Harpers

220 / CHAPTER 26OCH 3 C S CoA2 Acetyl-CoATHIOLASEOCCH 2– OOC C CH2 CH 2 OHCoA SHCH 3C CH 2OC S CoAOAcetoacetyl-CoA OH 2 OCH 3 C S CoAAcetyl-CoAHMG-CoA SYNTHASECoA SHCH 3– OOC CH 2 CH 2 C S CoAOH3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA)Bile acid, cholesterol2NADPH + 2H +HMG-CoA REDUCTASEStatins, eg,simvastatin2NADP + + CoA SHMevalonateCH 3OHMevalonateFigure 26–1. Biosynthesis of mevalonate. HMG-CoAreductase is inhibited by atorvastatin, pravastatin, andsimvastatin. The open and solid circles indicate the fateof each of the carbons in the acetyl moiety of acetyl-CoA.function oxidase in the endoplasmic reticulum, squaleneepoxidase. The methyl group on C 14 is transferredto C 13 and that on C 8 to C 14 as cyclization occurs, catalyzedby oxidosqualene:lanosterol cyclase.Step 5—Formation of Cholesterol: The formationof cholesterol from lanosterol takes place in themembranes of the endoplasmic reticulum and involveschanges in the steroid nucleus and side chain (Figure26–3). The methyl groups on C 14 and C 4 are removedto form 14-desmethyl lanosterol and then zymosterol.The double bond at C 8 –C 9 is subsequently moved toC 5 –C 6 in two steps, forming desmosterol. Finally, thedouble bond of the side chain is reduced, producingcholesterol. The exact order in which the steps describedactually take place is not known with certainty.Farnesyl Diphosphate Gives Riseto Dolichol & UbiquinoneThe polyisoprenoids dolichol (Figure 14–20 andChapter 47) and ubiquinone (Figure 12–5) are formedfrom farnesyl diphosphate by the further addition of upto 16 (dolichol) or 3–7 (ubiquinone) isopentenyldiphosphate residues, respectively. Some GTP-bindingproteins in the cell membrane are prenylated with farnesylor geranylgeranyl (20 carbon) residues. Proteinprenylation is believed to facilitate the anchoring ofproteins into lipoid membranes and may also be involvedin protein-protein interactions and membraneassociatedprotein trafficking.CHOLESTEROL SYNTHESIS ISCONTROLLED BY REGULATIONOF HMG-CoA REDUCTASERegulation of cholesterol synthesis is exerted near thebeginning of the pathway, at the HMG-CoA reductasestep. The reduced synthesis of cholesterol in starvinganimals is accompanied by a decrease in the activity ofthe enzyme. However, it is only hepatic synthesis that isinhibited by dietary cholesterol. HMG-CoA reductasein liver is inhibited by mevalonate, the immediate productof the pathway, and by cholesterol, the main product.Cholesterol (or a metabolite, eg, oxygenated sterol)represses transcription of the HMG-CoA reductasegene and is also believed to influence translation. A diurnalvariation occurs in both cholesterol synthesisand reductase activity. In addition to these mechanismsregulating the rate of protein synthesis, the enzyme activityis also modulated more rapidly by posttranslationalmodification (Figure 26–4). Insulin or thyroidhormone increases HMG-CoA reductase activity,whereas glucagon or glucocorticoids decrease it. Activityis reversibly modified by phosphorylation-dephosphorylationmechanisms, some of which may becAMP-dependent and therefore immediately responsiveto glucagon. Attempts to lower plasma cholesterol inhumans by reducing the amount of cholesterol in thediet produce variable results. Generally, a decrease of100 mg in dietary cholesterol causes a decrease of approximately0.13 mmol/L of serum.MANY FACTORS INFLUENCE THECHOLESTEROL BALANCE IN TISSUESIn tissues, cholesterol balance is regulated as follows (Figure26–5): Cell cholesterol increase is due to uptake ofcholesterol-containing lipoproteins by receptors, eg, theLDL receptor or the scavenger receptor; uptake of freecholesterol from cholesterol-rich lipoproteins to the cell