Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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CR39 is a cholesterol-repressible rat liver cDNA previously isolated by differential hybridization (Clarke, C.F., Tanaka, R.D., Svenson, K., Wamsley, M., Fogelman, A.M., and Edwards, P.A. (1987) Mol. Cell. Biol. 7, 3138-3146). To precisely identify the function of CR39 a fusion protein was constructed that contained the amino-terminal region of the bacterial protein anthranilate synthetase fused to the full length CR39 polypeptide. Affinity purified antisera directed against the fusion protein inactivated rat liver cytosolic prenyltransferase activity in vitro. In addition, affinity purified antisera made to purified chicken prenyltransferase cross-reacted with the fusion protein containing CR39. Rat hepatic prenyltransferase activity and enzyme mass were quantitated in animals fed diets or drugs known to alter endogenous cholesterol biosynthesis. Rats fed a diet supplemented with cholestyramine and mevinolin showed a 3.5-fold increase in activity and a 5.0-fold increase in mass of cytosolic prenyltransferase. A diet supplemented with cholesterol resulted in approximately a 4.0-fold decrease in hepatic enzyme activity and a 10-fold decrease in enzyme mass. Under these same dietary regimens the mass of prenyltransferase in the testes remained unchanged. We conclude that CR39 encodes the prenyltransferase of cholesterol biosynthesis, farnesyl pyrophosphate synthetase. Furthermore, in the liver this enzyme shows coordinate regulation with two other enzymes, 3-hydroxy-3-methylglutaryl-CoA reductase and 3-hydroxy-3-methylglutaryl-CoA synthase, in response to cholesterol feeding and hypocholesterolemic drugs.
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PMID:Identification and regulation of a rat liver cDNA encoding farnesyl pyrophosphate synthetase. 290 44

Differential hybridization and molecular cloning have been used to isolate CR39, a cDNA which hybridizes to a 1.2-kilobase (kb) mRNA in rat liver. The level of CR39 mRNA was increased seven- to ninefold over normal levels by dietary cholestyramine and mevinolin and decreased about fourfold compared with normal levels by cholesterol feeding or administration of mevalonate. Similar changes in the mRNA levels of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and HMG-CoA synthase were observed under the various conditions. In vitro translation of either CR39 hybrid selected RNA or 1.2-kb CR39 RNA generated by an SP6 in vitro transcription system produced a polypeptide of 39,000 daltons. As deduced from the nucleotide sequence of a full-length CR39 cDNA, the rat CR39 polypeptide contained 344 amino acids and had a molecular weight of 39,615. The predicted amino acid composition and submit molecular weight of the rat CR39 were very similar to those of prenyltransferases isolated from chicken, pig, and human. The sequence of amino acid residues 173 through 203 in the rat CR39 polypeptide showed that 17 out of 30 matched an active-site peptide of avian liver prenyltransferase. Thus, alterations in the rate of cholesterogenesis resulted in the coordinate regulation of three mRNAs encoding HMG-CoA reductase, HMG-CoA synthase, and CR39, the latter being tentatively identified as prenyltransferase.
Mol Cell Biol 1987 Sep
PMID:Molecular cloning and sequence of a cholesterol-repressible enzyme related to prenyltransferase in the isoprene biosynthetic pathway. 367 Mar 8

The detection of conserved sequence patterns (motifs) in related proteins often yields valuable structural and functional insights. We describe a method that utilizes rigorous statistics and a depth-first search procedure to efficiently and exhaustively search a set of proteins for significant patterns up to a specified length. Additional procedures classify related patterns into groups and identify protein segments most likely to share a common motif. The utility of the method was demonstrated on several difficult test problems; detection of motifs among 56 proteins in the acyltransferase family, detection of a dinucleotide-binding fold present within a small subset of a set of 91 distantly related and unrelated proteins, detection of the helix-turn-helix motif in 15 distantly related proteins and detection of subtle internal repeats in a prenyltransferase. In a search of a large set of sequences for internal repeats, the method detected novel ankyrin-like repeats in an Escherichia coli protein.
J Mol Biol 1994 Jun 24
PMID:Detecting patterns in protein sequences. 801 90

Two protein prenyltransferase enzymes, farnesyltransferase (FTase) and geranylgeranyltransferase-I (GGTase-I), catalyze the covalent attachment of a farnesyl or geranylgeranyl lipid group to the cysteine of a CaaX sequence (cysteine [C], two aliphatic amino acids [aa], and any amino acid [X]. In vitro studies reported here confirm previous reports that CaaX proteins with a C-terminal serine are farnesylated by FTase and those with a C-terminal leucine are geranylgeranylated by GGTase-I. In addition, we found that FTase can farnesylate CaaX proteins with a C-terminal leucine and can transfer a geranylgeranyl group to some CaaX proteins. Genetic data indicate that FTase and GGTase-I have the same substrate preferences in vivo as in vitro and also show that each enzyme can prenylate some of the preferred substrates of the other enzyme in vivo. Specifically, the viability of yeast cells lacking FTase is due to prenylation of Ras proteins by GGTase-I. Although this GGTase-I dependent prenylation of Ras is sufficient for growth, it is not sufficient for mutationally activated Ras proteins to exert deleterious effects on growth. The dependence of the activated Ras phenotype on FTase can be bypassed by replacing the C-terminal serine with leucine. This altered form of Ras appears to be prenylated by both GGTase-I and FTase, since it produces an activated phenotype in a strain lacking either FTase or GGTase-I. Yeast cells can grow in the absence of GGTase-I as long as two essential substrates are overexpressed, but their growth is slow. Such strains are dependent on FTase for viability and are able to grow faster when FTase is overproduced, suggesting that FTase can prenylate the essential substrates of GGTase-I when they are overproduced.
Mol Cell Biol 1993 Jul
PMID:Genetic evidence for in vivo cross-specificity of the CaaX-box protein prenyltransferases farnesyltransferase and geranylgeranyltransferase-I in Saccharomyces cerevisiae. 832 Dec 28

As an approach to understand the molecular mechanisms of endoplasmic reticulum (ER) protein sorting, we have isolated yeast rer mutants that mislocalize a Sec12-Mfalpha1p fusion protein from the ER to later compartments of the secretory pathway (S. Nishikawa and A. Nakano, Proc. Natl. Acad. Sci. USA 90:8179-8183, 1993). The temperature-sensitive rer2 mutant mislocalizes different types of ER membrane proteins, suggesting that RER2 is involved in correct localization of ER proteins in general. The rer2 mutant shows several other characteristic phenotypes: slow growth, defects in N and O glycosylation, sensitivity to hygromycin B, and abnormal accumulation of membranes, including the ER and the Golgi membranes. RER2 and SRT1, a gene whose overexpression suppresses rer2, encode novel proteins similar to each other, and their double disruption is lethal. RER2 homologues are found not only in eukaryotes but also in many prokaryote species and thus constitute a large gene family which has been well conserved during evolution. Taking a hint from the phenotype of newly established mutants of the Rer2p homologue of Escherichia coli, we discovered that the rer2 mutant is deficient in the activity of cis-prenyltransferase, a key enzyme of dolichol synthesis. This and other lines of evidence let us conclude that members of the RER2 family of genes encode cis-prenyltransferase itself. The difference in phenotypes between the rer2 mutant and previously obtained glycosylation mutants suggests a novel, as-yet-unknown role of dolichol.
Mol Cell Biol 1999 Jan
PMID:The yeast RER2 gene, identified by endoplasmic reticulum protein localization mutations, encodes cis-prenyltransferase, a key enzyme in dolichol synthesis. 985 71

Prenyltransferases (prenyl diphosphate synthases), which are a broad group of enzymes that catalyze the consecutive condensation of homoallylic diphosphate of isopentenyl diphosphates (IPP, C5) with allylic diphosphates to synthesize prenyl diphosphates of various chain lengths, have highly conserved regions in their amino acid sequences. Based on the above information, three prenyltransferase homologue genes were cloned from a thermophilic cyanobacterium, Synechococcus elongatus. Through analyses of the reaction products of the enzymes encoded by these genes, it was revealed that one encodes a thermolabile geranylgeranyl (C20) diphosphate synthase, another encodes a farnesyl (C15) diphosphate synthase whose optimal reaction temperature is 60 degrees C, and the third one encodes a prenyltransferase whose optimal reaction temperature is 75 degrees C. The last enzyme could catalyze the synthesis of five prenyl diphosphates of farnesyl, geranylgeranyl, geranylfarnesyl (C25), hexaprenyl (C30), and heptaprenyl (C35) diphosphates from dimethylallyl (C5) diphosphate, geranyl (C10) diphosphate, or farnesyl diphosphate as the allylic substrates. The product specificity of this novel kind of enzyme varied according to the ratio of the allylic and homoallylic substrates. The situations of these three S. elongatus enzymes in a phylogenetic tree of prenyltransferases are discussed in comparison with a mesophilic cyanobacterium of Synechocystis PCC6803, whose complete genome has been reported by Kaneko et al. (1996).
Plant Mol Biol 1999 May
PMID:A thermophilic cyanobacterium Synechococcus elongatus has three different Class I prenyltransferase genes. 1041 9

The control of ubiquinone biosynthesis by peroxisome proliferators was investigated using peroxisome proliferator activated receptor alpha (PPARalpha)-null mice. Administration of 2-(diethylhexyl)phthalate to control mice resulted in elevated ubiquinone levels in the liver, while dolichol, dolichyl-P and cholesterol concentrations remained unchanged. In PPARalpha-null mice, the level of these lipids were similar to control levels and administration of the peroxisome proliferator did not increase the levels of ubiquinone. The increase in ubiquinone levels was the result of increased synthesis. Induction was most pronounced in liver, kidney and heart, which have relatively high levels of PPARalpha. When the tissue concentration of hydrogen peroxide was elevated by inhibition of catalase activity with aminotriazole, the amount of ubiquinone was not increased, suggesting that the induction of ubiquinone synthesis occured through a direct mechanism. The activities of branch-point enzymes FPP-synthase, squalene synthase, cis-prenyltransferase, trans-prenyltransferase and NPHB-transferase were substantially increased in control but not in PPARalpha-null mice after treatment with peroxisome proliferators. These data suggest that the induction of ubiquinone biosynthesis after administration of peroxisome proliferators is dependent on the PPARalpha through regulation of some of the mevalonate pathway enzymes.
J Mol Biol 2000 Mar 31
PMID:Influence of peroxisome proliferator-activated receptor alpha on ubiquinone biosynthesis. 1073 15

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert pleiotropic effects on vascular cells independent of lowering plasma cholesterol. To elucidate the molecular mechanisms involved in these effects, we investigated the impact of statins on production of reactive oxygen species (ROS) in rat aortic vascular smooth muscle cells (VSMC). Exposure of VSMC to angiotensin II caused production of ROS via angiotensin AT1 receptor activation. Pretreatment with atorvastatin inhibited angiotensin II-induced ROS production. Atorvastatin decreased AT1 receptor mRNA levels in a time- and concentration-dependent manner and consistently reduced AT1 receptor density. L-Mevalonate but not hydroxy-cholesterol reversed the inhibitory effect of atorvastatin on AT1 receptor transcript levels. Inhibition of geranylgeranyl-transferase but not of farnesyl-transferase mimicked the effect of atorvastatin on AT1 receptor gene expression. Atorvastatin did not decrease AT1 receptor gene transcription but did reduce the half-life of the AT1 receptor mRNA. AT1 receptor activation by angiotensin II increased the expression of the GTPase rac1, enhanced rac1 GTP-binding activity, and increased the geranylgeranyl-dependent translocation of rac1 to the cell membrane. In contrast, statins inhibited rac1 activity and membrane translocation. Consequently, specific inhibition of rac1 with Clostridium sordellii lethal toxin blocked angiotensin II-induced production of free radicals. Finally, treatment of rats with atorvastatin caused down-regulation of aortic AT1 receptor mRNA expression and reduced aortic superoxide production in vivo. Cholesterol-independent down-regulation of AT1 receptor gene expression and inhibition of rac1, leading to decreased ROS production, demonstrates a novel regulatory mechanism of statins that may contribute to the beneficial effects of these drugs beyond lowering of plasma cholesterol.
Mol Pharmacol 2001 Mar
PMID:Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. 1117 61

A family of 40 terpenoid synthase genes ( AtTPS) was discovered by genome sequence analysis in Arabidopsis thaliana. This is the largest and most diverse group of TPS genes currently known for any species. AtTPS genes cluster into five phylogenetic subfamilies of the plant TPS superfamily. Surprisingly, thirty AtTPS closely resemble, in all aspects of gene architecture, sequence relatedness and phylogenetic placement, the genes for plant monoterpene synthases, sesquiterpene synthases or diterpene synthases of secondary metabolism. Rapid evolution of these AtTPS resulted from repeated gene duplication and sequence divergence with minor changes in gene architecture. In contrast, only two AtTPS genes have known functions in basic (primary) metabolism, namely gibberellin biosynthesis. This striking difference in rates of gene diversification in primary and secondary metabolism is relevant for an understanding of the evolution of terpenoid natural product diversity. Eight AtTPS genes are interrupted and are likely to be inactive pseudogenes. The localization of AtTPS genes on all five chromosomes reflects the dynamics of the Arabidopsis genome; however, several AtTPS genes are clustered and organized in tandem repeats. Furthermore, some AtTPS genes are localized with prenyltransferase genes ( AtGGPPS, geranylgeranyl diphosphate synthase) in contiguous genomic clusters encoding consecutive steps in terpenoid biosynthesis. The clustered organization may have implications for TPS gene evolution and the evolution of pathway segments for the synthesis of terpenoid natural products. Phylogenetic analyses highlight events in the divergence of the TPS paralogs and suggest orthologous genes and a model for the evolution of the TPS gene family.
Mol Genet Genomics 2002 Aug
PMID:Genomic analysis of the terpenoid synthase ( AtTPS) gene family of Arabidopsis thaliana. 1220 21

Latex of Hevea brasiliensis (Willd. ex A, Juss.) Mull. Arg. (Brazilian rubber tree) contains 30-50% (w/w) of natural rubber (cis-1,4-polyisoprene), which is an important raw material for many industrial uses. In order to gain insights into the molecular events occurring in latex, we analyzed more than 20,000 cDNA-AFLP-based TDFs (transcription-derived fragments) and 1176 ESTs. The results revealed several novel features of the latex transcriptome. First, the repertoire of the genes expressed in latex is unique. Only seven gene families accounted for more than 51% of the latex transcriptome. Among them, two of the most abundant ESTs were the genes encoding rubber particle proteins REF (rubber elongation factor) and SRPP (small rubber particle protein), comprising 29% of the total ESTs. Unexpectedly, several genes involved in the rubber biosynthesis were expressed at low levels in the latex. In fact, genes encoding cis -prenyltransferase (CPT), a potential candidate for rubber polymerase, were not present in the EST pool because of their low expression level. However, we were able to clone four full-length cDNAs by screening the same latex cDNA library used in the EST analysis and confirmed their enzyme activity in vitro. The second most abundant transcripts were defense- or stress-related genes, suggesting that defense is one of the functions of laticifers. Finally, the presence of the non-mevalonate DXP/MEP pathway for IPP synthesis in latex was noted by up-regulation of the 1-deoxy-D-xylulose 5-phosphate synthase gene.
Plant Mol Biol 2003 Nov
PMID:Transcriptome analysis reveals novel features of the molecular events occurring in the laticifers of Hevea brasiliensis (para rubber tree). 1501 Jun 14


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