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S577A
the mutant shows reduced activity compared to the wild type enzyme
A333P
mutation disrupts Insig binding and abolishes sterol-accelerated degradation. The pivotal event for sterol-induced degradation of the choletsreol biosynthetic enzyme HMG-CoA reductase is binding of its membrane domain to Insig proteins in the endoplasmic reticulum. Insig are carriers for gp78, an E3 ubiquitin ligase that marks reductase for proteasomal degradation
G87R
mutation disrupts Insig binding and abolishes sterol-accelerated degradation. The pivotal event for sterol-induced degradation of the choletsreol biosynthetic enzyme HMG-CoA reductase is binding of its membrane domain to Insig proteins in the endoplasmic reticulum. Insig are carriers for gp78, an E3 ubiquitin ligase that marks reductase for proteasomal degradation
S60N
mutation disrupts Insig binding and abolishes sterol-accelerated degradation. The pivotal event for sterol-induced degradation of the choletsreol biosynthetic enzyme HMG-CoA reductase is binding of its membrane domain to Insig proteins in the endoplasmic reticulum. Insig are carriers for gp78, an E3 ubiquitin ligase that marks reductase for proteasomal degradation
Q766H
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restores viability of Saccharomyces cerevisiae strains lacking the HMG1 and HMG2 genes, thus is catalytically active in yeast cells. Q766H mutation, which affects the structure of the catalytic domain, increases the sensitivity of the enzyme towards statin treatment
R393Q
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restores viability of Saccharomyces cerevisiae strains lacking the HMG1 and HMG2 genes, thus is catalytically active in yeast cells. R393Q mutation does not change the properties of the enzyme towards statin treatment
S872D
the mutation reduces the catalytic activity of the enzyme similarly to that of the phosphorylated enzyme
R387S
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regulation of activity by phosphorylation
synthesis
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due to use of rare codon, expression of enzyme in Escherichia coli is poor. Coexpression of the S. solfataricus hmgA gene with the argU gene that encodes tRNAAGA,AGG resulted in an over 10-fold increase in enzyme yield
L498I
the naturally occuring mutation T1564C creates a c-Rel binding site
M430T
naturally occuring mutation T1392C
H398Q
low activity for catalysis of reductive deacylation of (S)-3-hydroxy-3-methylglutaryl-CoA or oxidative acylation of mevaldehyde, but readily catalyzed mevaldehyde reduction
H398Q
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low activity for catalysis of reductive deacylation of (S)-3-hydroxy-3-methylglutaryl-CoA or oxidative acylation of mevaldehyde, but readily catalyzed mevaldehyde reduction
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L403R/G404R/A406S
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regulation of activity by phosphorylation
L403R/G404R/A406S
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engineering of an appropriately located phosphoacceptor serine and cAMP-dependent protein kinase recognition motif to create a phosphorylation site. Km values, Vmax, optimal pH and temperature of mutant are identical to wild-type. Exposure of mutant to ATP and cAMP-dependent protein kinase is accompanied by incorporation of phosphate and by a parallel decrease in catalytic activity. Subsequent treatment with a protein phosphatase releases enzyme-bound 32Pi and restores activity to pretreatment levels
additional information
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construction of insertion mutants of the 2 isozymes leads to loss of enzyme function, the hmg1 mutant plants show an altered phenotype with dwarfing, early senescence, male sterility, and both mutants of hmg1 and hmg2 show reduced sterol levels, the mutants are more sensitive to the inhibitor lovastatin and squalestatin, overview
additional information
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transgenic expression of the N-terminal truncated 3-hydroxy-3-methylglutaryl CoA reductase from Arabidopsis thaliana in Lavandula latifolia plants enhances production of essential oils and sterols in the different lines of transgenic plants, expression of HMGR1S also increases the amount of the end-product sterols beta-sitosterol and stigmasterol by 1.8fold and 1.9fold, respectively, but does not affect the accumulation of carotenoids or chlorophylls, overview
additional information
mutant forms of the 403 residue Haloferax volcanii enzyme are constructed to model phosphorylation and infer whether attenuated activity involves interaction with His398. Chimeric Haloferax volcanii-hamster enzymes constructed in an effort to create an active, phosphorylatable chimeric enzyme are inactive or not phosphorylated. Asp is added at position 404 to mimic the introduction of negative charge that would accompany phosphorylation. Enzyme 404D/H398Q was inactive for reductive deacylation of (S)-3-hydroxy-3-methylglutaryl-CoA or oxidative acylation of mevaldehyde, but catalyzed reaction mevaldehyde reduction at 35% the wild-type rate. These observations are consistent with the model that attenuation of catalytic activity results from an ionic interaction between the imidazolium cation of His 398 and the carboxylate anion of Asp404
additional information
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mutant forms of the 403 residue Haloferax volcanii enzyme are constructed to model phosphorylation and infer whether attenuated activity involves interaction with His398. Chimeric Haloferax volcanii-hamster enzymes constructed in an effort to create an active, phosphorylatable chimeric enzyme are inactive or not phosphorylated. Asp is added at position 404 to mimic the introduction of negative charge that would accompany phosphorylation. Enzyme 404D/H398Q was inactive for reductive deacylation of (S)-3-hydroxy-3-methylglutaryl-CoA or oxidative acylation of mevaldehyde, but catalyzed reaction mevaldehyde reduction at 35% the wild-type rate. These observations are consistent with the model that attenuation of catalytic activity results from an ionic interaction between the imidazolium cation of His 398 and the carboxylate anion of Asp404
additional information
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mutant forms of the 403 residue Haloferax volcanii enzyme are constructed to model phosphorylation and infer whether attenuated activity involves interaction with His398. Chimeric Haloferax volcanii-hamster enzymes constructed in an effort to create an active, phosphorylatable chimeric enzyme are inactive or not phosphorylated. Asp is added at position 404 to mimic the introduction of negative charge that would accompany phosphorylation. Enzyme 404D/H398Q was inactive for reductive deacylation of (S)-3-hydroxy-3-methylglutaryl-CoA or oxidative acylation of mevaldehyde, but catalyzed reaction mevaldehyde reduction at 35% the wild-type rate. These observations are consistent with the model that attenuation of catalytic activity results from an ionic interaction between the imidazolium cation of His 398 and the carboxylate anion of Asp404
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additional information
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coexpression of N-terminal truncated Hevea brasiliensis (S)-3-hydroxy-3-methylglutaryl CoA reductase and tobacco C24-sterol methyltransferase type 1 in transgenic Nicotiana tabacum plants enhances carbon flux towards end-product sterols, expression under control of both seed-specific and constitutive promotors leads to enhancement of sterol accumulation by 2.5 and 2.1fold, respectively, analysis of the sterol spectrum, overview
additional information
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expression of human HMG-CoA reductase in yeast complements the lethal phenotype of Saccharomyces cerevisiae strains lacking the HMG1 and HMG2 genes
additional information
identification of five single nucleotide polymorphisms, three of them are synonymous mutations and the other two are missense mutations, the naturally occuring mutation T1541C causes a deletion of a CdxA element and a C/EBP binding site and created a c-Ets-binding site, and naturally occuring mutation G973T in exon 9, which is a synonymous mutation
additional information
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identification of five single nucleotide polymorphisms, three of them are synonymous mutations and the other two are missense mutations, the naturally occuring mutation T1541C causes a deletion of a CdxA element and a C/EBP binding site and created a c-Ets-binding site, and naturally occuring mutation G973T in exon 9, which is a synonymous mutation