Disease relevance of hydroxymethylglutaryl-CoA

• The EGF receptor gene promoter has some resemblance to the promoter of the hydroxymethylglutaryl-CoA reductase gene and the early promoter of simian virus 40 [1].
• Hydroxymethylglutaryl-CoA (HMG-CoA) reductase is the primary target in the current clinical treatment of hypercholesterolemias with specific inhibitors of the "statin" family [2].
• cDNA encoding avian liver hydroxymethylglutaryl-CoA synthase has been cloned into a pET vector, and the resulting expression plasmid has been used to transform Escherichia coli BL21 (DE3) [3].
• This increase in intestinal HMG-CoA reductase activity in the poorly controlled diabetic animals occurred in the absence of hyperphagia [4].
• Three-dimensional modeling reveals that the overall structure of L. monocytogenes HMG-CoA reductase is likely similar to the known structure of the class II enzyme from Pseudomonas mevalonii [5].

Psychiatry related information on hydroxymethylglutaryl-CoA

• HMG-CoA (3-hydroxy-3-methylglutarylcoenzyme A) reductase inhibitors (statins) mediate clinically significant vascular risk reduction in patients without inflammatory disease and might have immunomodulatory function [6].

High impact information on hydroxymethylglutaryl-CoA

• The statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site [7].
• Hepatic 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase activity increased 73% with a 3.9-fold rise in mRNA levels but cholesterol 7 alpha-hydroxylase activity decreased slightly though mRNA levels increased 1.4 times with BM 15.766 treatment [8].
• The finding of antiviral activity associated with the HMG-CoA reductase inhibitors implies an important role for lipid metabolism in the viral life cycle [9].
• Comparison with the amino acid sequence predicted from the cDNAs encoding other mammalian HMG-CoA reductases identifies this site as a serine residue close to the C-terminus (Ser872 in the human enzyme) [10].
• Cells cultured in lipid-depleted medium containing one of two inhibitors of hydroxymethylglutaryl-CoA reductase, 25-hydroxycholesterol or compactin, display a rapid, dose-dependent inhibition of cholesterol synthesis [11].

Chemical compound and disease context of hydroxymethylglutaryl-CoA

• Lovastatin (LS) is a potent HMG-CoA inhibitor used in the treatment of hypercholesterolemia [12].
• In nephrotic syndrome the greatest and most consistent reductions in low density lipoprotein cholesterol (LDL) were seen with 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (regression coefficient with 95% confidence interval in mg/dl = -63, -79 to -46) [13].
• Cloning, characterization and expression of the gene encoding cytochrome P-450sca-2 from Streptomyces carbophilus involved in production of pravastatin, a specific HMG-CoA reductase inhibitor [14].
• We have also assessed 25-hydroxycholesterol for toxicity because it has often been used in studies of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibition and LDL receptor down-regulation [15].
• When overexpressed in Escherichia coli, the catalytic domain of Syrian hamster 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase, EC 1.1.1.34) is catalytically active, but exhibits major heterogeneity [16].

Biological context of hydroxymethylglutaryl-CoA

• A similar alternative splicing pattern for hydroxymethylglutaryl-CoA synthase was observed in three human tissues: cultured fibroblasts, fetal adrenal gland, and fetal liver [17].
• Our findings suggest that cholesterol may regulate its own biosynthesis, at least in part, by suppression of hydroxymethylglutaryl-CoA reductase mediated through changes in membrane fluidity as measured by ESR order parameter [18].
• Regulation of liver hydroxymethylglutaryl-CoA reductase by a bicyclic phosphorylation system [19].
• Compensatory up-regulation of hepatic cholesterol 7alpha-hydroxylase and hydroxymethylglutaryl-CoA reductase (9- and 2-3-fold increases in mRNA levels, respectively) was found [20].
• Mannose 6-phosphate receptor-mediated uptake of modified low density lipoprotein results in down regulation of hydroxymethylglutaryl-CoA reductase in normal and familial hypercholesterolemic fibroblasts [21].

Anatomical context of hydroxymethylglutaryl-CoA

• Using a cell line, C100, that overproduces 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase; EC 1.1.1.34) 100-fold, we have studied the synthesis and insertion of this protein into the endoplasmic reticulum [22].
• The two HMG-CoA synthases have 69% identical amino acid residues, and both lack an N-terminal leader peptide to target the protein into mitochondria [23].
• HMG-CoA reductase is an integral membrane protein of the endoplasmic reticulum, the largest nonmitochondrial pool of cellular Ca2+ [24].
• In any event, under these experimental circumstances hydroxymethylglutaryl-CoA redutase activity no longer reflects the rate at which the liver cell is synthesizing cholesterol [25].
• Recombinant PTE-2 showed a broad chain length specificity with acyl-CoAs from short- and medium-, to long-chain acyl-CoAs, and other substrates including trihydroxycoprostanoyl-CoA, hydroxymethylglutaryl-CoA, and branched chain acyl-CoAs, all of which are present in peroxisomes [26].

Associations of hydroxymethylglutaryl-CoA with other chemical compounds

• Here we treated Chinese hamster ovary cell lines with lovastatin (a hydroxymethylglutaryl-CoA reductase inhibitor) and mevalonate (a precursor for isoprenoids) to block endo-CHOL synthesis and then examined its effects on the fate of cholesterol liberated from low density lipoprotein (LDL-CHOL) [27].
• Furthermore, the identification of oatp1 and OATP2 as pravastatin transporters suggests that they are responsible for the hepatic uptake of this liver-specific hydroxymethylglutaryl-CoA reductase inhibitor in rat and man [28].
• Solutions of hydroxymethylglutaryl-CoA or CoASH incubated for 1.5 h with 10 mM dithiothreitol at pH 7.0, 22 degrees C, do not inactivate the enzyme [29].
• The approach relies upon trapping [3-13C]acetoacetate-derived hydroxymethylglutaryl-CoA, hydrolyzing this metabolite, and esterifying the resulting hydroxymethylglutaric acid to allow gas chromatography/mass spectrometry analysis of the dimethyl esters for the 13C enrichment and labeling pattern [30].
• However, in L. monocytogenes HMG-CoA reductase histidine 143 and methionine 186 are present in the putative NAD(P)(H)-selective site, possibly interacting with the 2' phosphate of NADP(H) or 2' hydroxyl of NAD(H) and providing the active site architecture necessary for dual coenzyme specificity [5].

Gene context of hydroxymethylglutaryl-CoA

• A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters [28].
• Two recessive alleles of ERG10 and three temperature-sensitive recessive alleles of HMG1 (3-hydroxy-3-methyl-glutaryl-CoA reductase isoenzyme 1) were isolated in a screen for mevalonate auxotrophs in Saccharomyces cerevisiae [31].
• In addition, a screen for high-copy suppressors of the mating defect of one of the ER-retained ste6 mutants has identified a proteasome subunit, Hrd2p/p97, previously implicated in the regulated degradation of wild-type hydroxymethylglutaryl-CoA reductase in the ER membrane [32].
• No significant differences were observed between the Km values of HMGR1cd for NADPH (71 +/- 7 microM) and (S)-3-hydroxy-3-methylglutaryl-CoA (8.3 +/- 1.5 microM) and those of pure HMGR preparations obtained from different plant sources [33].
• However, elevated HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase activity and LDL (low-density lipoprotein) receptor expression, as well as enhanced transport of newly synthesized cholesterol to a cyclodextrin-accessible pool, suggest that the ORP2 expression stimulates transport of cholesterol out of the endoplasmic reticulum [34].

Analytical, diagnostic and therapeutic context of hydroxymethylglutaryl-CoA

• By immunoblotting, no cross-reactive HMG-CoA reductase protein was detected in UT-2 cells [35].
• No gross deletions or rearrangements in the gene for HMG-CoA reductase were apparent when DNA from UT-2 cells was digested with restriction endonucleases, subjected to Southern blotting, and probed with a 32P-labeled cDNA for HMG-CoA reductase [35].
• On Superose 12 FPLC gel filtration and also on ultrafiltration, both in the presence and in the absence of HMG-CoA), pHL behaves as a monomer whereas mHL migrates as a dimer [36].
• Protein engineering of the HMG-CoA reductase of Pseudomonas mevalonii. Construction of mutant enzymes whose activity is regulated by phosphorylation and dephosphorylation [37].
• 26-hydroxycholesterol: regulation of hydroxymethylglutaryl-CoA reductase activity in Chinese hamster ovary cell culture [38].

References