3 -Hydroxy-3 -methylglutaryl

The product of this reaction 3 hydroxy 3 methylglutaryl coenzyme A (HMG CoA) has the carbon skeleton of mevalonic acid and is converted to it by enzymatic reduction... 

The statins lower cholesterol by inhibiting the en zyme 3 hydroxy 3 methylglutaryl coenzyme A reduc tase which is required for the biosynthesis of meva Ionic acid (see Section 26 10) Mevalonic acid is an obligatory precursor to cholesterol so less mevalonic acid translates into less cholesterol... 

As summarized in Figure 27.7, the mevalonate pathway begins with the conversion of acetate to acetyl CoA, followed by Claisen condensation to yield acetoacety) CoA. A second carbonyl condensation reaction with a third molecule of acetyl CoA, this one an aldol-like process, then yields the six-carbon compound 3-hydroxy-3-methylglutaryl CoA, which is reduced to give mevalonate. Phosphorylation, followed by loss of C02 and phosphate ion, completes the process. 

Step 2 of Figure 27.7 Aldol Condensation Acetoacetyl CoA next undergoes an aldol-like addition (Section 23.1) of an acetyl CoA enolate ion in a reaction catalyzed by 3-hydroxy-3-methylglutaryl-CoA synthase. The reaction again occurs... 

Statins (3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors)... 

Most of the acetyl-CoA formed by 3-oxidation in liver is converted to acetoacetate by the 3-hydroxy-3-methylglutaryl-CoA pathway (Guzman and Gelen, 1993). Acetoacetate is reversibly converted to D-3-hydroxybutyrate by D-3-hy-droxybutyrate dehydrogenase in the mitochondrial matrix in all tissues. 

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. 

Figure26-2. Biosynthesis of squalene, ubiquinone, dolichol, and other polyisoprene derivatives. (HMG, 3-hydroxy-3-methylglutaryl x, cytokinin.) A farnesyl residue is present in heme a of cytochrome oxidase. The carbon marked with asterisk becomes C or C,2 in squalene. Squalene synthetase is a microsomal enzyme all other enzymes indicated are soluble cytosolic proteins, and some are found in peroxisomes.

Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to improve vascular outcomes due to their cholesterol-lowering effects as well as multiple pleiotropic effects. In high-risk populations, statin therapy is known to reduce the risk of vascular events such as myocardial infarction and stroke. A meta-analysis of 10 trials involving 79,494 subjects showed that statin therapy reduced the incidence of stroke by 18%, major coronary events by 27%, and all-cause mortality by 15%. The SPARCL trial recently showed that high-dose HMG-CoA reductase inhibitors prevent recurrent stroke and transient ischemic attacks. ... 

The NKF suggests that CKD should be classified as a coronary heart disease (CHD) risk equivalent and the goal LDL-C level should be below 100 mg/dL in all patients with CKD.22 The most frequently used agents for the treatment of dyslipidemias in patients with CKD are the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ( statins ) and the fibric acid derivatives. However, other treatments have been studied in patients with CKD and should be considered if first-line therapies are contraindicated. 

ACE-I, angiotensin-converting enzyme inhibitors ARB, angiotensin-receptor blockers AZA, azathioprine CMV, cytomegalovirus CPK, creatinine phos-phokinase CSA, cyclosporine HMG-CoA, 3-hydroxy 3-methylglutaryl coenzyme A reductase K+, potassium LFTs, liver function tests Rl, renal insufficiency SCr, serum creatinine SRL, sirolimus TAC, tacrolimus TMP-SMX, trimethoprim-sulfamethoxazole. 

From the preceding sections, it is clear that chemokines are important players in atherosclerotic disease and, as such, are being considered as possible targets in the treatment of this prevalent inflammatory condition. Under consideration at this time are both traditional nonspecific therapies [e.g., 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, fibrates, etc.], as well as chemokine specific approaches (142). 

During the preparation of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, the benzyl ester protecting group was removed by catalytic hydrogenolysis (Scheme 4.42). 

Roberts, J.R. and Miziorko, H.M. 1997. Evidence supporting a role for histidine-235 in cation binding to human 3-hydroxy-3-methylglutaryl-CoA lyase. Biochemistry 36 7594—7600. 

It has been found that the 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) inhibitors statins (atorvastatin, pravastatin, and cerivastatin), widely prescribed cholesterol-lowering agents, are able to inhibit phorbol ester-stimulated superoxide formation in endothelial-intact segments of the rat aorta [64] and suppress angiotensin II-mediated free radical production [65]. Delbose et al. [66] found that statins inhibited NADPH oxidase-catalyzed PMA-induced superoxide production by monocytes. It was suggested that statins can prevent or limit the involvement of superoxide in the development of atherosclerosis. It is important that statin... 

Shefer, S., Tint, G. S., Jean-Guillaume, D. etal. Is there a relationship between 3-hydroxy- 3-methylglutaryl coenzyme a reductaseactivity and forebrain pathology in the PKU mouse /. Neurosci. Res. 61 549-563,2000. 

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