Cholesterol biosynthesis pathway

Several target enzymes in the cholesterol biosynthesis pathway have been targeted in attempts to lower blood cholesterol. The HMG-CoA reductase inhibitor (106) is 10 times more potent than lovastatin <93JMC3658>, and both SQ-33600 (107) and XU 62-320 (108) also inhibit this enzyme . The indole compound SaH 57-118 (109) inhibits acyl CoA cholesterol acyltransferase and lowers cholesterol absorption in rabbits by 65% . 

Figure 10.1 Cholesterol biosynthesis pathway. Statins inhibit the rate-limiting step, HMG-CoA reductase.

Drugs that lower blood cholesterol by retarding its synthesis in the liver are called statins [165] and are epitomized by atorvastatin (Lipitor a pyrrole, not an indole). These drugs function by inhibiting the enzyme hydroxym-ethylglutaryl-coenzyme A (HMG-CoA), crucial for a step in the cholesterol biosynthesis pathway. The one indole... 

Vitamin D is the sunshine vitamin . It was originally discovered as a crude mixture called vitamin Dj (no longer available as a supplement). Ergosterol, the plant equivalent of cholesterol, is converted to vitamin D2 by ultraviolet light. Vitamin D3 (cholecalciferol) is formed in the skin from 7-dehydrocholesterol (an intermediate in the cholesterol biosynthesis pathway) in the presence of ultraviolet light, which opens the B-ring of the steroid nucleus (Fig. 51.3). Cholecalciferol is successively hydroxylated first in the liver forming 25-hydroxycholecalciferol (25-HCC) and then in the kidney to form the most active form 1,25-dihydroxy cholecalciferol (1,25-DHCC), also known as calcitriol. 

Animals accumulate cholesterol from then diet but are also able to biosynthesize It from acetate The pioneering work that identified the key intermediates m the com plicated pathway of cholesterol biosynthesis was carried out by Konrad Bloch (Harvard) and Feodor Lynen (Munich) corecipients of the 1964 Nobel Prize for physiology or... 

HMG-CoA-Reductase Inhibitors. Figure 1 Mechanism of action of statins - cholesterol synthesis pathway. The conversion of acetyl CoA to cholesterol in the liver. The step of cholesterol biosynthesis inhibited by HMG-CoA reductase inhibitors (statins) is shown. 

Inhibit Enzymes Many drugs are competitive inhibitors of key enzymes in pathways. The statin drugs (lovastatin, simvastatin), used to control blood cholesterol levels, competitively inhibit 3-hvdroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in cholesterol biosynthesis. Methotrexate, an antineoplastic drug, competitively inhibits dihydrofolate reductase, depriving the cell of active folate needed for purine and deoxythymidine synthesis, thus interfering with DNA replication during S phase. 

Formation of mevalonate. The conversion of acetyl CoA to acetoacetyl CoA and then to 3-hydroxy-3-methylglutaryl CoA (3-HMG CoA) corresponds to the biosynthetic pathway for ketone bodies (details on p. 312). In this case, however, the synthesis occurs not in the mitochondria as in ketone body synthesis, but in the smooth endoplasmic reticulum. In the next step, the 3-HMG group is cleaved from the CoA and at the same time reduced to mevalonate with the help of NADPH+H 3-HMG CoA reductase is the key enzyme in cholesterol biosynthesis. It is regulated by repression of transcription (effectors oxysterols such as cholesterol) and by interconversion... 

The endergonic biosynthetic pathway described above is located entirely in the smooth endoplasmic reticulum. The energy needed comes from the CoA derivatives used and from ATP. The reducing agent in the formation of mevalonate and squalene, as well as in the final steps of cholesterol biosynthesis, is NADPH+H ... 

Fig. 1 Relationship of posttranslational protein isoprenylation pathways to the mevalonate pathway of cholesterol biosynthesis...

FTase catalyzes the covalent attachment of a farnesyl moiety via a thioether Unkage to the proteins bearing a C-terminal amino acid sequence known as the CAAX motif (Fig. 2) [12,21]. The farnesyl moiety is derived from farnesyl pyrophosphate (FPP), a 15-carbon isoprenyl intermediate in the mevalonate pathway of cholesterol biosynthesis. The binding of FPP to the enzyme has relatively high affinity (K = 1-lOnM), and FPP binding must precede the binding of the peptide substrate for successful catalysis [22,23]. 

Oximes of certain sterols were examined as inhibitors of cholesterol biosynthesis, by suppressing two enzymes that are involved in the biochemical pathway of cholesterol biosynthesis. This dual activity indicates a promising series of biologically reactive oximes (and oxime ethers) capable of reducing cholesterol levels . 

Figure 9-4. Metabolism of the branched-chain amino acids. The first two reactions, transamination and oxidative decarboxylation, are catalyzed by the same enzyme in all cases. Details are provided only for isoleucine. Further metabolism of isoleucine and valine follows a common pathway to propionyl CoA. Subsequent steps in the leucine degradative pathway diverge to yield acetoacetate. An intermediate in the pathway is 3-hydroxy-3-methylglutaryl CoA (HMG-CoA), which is a precursor for cytosolic cholesterol biosynthesis.

De novo synthesis of cholesterol is catalyzed by the isoprenoid biosynthesis pathway. This pathway produces a variety of sterol and nonsterol isoprenoids with... 

Fig. 5.1.2 Cholesterol biosynthesis branch of the isoprenoid biosynthetic pathway. Enzymes are numbered as follows 1 squalene synthase 2 squalene epoxidase 3 2,3-oxidosqua-lene sterol cyclase 4 sterol A24-reductase (desmosterolosis) 5 sterol C-14 demethylase 6 sterol A14-reductase (hydrops-ectopic calcification-moth-eaten, HEM, dysplasia) 7 sterol C-4 demethylase complex (including a 3/ -hydroxysteroid dehydrogenase defective in congenital hemidyspla-sia with ichthyosiform nevus and limb defects, CHILD, syndrome) 8 sterol A8-A7 isomerase (Conradi-Hunermann syndrome CDPX2) 9 sterol A5-desaturase (lathosterolosis) 10 sterol A7-reductase (Smith-Lemli-Opitz syndrome). Enzyme deficiencies are indicated by solid bars across the arrows...

Stage Synthesis of Mevalonate from Acetate The first stage in cholesterol biosynthesis leads to the intermediate mevalonate (Fig. 21-34). Two molecules of acetyl-CoA condense to form acetoacetyl-CoA, which condenses with a third molecule of acetyl-CoA to yield the six-carbon compound /3-hydroxy-/3-methylglu-taryl-CoA (HMG-CoA). These first two reactions are catalyzed by thiolase and HMG-CoA synthase, respectively. The cytosolic HMG-CoA synthase in this pathway is distinct from the mitochondrial isozyme that catalyzes HMG-CoA synthesis in ketone body formation (see Fig. 17-18). 

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