Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.2.1.1 (ACS)
 78,556 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phenylmethylsulfonyl fluoride (PMSF), a reagent commonly employed for the inhibition of serine proteases, has been found to cause significant inhibition of the incorporation of labeled acetate, but not mevalonate, into nonsaponifiable lipid and digitonin-precipitable sterols in the 10,000 X g supernatant fraction of rat liver homogenate preparations. In two experiments, the extent of inhibition of the synthesis of digitonin-precipitable sterols from acetate by PMSF at 1 mM was 81 and 65%. PMSF inhibited the synthesis of nonsaponifiable lipid from acetate at concentrations as low as 0.1 microM. Preincubation of the 10,000 X g supernatant fraction of rat liver homogenates with PMSF (1 mM) resulted in a significant reduction of the activities of acetate thiokinase and 3-hydroxy-3-methylglutaric acid (HMG)-CoA synthase, but did not affect the activities of acetoacetyl-CoA thiolase. Preincubation of rat liver microsomes with PMSF (1 mM) caused a 50% reduction in the level of HMG-CoA reductase activity. The combined results indicate that major sites of action of PMSF in the inhibition of sterol biosynthesis from labeled acetate appear to be on the activities of acetate thiokinase, HMG-CoA synthase, and HMG-CoA reductase. Another reagent used to inhibit serine proteases, diisopropylfluorophosphate, had (at a concentration of 1 mM) no effect on the activities of cytosolic acetoacetyl-CoA thiolase, HMG-CoA synthase, and HMG-CoA reductase.
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PMID:Effect of phenylmethylsulfonyl fluoride on sterol biosynthesis in 10,000 x g supernatant fraction of rat liver homogenates. 611 96

Cycloheximide, frequently used as an inhibitor of protein synthesis in vivo and in vitro, has been found to cause a significant reduction of the synthesis of digitonin-precipitable sterols from acetate, but not from mevalonate, at a concentration of 1 mM in the 10,000 x g supernatant fraction of rat liver homogenate preparations. The results of studies of the metabolism of labeled leucine under the same conditions indicated that the effect of cycloheximide on sterol synthesis from acetate was not related to an effect of cycloheximide on protein synthesis. Preincubation of the 10,000 x g supernatant fraction of rat liver homogenates with cycloheximide (1 mM) caused a significant reduction in the levels of acetate thiokinase and hydroxymethylglutaryl-CoA synthase activities but not of acetoacetyl-CoA thiolase activity. Preincubation of the 100,000 x g supernatant fraction of rat liver homogenates with cycloheximide (1 mM or 0.3 mM) also caused a significant reduction of the levels of hydroxymethylglutaryl-CoA synthase activity. When cycloheximide (1 mM) was preincubated with the 100,000 x g supernatant fraction, a reduction in the level of acetate thiokinase activity was observed. Preincubation of rat liver microsomes with cycloheximide (1 mM and 3 mM) had no effect on the level of hydroxymethylglutaryl-CoA reductase activity. These results suggest that biological effects observed upon exposure of cells or tissues to high concentrations of cycloheximide may not be exclusively due to effects of the cycloheximide on the synthesis of protein.
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PMID:Cycloheximide inhibits sterol biosynthesis in cell-free preparations of rat liver. 737 3

Pitavastatin is the newest member of the HMG-CoA reductase inhibitor family and is approved as adjunctive therapy to diet to reduce elevated levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein (Apo) B, and triglycerides and to increase levels of high-density lipoprotein (HDL) cholesterol in adult patients with primary hyperlipidemia or mixed dyslipidemia. Pitavastatin undergoes minimal metabolism by cytochrome P450 (CYP) enzymes and, therefore, has a low propensity for drug-drug interactions with drugs metabolized by CYP enzymes or the CYP3A4 substrate grapefruit juice. In clinical trials, pitavastatin potently and consistently reduced serum levels of total, LDL, and non-HDL cholesterol, and triglycerides in patients with primary hypercholesterolemia where diet and other non-pharmacological measures were inadequate. Mean reductions from baseline in serum total and LDL cholesterol and triglyceride levels were 21-32%, 30-45%, and 10-30%, respectively. Moreover, a consistent trend towards increased HDL cholesterol levels of 3-10% was seen. Long-term extension studies show that the beneficial effects of pitavastatin are maintained for up to 2 years. Pitavastatin produces reductions from baseline in serum total and LDL cholesterol levels to a similar extent to those seen with the potent agent atorvastatin and to a greater extent than those seen with simvastatin or pravastatin. In the majority of other studies comparing pitavastatin and atorvastatin, no significant differences in the favorable effects on lipid parameters were seen, although pitavastatin was consistently associated with trends towards increased HDL cholesterol levels. Pitavastatin also produces beneficial effects on lipids in patients with type 2 diabetes mellitus and metabolic syndrome without deleterious effects on markers of glucose metabolism, such as fasting blood glucose levels or proportion of glycosylated hemoglobin. Pitavastatin appears to exert a number of beneficial effects on patients at risk of cardiovascular events independent of lipid lowering. In the JAPAN-ACS (Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome) study, pitavastatin was non-inferior to atorvastatin at reducing plaque volume in patients with ACS undergoing percutaneous coronary intervention. Further beneficial effects, including favorable effects on the size and composition of atherosclerotic plaques, improvements in cardiovascular function, and improvements in markers of inflammation, oxidative stress, and renal function, have been demonstrated in a number of small studies. Pitavastatin is generally well tolerated in hyperlipidemic patients with or without type 2 diabetes, with the most common treatment-related adverse events being musculoskeletal or gastrointestinal in nature. Increases in plasma creatine kinase levels were seen in <5% of pitavastatin recipients and the incidence of myopathy or rhabdomyolysis was extremely low. In summary, pitavastatin, the latest addition to the statin family, produces potent and consistent beneficial effects on lipids, is well tolerated, and has a favorable pharmacokinetic profile. The combination of a potent decrease in total and LDL cholesterol levels and increase in HDL cholesterol levels suggest that pitavastatin may produce substantial cardiovascular protection.
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PMID:Are all statins the same? Focus on the efficacy and tolerability of pitavastatin. 2144 76

Reduction of LDL-cholesterol concentration in serum, blocking the isoprenylation of GTPases and the activation of myocyte-protective enzyme systems are three mechanisms that currently explain the lipid and non-lipid effects of statins. However, the decrease of LDL-cholesterol, the reduction of inflammation biomarkers and even the atheroregresion, as surrogate effects to the mechanisms of action of statins would be irrelevant if not accompanied by a significant decrease in the incidence of cardiovascular events. Statins like no other pharmacological group have proven to reduce the incidence of cardiovascular events and prolong life in any clinical scenario. This article review the basic and clinical evidence that support a new indication for HMG-CoA reductase inhibitors "pharmacological myocardial preconditioning before anticipated ischemia" or hyperacute use of statins in subjects with any coronary syndrome eligible for elective, semi-urgent or primary percutaneous coronary intervention: ARMYDA-Original, NAPLES I-II, ARMYDA-ACS, ARMYDA-RECAPTURE, Non-STEMI-Korean, Korean-STEMI trials.
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PMID:Statins: cardiovascular risk reduction in percutaneous coronary intervention-basic and clinical evidence of hyperacute use of statins. 2146 36

The reduction of plasma low-density lipoprotein levels by HMG-CoA reductase inhibitors, or statins, has had a revolutionary impact in medicine, but muscle-related side effects remain a dose-limiting toxicity in many patients. We describe a chemical epistasis approach that can be useful in refining the mechanism of statin muscle toxicity, as well as in screening for agents that suppress muscle toxicity while preserving the ability of statins to increase the expression of the low-density lipoprotein receptor. Using this approach, we identified one compound that attenuates the muscle side effects in both cellular and animal models of statin toxicity, likely by influencing Rab prenylation. Our proof-of-concept screen lays the foundation for truly high-throughput screens that could help lead to the development of clinically useful adjuvants that can one day be co-administered with statins.
ACS Chem Biol 2011 Sep 16
PMID:A small-molecule screening strategy to identify suppressors of statin myopathy. 2173 24

Primary amebic meningoencephalitis (PAM), caused by the free-living ameba Naegleria fowleri, has a fatality rate of over 97%. Treatment of PAM relies on amphotericin B in combination with other drugs, but few patients have survived with the existing drug treatment regimens. Therefore, development of effective drugs is a critical unmet need to avert deaths from PAM. Since ergosterol is one of the major sterols in the membrane of N. fowleri, disruption of isoprenoid and sterol biosynthesis by small-molecule inhibitors may be an effective intervention strategy against N. fowleri. The genome of N. fowleri contains a gene encoding HMG-CoA reductase (HMGR); the catalytic domains of human and N. fowleri HMGR share <60% sequence identity with only two amino acid substitutions in the active site of the enzyme. Considering the similarity of human and N. fowleri HMGR, we tested well-tolerated and widely used HMGR inhibitors, known as cholesterol-lowering statins, against N. fowleri. We identified blood-brain-barrier-permeable pitavastatin as a potent amebicidal agent against the U.S., Australian, and European strains of N. fowleri. Pitavastatin was equipotent to amphotericin B against the European strain of N. fowleri; it killed about 80% of trophozoites within 16 h of drug exposure. Pretreatment of trophozoites with mevalonate, the product of HMGR, rescued N. fowleri from inhibitory effects of statins, demonstrating that HMGR of N. fowleri is the target of statins. Because of the good safety profile and availability for both adult and pediatric uses, consideration should be given to repurposing the fast-acting pitavastatin for the treatment of PAM.
ACS Chem Neurosci 2020 10 07
PMID:HMG-CoA Reductase Inhibitors as Drug Leads against Naegleria fowleri. 3288 78