Hydroxy-3-methyl-coenzyme

Abbreviations, Ac CoA acetyl Coenzyme A DMAPP dimethylallyl alcohol diphosphate HMGCoA 3-hydroxy-3-methyl Coenzyme A IPP iso-pentenyl diphosphate. 

Atorvastatin is a selective, competitive inhibitor of the 3-hydroxy methyl glutaryl coenzyme A (HMG-CoA) reductase enzyme that is involved in the conversion of HMG-CoA to mevalonate (a precursor of sterols, including cholesterol). A reduction of intracellular cholesterol levels... 

An example of reversible ring closure is found with mevinolin and compactin that are both potent inhibitors of hydroxy-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), the rate-determining enzyme in the de novo biosynthesis of cholesterol. 

Bacteria use/ -aminobenzoic acid only for conversion to 7.8-dihydrofolic acid (Griffin and Brown, 1964). Thus, E, coli condenses j -aminobenzoic acid (and, alternatively, -aminobenzoylglutamic acid) with 2-amino-4-oxo-6-hydroxy-methyl-7,8-dihydropteridine 9.21) (as the 6-pyrophosphate) to give dihydro-pteroic acid (and alternatively, dihydrofolic acid) (Jaenicke and Chan, 1960). The sulfonamides competitively inhibit the isolated enzyme dihydrofolate the-tase which catalyses these steps (G. Brown, 1962). From Lactobacillus plantamm two enzymes responsible for this synthesis have been isolated in a pure state (Shiota et al., 1969a). The first of these catalyses the esterification of the pteridine 9.21) to its pyrophosphoryl derivative. The second is Brown s dihydrofolate synthetase. This second enzyme has also been isolated from several strains of Pneumococcus, found to have a mol. wt. of 90000, and to need ATP and Mg " as coenzymes (Ortiz, 1970). 

There exists unequivocal evidence of the biosynthesis of mevalonic acid (MVA) from acetate in yeast and rat liver enzyme systems. The first step appears to be the S5mthesis of 3-hydroxy-3-methylglutarate. This initial step involves the condensation of acetoacetyl-coenzyme A and acetylcoenzyme A [295]. Yeast enzymes reduce the asymmetric monocoenz5nne A ester of hydroxy-methyl-glutaric acid in two steps, (a) to mevaldic acid and (b) to mevalonic acid [296]. The next step is the oxidative generation of the five-carbon biological building... 

A second enzymatic site, which has been selected as a target to direct the chelating potential of the thiosemicarbazone molecule, is pyridoxal phospho-kinase [65], This catalyst is a zinc-requiring enzyme [66] that catalyzes the phosphorylation of pyridoxine at position 5 to form the active coenzyme form. In an effort to accomplish inhibition, 2-formyl-3-hydroxy4,5-bis(hydroxy-methyl)pyridine thiosemicarbazone (117) was synthesized [65]. This was accomplished by two different procedures. The common intermediate, 3-acetoxy-2,4,5-tris(acetoxymethyl)pyridine (111) [67], upon acid hydrolysis afforded 3-hydroxy-2,4,5-tris(hydroxymethyl)pyridine hydrochloride (112), which was treated with hydrogen chloride as a suspension in acetone [68]. The amount of hydrogen chloride taken up by the suspension is a critical factor and. 

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). 

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. 

This enzyme [EC 4.1.3.12] catalyzes the reaction of 3-carboxy-3-hydroxy-4-methylpentanoate with coenzyme A to produce acetyl-CoA, 3-methyl-2-oxobutanoate, and water. This enzyme has a potassium-ion requirement. 

Metabolites that contain pyridoxol (2-methyl-3-hydroxy-4,5-di[hydroxymethyl]pyridine), the water-soluble vitamin B6. Phosphorylated forms of pyridoxal (the aldehyde form) and pyridoxamine (the amino form), known respectively as pyridoxal 5-phosphate (PLP) and pyridoxamine 5-phosphate (PMP), are tightly-bound coenzymes. 

Fig. 8. Most important steps in the biosynthesis of cholesterol. The reduction of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) to yield mevalonic acid is an important rate-limiting step and also the site of attack of the HMG-CoA-reductase inhibitors (statins).

Fig. 5.1.1 Isoprenoid biosynthetic pathway. The enzyme mevalonate kinase (black solid bar) is deficient in patients affected with mevalonic aciduria and hyperimmunoglobulinemia D and periodic fever syndrome. -CoA -Coenzyme A, HMG-CoA 3-hydroxy-3-methyl-glutaryl-coenzyme A, -PP -pyrophosphate...

Thiamin is synthesized in bacteria, fungi, and plants from 1-deoxyxylulose 5-phosphate (Eq. 25-21), which is also an intermediate in the nonmevalonate pathway of polyprenyl synthesis. However, thiamin diphosphate is a coenzyme for synthesis of this intermediate (p. 736), suggesting that an alternative pathway must also exist. Each of the two rings of thiamin is formed separately as the esters 4-amino-5-hydroxy-methylpyrimidine diphosphate and 4-methyl-5-((i-hydroxyethyl) thiazole monophosphate. These precursors are joined with displacement of pyrophosphate to form thiamin monophosphate.92b In eukaryotes this is hydrolyzed to thiamin, then converted to thiamin diphosphate by transfer of a diphospho group from ATP.92b c In bacteria thiamin monophosphate is converted to the diphosphate by ATP and thiamin monophosphate kinase.92b... 

RADIOACTIVETRACERS] (Vol20) HMG-CoA. See b-Hydroxy-b-methyl glutarate-coenzyme A. 

An important dmg in the regulation of cholesterol metabolism is lovastatin [75330-75-5] which is an HMG—CoA reductase inhibitor (see Cardiovascularagents). p-Hydroxy-p-methyl glutarate—coenzyme A (HMG—CoA) reductase is the rate-limiting enzyme of cholesterol synthesis. Lovastatin is actually a prodmg, which is eventually hydrolyzed in the liver to its active, p-hydroxylated form (5). 

ACE angiotensin-converting enzyme HIV human immunodeficiency virus HMG-CoA reductase 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. 

If sterol content and conformation are so important for membrane stability, we should study the biosynthesis of sterols (Figure 3). The first enzyme in terpenoid biosynthesis is the 3-Hydroxy-3-Methyl-Glutary1-Coenzyme A-reductase (HMG-CoA-reductase) that catalyzes the synthesis of mevalonate. Two phosphorylations and decarboxylation of mevalonate lead to isopentenylpyrophosphate, the basic C -unit in sterol synthesis. Isopentenylpyrophosphate reacts with its isomer, the dimethylally1-pyrophosphate, in a head/tail-reaction to geranyl-pyrophosphate reaction with another C -unit leads to farnesyl-pyro-phosphate, that dimerizes in a tail/tail-reaction to squalene. After expoxidation of its A -double bond, squalene cyclizes to lano-... 

The structure, synthesis and biological activity of natural 2-oxetanones and their derivatives has been reviewed (95S729). The synthesis of some novel 3-(hydroxymethyl)-4-(2-substituted ethyl)-2-oxetanones and their biological activity as 3-hydroxy-3-methyl-glutaryl coenzyme-A inhibitors has been reported (94CPB1272, 94CPB2097). 

Romo et al. have used Lewis acids to catalyze the formation of a-silyl-/ -lactones in their synthesis of potential inhibitors of yeast 3-hydroxy-3-methyl glutaryl-coenzyme A (HMG-CoA) synthase <1998BMC1255>. In addition to various Lewis acid catalysts, a chiral promoter based on the chiral diol (l/ ,2R)-2-[(diphenyl)hydroxymethyl]cyclo-hexan-l-ol was introduced to the reaction in an attempt to improve the stereoselectivity. A variety of chiral 2-oxetanones were formed, with enantioselectivities ranging from 22% to 85%. Dichlorotitanium-TADDOL catalysts 113 and 114 have also been used in an attempt to encourage the stereoselective [2+2] cycloaddition of silyl ketenes and aldehydes (TADDOL = (—)-/ra r-4,5-bis(diphenyl-hydroxymethyl)-2,2-dimethyl-l,3-dioxolane), although this method only afforded 2-oxetanones in moderate yields and optical purity (Equation 41) <1998TL2877>. 

Fig. 3. Steroidogenic pathway in granulosa cells. A. Lipoprotein in receptors. B. 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase). C. Acyl-coenzyme A (cholesterol acyl transferase). D. Cholesterol esterase. E. Cholesterol transport to the mitochondria. F. Cholesterol side-chain cleavage enzymes (phospholipid membrane environment and enzyme levels). G. 3/3-Hydroxysteroid dehydrogenase (3/3-HSD). H. 20a-Hydroxysteroid dehydrogenase (20a-HSD). I. Aromatases.

HMG-CoA reductase catalyzes the rate-limiting conversion of 3-hydroxy-3-methyl-glutaryl coenzyme A to mevalonic acid which is a key intermediate in biosynthesis of cholesterol (Fig. 4.1)... 

Xu, L., and Simoni, R.D. (2003). The inhibition of degradation of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase by sterol regulatory element binding protein cleavage-activating protein requires four phenylalanine residues in span 6 of HMG-CoA reductase transmembrane domain. Arch Biochem Biophys 414 232-243. 

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