Disease relevance of CHEBI:11814

• Control of 3-hydroxy-3-methylglutaryl-CoA reductase activity in cultured human fibroblasts by very low density lipoproteins of subjects with hypertriglyceridemia [1].
• Inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, also known as statins, are lipid-lowering agents widely used in the prevention of coronary heart disease [2].
• These results indicate that the increase in mitochondrial reactive oxygen species can result in biochemical aberrations with features reminiscent of mitochondrial myopathy, Friedreich ataxia, and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency [3].
• The statin family of drugs are well-established inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase and are used clinically in the control of hypercholesterolemia [4].
• Pseudomonas mevalonii 3-hydroxy-3-methylglutaryl-CoA reductase. Characterization and chemical modification [5].

Psychiatry related information on CHEBI:11814

• Deficiency of mitochondrial 3-hydroxy-3-methylglutaryl CoA lyase (HL, EC4.1.3.4.) is an autosomal recessive genetic disorder characterized by acute episodes of vomiting, hypotonia, and lethargy in the neonatal period or in infancy [6].

High impact information on CHEBI:11814

• Fasting hypoketotic coma in a child with deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase [7].
• Sterols accelerate degradation of the ER enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase), which catalyzes a rate-controlling step in cholesterol biosynthesis [8].
• Inhibition by bile acids of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity, resulting in a reduction of the endogenous cholesterol synthesis required for cell growth and proliferation, might account for our observations [9].
• The mutant Insig-1 was ineffective also in accelerating sterol-stimulated degradation of 3-hydroxy-3-methylglutaryl CoA reductase [10].
• Lipid synthesis was accompanied by increased transcription of several lipogenic proteins, including the low-density lipoprotein receptor, enzymes required for cholesterol synthesis (3-hydroxy-3-methylglutaryl CoA synthase, 3-hydroxy-3-methylglutaryl CoA reductase), and fatty acid synthase [11].

Chemical compound and disease context of CHEBI:11814

• HSV-2 also increases CE synthesis and 3-hydroxy- 3-methylglutaryl-CoA reductase activity but concomitantly reduces CE hydrolysis and cholesterol efflux [12].
• Role of cysteine residues in Pseudomonas mevalonii 3-hydroxy-3-methylglutaryl-CoA reductase. Site-directed mutagenesis and characterization of the mutant enzymes [13].
• The statin family of drugs inhibits 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme of the mevalonate pathway, and is used clinically as a safe and effective approach in the control of hypercholesterolemia [14].
• Tyrosine kinase-dependent modulation of 3-hydroxy-3-methylglutaryl-CoA reductase in human breast adenocarcinoma SKBR-3 cells [15].
• ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase, was administered to 11 patients with primary hypercholesterolemia [16].

Biological context of CHEBI:11814

• We conclude that 3-hydroxy-3-methylglutaryl-CoA reductase is a transmembrane glycoprotein with an active site facing the cytoplasm and a carbohydrate-bearing site oriented toward the lumen of the endoplasmic reticulum [17].
• Our evidence also indicates that the exon 3 acceptor site of the 3-hydroxy-3-methylglutaryl-CoA reductase gene can be spliced either to the SL by trans-splicing or to an upstream exon, 2, by cis-splicing [18].
• 3-Hydroxy-3-methylglutaryl-CoA reductase (EC 1.1.1.34) is an abundant protein of the crystalloid endoplasmic reticulum of UT-1 cells, a line of cultured hamster cells that over-produces the reductase as a result of gene amplification [17].
• 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors up-regulate transforming growth factor-beta signaling in cultured heart cells via inhibition of geranylgeranylation of RhoA GTPase [19].
• Phosphorylation of Ser871 impairs the function of His865 of Syrian hamster 3-hydroxy-3-methylglutaryl-CoA reductase [20].

Anatomical context of CHEBI:11814

• UT-1 cells, a clone of Chinese hamster ovary (CHO) cells, have a 100- to 1,000-fold elevation in the amount of 3-hydroxy-3-methylglutaryl CoA reductase and therefore grow in the presence of compactin, an inhibitor of reductase [21].
• The coordinate control of 3-hydroxy-3-methylglutaryl CoA synthase and reductase in rat adrenal gland provides a model system to study the biochemical mechanism for the regulation of cholesterol synthesis in a tissue that uses cholesterol for the synthesis of steroid hormones [22].
• The regulation of 3-hydroxy-3-methylglutaryl-CoA reductase and acyl-CoA: (cholesterol acyltransferase), the key enzymes governing intracellular cholesterol handling, have also been extensively examined in Caco-2 cells [23].
• Incubation of hepatocytes for 3 h normally results in induction of 3-hydroxy-3-methylglutaryl-CoA reductase [24].
• Immunotitrations of microsomes obtained from rats killed at the nadir or peak of the diurnal rhythm of 3-hydroxy-3-methylglutaryl-CoA reductase indicated that the rhythm results both from enzyme activation and an increased number of reductase molecules [25].

Associations of CHEBI:11814 with other chemical compounds

• Regulation of the sterol-synthesizing mevalonate pathway occurs in part through feedback-regulated endoplasmic reticulum degradation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-R) [26].
• Rat liver microsomal 3-hydroxy-3-methylglutaryl-CoA reductase [HMG-CoA reductase; mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34], the key regulatory enzyme in cholesterol biosynthesis, has been purified to apparent homogeneity [27].
• Preclinical and clinical studies have provided evidence that aspirin, celecoxib, (cyclooxygenase-2 inhibitor), and statins (3-hydroxy-3-methylglutaryl CoA reductase inhibitors) inhibit colon carcinogenesis [28].
• Mevinolin is demonstrated to inhibit the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase in Chinese hamster ovary cells [29].
• In the presence of either substrate (NADPH or 3-hydroxy-3-methylglutaryl-CoA), the equilibrium thiol/disulfide redox behavior of HMGR-C is substantially different than that observed in the absence of substrates or in the presence of both substrates [30].

Gene context of CHEBI:11814

• Two proteins are central in this role; the LDL receptor and 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase), the rate-limiting enzyme in cholesterol biosynthesis [31].
• The high-cholesterol diets reduced the amount of low density lipoprotein receptor mRNA by 30% and produced a more profound 70-90% reduction in mRNAs encoding 3-hydroxy-3-methylglutaryl CoA synthase and reductase [32].
• The expression level of the AACS mRNA was high in kidney, heart and brain, but low in liver, and the expression profile of AACS in the human brain was quite similar to that of 3-hydroxy-3-methylglutaryl-CoA reductase [33].
• Overproduction of chimeric proteins containing the HMG2/1 peptide, which comprises the seven transmembrane domains of Saccharomyces cerevisiae 3-hydroxy-3-methylglutaryl-CoA reductase isozymes 1 and 2, has previously been observed to induce the proliferation of internal endoplasmic reticulum-like membranes [34].
• Moreover, the levels of 3-hydroxy-3-methylglutaryl CoA reductase and farnesyl diphosphate synthase, two key enzymes in dolichol biosynthesis, are decreased in the absence of a functional PEX1 gene [35].

Analytical, diagnostic and therapeutic context of CHEBI:11814

• 3-Hydroxy-3-methylglutaryl-CoA lyase (HL): gene targeting causes prenatal lethality in HL-deficient mice [36].
• In order to evaluate the potential contribution of conserved aromatic residues to the hydrophobic active site of 3-hydroxy-3-methylglutaryl-CoA synthase, site-directed mutagenesis was employed to produce Y130L, Y163L, F204L, Y225L, Y346L, and Y376L proteins [37].
• 2. This value, while identical to that of the single isoelectric-focusing species of broken mitochondrial preparations, differs from those of the multiple 3-hydroxy-3-methylglutaryl-CoA synthases found in the cytoplasmic fraction which exhibit pI values of 4.8 and 6 [38].
• Molecular cloning of rat mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase and detection of the corresponding mRNA and of those encoding the remaining enzymes comprising the ketogenic 3-hydroxy-3-methylglutaryl-CoA cycle in central nervous system of suckling rat [39].
• When this preparation was examined by immunoblotting with a rabbit antiserum to rat 3-hydroxy-3-methylglutaryl-CoA reductase, a single band corresponding to an Mr of 100000 was observed [40].

References