Hydroxy reductase

The primary transporter of cholesterol in the blood is low density Hpoprotein (LDL). Once transported intraceUularly, cholesterol homeostasis is controlled primarily by suppressing cholesterol synthesis through inhibition of P-hydroxy-P-methyl gluterate-coenzyme A (HMG—CoA) reductase, acyl CoA—acyl transferase (ACAT), and down-regulation of LDL receptors. An important dmg in the regulation of cholesterol metaboHsm is lovastatin, also known as mevinolin, MK-803, and Mevacor, which is an HMG—CoA reductase inhibitor (Table 5). 

The statins lower cholesterol by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is required for the biosynthesis of mevalonic acid (see Section 26.10). Mevalonic acid is an obligatory precursor to cholesterol, so less mevalonic acid translates into less cholesterol. 

The NAD- and NADP-dependent dehydrogenases catalyze at least six different types of reactions simple hydride transfer, deamination of an amino acid to form an a-keto acid, oxidation of /3-hydroxy acids followed by decarboxylation of the /3-keto acid intermediate, oxidation of aldehydes, reduction of isolated double bonds, and the oxidation of carbon-nitrogen bonds (as with dihydrofolate reductase). 

Steps 6-8 of Figure 29.5 Reduction and Dehydration The ketone carbonyl group in acetoacetyl ACP is next reduced to the alcohol /S-hydroxybutyry] ACP by yS-keto thioester reductase and NADPH, a reducing coenzyme closely related to NADH. R Stereochemistry results at the newly formed chirality center in the /3-hydroxy thioester product. (Note that the systematic name of a butyryl group is biitanoyl.)... 

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

A class of cholesterol lowering drugs that inhibit 3-hydroxy-3-methylglutary 1-CoA reductase, the rate-limiting enzyme step in cholesterol biosynthesis. 

Ness GC> Chambers CM Feedback and hormonal regulation of hepatic d-hydroxy-d-methylglutaryl coen me A reductase the concept of cholesterol buffering capacity. Proc Soc Exp Biol Med 2000 224 8. 

Figure 45-6. Interaction and synergism between antioxidant systems operating in the lipid phase (membranes) of the cell and the aqueous phase (cytosol). (R-,free radical PUFA-00-, peroxyl free radical of polyunsaturated fatty acid in membrane phospholipid PUFA-OOH, hydroperoxy polyunsaturated fatty acid in membrane phospholipid released as hydroperoxy free fatty acid into cytosol by the action of phospholipase Aj PUFA-OH, hydroxy polyunsaturated fatty acid TocOH, vitamin E (a-tocopherol) TocO, free radical of a-tocopherol Se, selenium GSH, reduced glutathione GS-SG, oxidized glutathione, which is returned to the reduced state after reaction with NADPH catalyzed by glutathione reductase PUFA-H, polyunsaturated fatty acid.)...

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. ... 

PARKER R A, PEARCE B 0, CLARK R w, GORDON D A, WRIGHT J J (1993) Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy 3-methyl-glutaryl-coenzyme A reductase. J Biol Chem, 268 11230-38. 

Brackmann R, G Fuchs (1993) Enzymes of anaerobic metabolism of phenolic compounds 4-hydroxy benzoyl-CoA reductase (dehydroxylating) from a denitrifying Pseudomonas sp. Eur J Biochem 213 563-571. 

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). 

Isoprenoids or terpenoids are a large class of naturally occurring organic compounds with tremendous chemical and structural diversity. They are organic materials produced in the HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase pathway... 

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). 

Further, p-hydroxy-(3-methylglutaryl-CoA is converted with hydroxymethylgluta-ryl-CoA reductase to mevalonic acid ... 

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. 

In a study aim to develop biocatalytic process for the synthesis of Kaneka alcohol, apotential intermediate for the synthesis of HMG-CoA reductase inhibitors, cell suspensions of Acine-tobacter sp. SC 13 874 was found to reduce diketo ethyl ester to give the desired syn-(AR,5S)-dihydroxy ester with an ee of 99% and a de of 63% (Figure 7.4). When the tert-butyl ester was used as the starting material, a mixture of mono- and di-hydroxy esters was obtained with the dihydroxy ester showing an ee of 87% and de of 51% for the desired, sy -(3/t,5,Sr)-dihydroxy ester [16]. Three different ketoreductases were purified from this strain. Reductase I only catalyzes the reduction of diketo ester to its monohydroxy products, whereas reductase II catalyzes the formation of dihydroxy products from monohydroxy substrates. A third reductase (III) catalyzes the reduction of diketo ester to, vv -(3/t,55)-dihydroxy ester. 

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