catalyzed by HMG-CoA reductase. HMG-CoA is the substrate for HMGR, a key enzyme that catalyzes this committed step in the cholesterol biosynthesis pathway. Statins seek to suppress this pathway by out-competing HMG-CoA for binding in the active site of HMGR (adapted from reference 1).
Figure 4. Schematic showing the endogenous human cholesterol biosynthesis pathway. The diagram is divided into the three main steps of the process: The synthesis of the isopentenyl pyrophosphate subunit from acetyl CoA is shown in red; squalene formation from six isoprene molecules is shown in black, while the cyclization of squalene into cholesterol is shown in blue. For simplification, only the most relevant intermediates are included. A dotted box has been drawn around the step in which HMG-CoA is converted into mevalonate, as this is the most pertinent reaction to the drug described in this paper. This step is shown in more detail in Figure 3 (adapted from reference 3).
Cholesterol Biosynthesis Inhibitors of Microbial Origin
Cooper MK, Wasif CA, Krakowiak PA, et al. (2003) A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nature Genetics 33: 508–513.
THE BIOSYNTHESIS OF SQUALENE AND CHOLESTEROL 1
Xu G, Salen G, Shefer S, et al. (1995) Treatment of the cholesterol biosynthetic defect in Smith–Lemli–Opitz syndrome reproduced in rats by BM 15.766. Gastroenterology 109 (4): 1301–1307.
The utilization of squalene in the biosynthesis of cholesterol
Squalene epoxidase, a membrane-associated enzyme that converts squalene to squalene 2,3-oxide, plays an important role in the maintenance of cholesterol homeostasis. In 1957, Bloch and colleagues identified a factor from rat liver cytosol termed "supernatant protein factor (SPF)," which promotes the squalene epoxidation catalyzed by rat liver microsomes with oxygen, NADPH, FAD, and phospholipid [Tchen, T. T. & Bloch, K. (1957) J. Biol. Chem. 226, 921-930]. Although purification of SPF by 11,000-fold was reported, no information is so far available on the primary structure or biological function of SPF. Here we report the cDNA cloning and expression of SPF from rat and human. The encoded protein of 403 amino acids belongs to a family of cytosolic lipid-binding/transfer proteins such as α-tocopherol transfer protein, cellular retinal binding protein, yeast phosphatidylinositol transfer protein (Sec14p), and squid retinal binding protein. Recombinant SPF produced in Escherichia coli enhances microsomal squalene epoxidase activity and promotes intermembrane transfer of squalene in vitro. SPF mRNA is expressed abundantly in the liver and small intestine, both of which are important sites of cholesterol biosynthesis. SPF is expressed significantly in isolated hepatocytes, but the expression level was markedly decreased after 48 h of in vitro culture. Moreover, SPF was not detectable in most of the cell lines tested, including HepG2 and McARH7777 hepatomas. Transfection of SPF cDNA in McARH7777 significantly stimulated de novo cholesterol biosynthesis. These data suggest that SPF is a cytosolic squalene transfer protein capable of regulating cholesterol biosynthesis.
BIOSYNTHESIS OF SQUALENE - [PDF Document]
Smith–Lemli–Opitz syndrome (SLOS) is the most common and best understood of the inborn errors of cholesterol metabolism. Comprising a heterogeneous group of disorders, inborn errors in cholesterol biosynthesis result in characteristic but variable phenotypes. SLOS is an inherited disorder caused by mutations in which encodes the final enzyme in the cholesterol synthetic pathway. There are eight other cholesterol biosynthesis disorders described in the pre‐Squalene and post‐Squalene pathways. Phenotypic features of SLOS and the other eight disorders are thought to be related to cholesterol deficiency and/or accumulation of cholesterol precursors and their metabolites. A better understanding of SLOS and these other inborn errors of cholesterol biosynthesis may shed light on the importance of cholesterol biosynthesis in embryo‐ and morphogenesis as well as provide clues to treatment.