Synthesis 3-hydroxy-3-methylglutaryl

Starvation elicits mobilization of triglycerides from the adipose tissue and inhibits the endogenic cholesterol synthesis owing to the low activity of hydroxy-methylglutaryl-CoA reductase. The latter process provides the possibility for the active production of ketone bodies in the liver. 

Weakness can result from medications that have a direct myotoxic effect, such as blockade of myocyte glycoprotein synthesis and eleetron transport eaused by statins (inhibitors of the hydroxy-methylglutaryl-coenzyme A reduetase) used in patients with hyperlipidemia or nucleoside analogues used in patients with human immunodefieieney virus (40). Weakness can also result from neuromuscular blocking agents and aminoglyeosides, which interfere with neuromuscular transmission. 

This effect may be due to the high level of PUFA, which is supported by evidence that com oil is more effective than olive oil in lowering LDL-cholesterol because com oil has higher PUFA (58.7 g/100 g oil) than olive oil (8.4 g/100 g oil) (Howell et al., 1998 Dupont et al., 1990). Com oil has a plant sterols content of 128 mg/lOOOkcal vs. 66 mg/lOOOkcal for olive oil, and these plant sterols can reduce cholesterol absorption from the gut which in turn lowers body pools and enhances synthesis rate through de-suppression of cellular hydroxy-methylglutaryl-CoA reductase activity (Howell et al., 1998 Maki, et al., 2015). This is supported by a recent human study that the hypocholesteremic effect of com oil is connected with the high amount of phytosterols (Wagner et al., 2001). 

The ketone bodies (acetoacetate, 3-hydroxybutyrate, and acetone) are formed in hepatic mitochondria when there is a high rate of fatty acid oxidation. The pathway of ketogenesis involves synthesis and breakdown of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by two key enzymes, HMG-CoA synthase and HMG-GoA lyase. 

The synthesis of the decalin unit of compactin (59), a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which acts as an effective hypocholesterolemic agent, was planned to incorporate an intramolecular Diels-Alder reaction (Scheme 9.15) [57]. 

Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, interrupting the conversion of HMG-CoA to mevalonate, the rate-limiting step in de novo cholesterol biosynthesis. Reduced synthesis of LDL and enhanced catabohsm of LDL mediated through LDL-Rs appear to be the principal mechanisms for lipid-lowering effects. 

The therapeutic class that uniquely exemplifies lactone prodrugs are the statins, i.e., the cholesterol-lowering agents that act by inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.34). This microsomal enzyme catalyzes conversion of HMG-CoA to mevalonate, an important rate-limiting step in cholesterol biosynthesis. Cholesterol synthesis occurs mainly... 

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... 

At high concentrations of acetyl-CoA in the liver mitochondria, two molecules condense to form acetoacetyl CoA [1]. The transfer of another acetyl group [2] gives rise to 3-hydroxy-3-methylglutaryl-CoA (HMC CoA), which after release of acetyl CoA [3] yields free acetoacetate (Lynen cycle). Acetoacetate can be converted to 3-hydroxybutyrate by reduction [4], or can pass into acetone by nonenzymatic decarboxylation [5]. These three compounds are together referred to as "ketone bodies," although in fact 3-hydroxy-butyrate is not actually a ketone. As reaction [3] releases an ion, metabolic acidosis can occur as a result of increased ketone body synthesis (see p. 288). 

The statin family of six closely related hypocholesterolemic drugs are all potent competitive inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase), the rate-limiting enzyme in cholesterol biosynthesis. The liver is their target organ, and decreased hepatic cholesterol synthesis ultimately leads to increased removal of LDL particles from the circulation. As a consequence, all other hypocholesterolemic drugs have been relegated to secondary status. 

A very similar reaction is catalyzed by 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase), which functions in the formation of acetoacetate in the human body (Eq. 17-5, step c) and also in the catabolism of leucine (Fig. 24-18)182183 and in the synthesis of 3-hydroxy-3-methyIgIutaryI-CoA, the presursor of cholesterol (Eq. 17-5, step fr)183a... 

Other Claisen condensations are involved in synthesis of fatty acids and polyketides217 (Chapter 21) and in formation of 3-hydroxy-3-methylglutaryl-CoA, the precursor to the polyprenyl family of compounds (Chapter 22). In these cases the acetyl group of acetyl-CoA is transferred by a simple displacement mechanism onto an -SH group at the active site of the synthase to form an acetyl-enzyme.218 219 The acetyl-enzyme is the actual reactant in step b of Eq. 17-5 where this reaction, as well as that of HMG-CoA lyase, is illustrated. 

This category includes atorvastatin (Lipitor), fluvas-tatin (Lescol), lovastatin (Mevacor), pravastatin (Prava-chol), and simvastatin (Zocor) (Table 25-2). These drugs, known commonly as statins, are characterized by their ability to inhibit an enzyme known as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.96 This enzyme catalyzes one of the early steps of cholesterol synthesis, and drugs that inhibit HMG-CoA reductase decrease cholesterol produc-... 

Dideoxy-D-eryt/zro-hexopyranose (172) has been obtained from 3-deoxy-D-eryt/zro-pentose (171, Scheme 51)248 as an intermediate for the synthesis of the lactone moiety of inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, that lowers cholesterol levels. 

SY Sit, RA Parker, I Motoe, HW Balsubramanian, CD Cott, PJ Brown, WE Harte, MD Thompson, J Wright. Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. J Med Chem 33 2982-2999, 1990. 

Endo A, Tsujita Y Kuroda M, Tanzawa K. Inhibition of cholesterol synthesis in vitro and in vivo by ML-236A and ML-236B, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, EurJ Biochem I 977 77 31-36,... 

The first stage in the synthesis of cholesterol is the formation of isopentenyl pyrophosphate Fig. 1). Acetyl CoA and acetoacetyl CoA combine to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA). This process takes place in the liver, where the HMG CoA in the mitochondria is used to form ketone bodies during starvation (see Topic K2), whereas that in the cytosol is used to synthesize cholesterol in the fed state (under the influence of cholesterol). HMG CoA is then reduced to mevalonate by HMG CoA reductase Fig. 1). This is the committed step in cholesterol biosynthesis and is a key control point. Mevalonate is converted into 3-isopentenyl pyrophosphate by three consecutive reactions each involving ATP, with C02 being released in the last reaction Fig. 1). 

Lactone 7 can serve as a versatile starting material for the synthesis of a range of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, commonly referred to as statins, which includes Lipitor (8) and Crestor (9) compounds (Scheme 20.7). In a single transformation, the lactone ring can be opened and the chloride can be displaced by either cyanide or hydroxide to access advanced Lipitor or Crestor intermediates, respectively. 

Which one of the following drugs decreases de novo cholesterol synthesis by inhibiting the enzyme 3-hydroxy-3-methylglutaryl CoA reductase ... 

---