Showing papers on "Mevalonic acid published in 2000"
TL;DR: Phylogenetic and comparative genome analyses suggest that the genes for mevalonate biosynthesis in gram-positive cocci, which are highly divergent from those of mammals, were horizontally transferred from a primitive eukaryotic cell.
Abstract: The mevalonate pathway and the glyceraldehyde 3-phosphate (GAP)–pyruvate pathway are alternative routes for the biosynthesis of the central isoprenoid precursor, isopentenyl diphosphate. Genomic analysis revealed that the staphylococci, streptococci, and enterococci possess genes predicted to encode all of the enzymes of the mevalonate pathway and not the GAP-pyruvate pathway, unlike Bacillus subtilis and most gram-negative bacteria studied, which possess only components of the latter pathway. Phylogenetic and comparative genome analyses suggest that the genes for mevalonate biosynthesis in gram-positive cocci, which are highly divergent from those of mammals, were horizontally transferred from a primitive eukaryotic cell. Enterococci uniquely encode a bifunctional protein predicted to possess both 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and acetyl-CoA acetyltransferase activities. Genetic disruption experiments have shown that five genes encoding proteins involved in this pathway (HMG-CoA synthase, HMG-CoA reductase, mevalonate kinase, phosphomevalonate kinase, and mevalonate diphosphate decarboxylase) are essential for the in vitro growth of Streptococcus pneumoniae under standard conditions. Allelic replacement of the HMG-CoA synthase gene rendered the organism auxotrophic for mevalonate and severely attenuated in a murine respiratory tract infection model. The mevalonate pathway thus represents a potential antibacterial target in the low-G+C gram-positive cocci.
273 citations
TL;DR: The recombinant enzyme overexpressed in Escherichia coli was purified as a soluble protein and characterized, showing the same enzymatic properties of E. coli DXP synthases, although these two enzymes had different origins.
Abstract: In addition to the ubiquitous mevalonate pathway, Streptomyces sp. strain CL190 utilizes the nonmevalonate pathway for isopentenyl diphosphate biosynthesis. The initial step of this nonmevalonate pathway is the formation of 1-deoxy-D-xylulose 5-phosphate (DXP) by condensation of pyruvate and glyceraldehyde 3-phosphate catalyzed by DXP synthase. The corresponding gene, dxs, was cloned from CL190 by using PCR with two oligonucleotide primers synthesized on the basis of two highly conserved regions among dxs homologs from six genera. The dxs gene of CL190 encodes 631 amino acid residues with a predicted molecular mass of 68 kDa. The recombinant enzyme overexpressed in Escherichia coli was purified as a soluble protein and characterized. The molecular mass of the enzyme was estimated to be 70 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and 130 kDa by gel filtration chromatography, suggesting that the enzyme is most likely to be a dimer. The enzyme showed a pH optimum of 9.0, with a V(max) of 370 U per mg of protein and K(m)s of 65 microM for pyruvate and 120 microM for D-glyceraldehyde 3-phosphate. The purified enzyme catalyzed the formation of 1-deoxyxylulose by condensation of pyruvate and glyceraldehyde as well, with a K(m) value of 35 mM for D-glyceraldehyde. To compare the enzymatic properties of CL190 and E. coli DXP synthases, the latter enzyme was also overexpressed and purified. Although these two enzymes had different origins, they showed the same enzymatic properties.
141 citations
TL;DR: This system is used to show that the ygbP, ychB and ygbB genes are essential in E. coli and that the steps catalysed by the products of these genes belong to the trunk line of the MEP pathway.
Abstract: Isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP) constitute the basic building block of isoprenoids, a family of compounds that is extraordinarily diverse in structure and function. IPP and DMAPP can be synthesized by two independent pathways: the mevalonate pathway and the recently discovered 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway. Although the MEP pathway is essential in most eubacteria, algae and plants and has enormous biotechnological interest, only some of its steps have been determined. We devised a system suitable for the genetic analysis of the MEP pathway in Escherichia coli. A synthetic operon coding for yeast 5-diphosphomevalonate decarboxylase, human 5-phosphomevalonate kinase, yeast mevalonate kinase and E. coli isopentenyl diphosphate isomerase was incorporated in the chromosome of this bacterium. The expression of this operon allowed the synthesis of IPP and DMAPP from mevalonate added exogenously and complementation of lethal mutants of the MEP pathway. We used this system to show that the ygbP, ychB and ygbB genes are essential in E. coli and that the steps catalysed by the products of these genes belong to the trunk line of the MEP pathway.
112 citations
TL;DR: The inhibition of the intrinsic mevalonate cascade induces the apoptotic NCD with the induction of p53 followed by that of Bax, the inhibition of HMG-CoA reductase concomitantly causes blockage of the translocation or redistribution of Rho small GTPase families, not Ras smallGTPase, to membrane.
Abstract: We investigated the role of the intrinsic mevalonate cascade in the neuronal cell death (NCD) induced by the inhibition of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase in rat primary cortical neurons cultured from the brains of 17-d-old fetal SD rats. HMG-CoA reductase inhibitors induced NCD [HMG-CoA reductase inhibitor-induced NCD (H-NCD)] in time- and dose-dependent manners. The apoptotic characteristics were revealed by the formation of the DNA ladder and by the electron microscopical observation. During the progression of H-NCD, p53 was induced followed by the expression of Bax. Although the mevalonate completely inhibited H-NCD, the cholesterol did not. Thus, we examined two major metabolites of mevalonate, geranylgeranyl-pyrophosphate (GGPP) and farnesyl-pyrophosphate (FPP), using a novel liposome system for uptake into the cells. GGPP, not FPP, prohibited H-NCD with inhibition of the induction of p53 and Bax. The inhibition of HMG-CoA reductase decreased the amount of membrane-associated Rho small GTPase families, but not Ras small GTPase, and GGPP restored the blockage by HMG-CoA reductase inhibitor in the translocation or redistribution of Rho small GTPase families to membrane. These data indicated that (1) the inhibition of the intrinsic mevalonate cascade induces the apoptotic NCD with the induction of p53 followed by that of Bax, (2) the inhibition of HMG-CoA reductase concomitantly causes blockage of the translocation or redistribution of Rho small GTPase families, not Ras small GTPase, to membrane, and (3) GGPP, not FPP, is one of the essential metabolites in the mevalonate cascade for protecting neurons from H-NCD.
108 citations
TL;DR: The biochemical and molecular properties of MK are reviewed, and its biological significance, the regulation of its enzyme activity and finally its subcellular localization are discussed.
95 citations
TL;DR: The hmgr gene and orfABCDE are unambiguously shown to be responsible for the mevalonate pathway and to form a gene cluster in the genome of Streptomyces sp.
Abstract: A biosynthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1. 1.1.34), the rate-limiting enzyme of the mevalonate pathway for isopentenyl diphosphate biosynthesis, had previously been purified from Streptomyces sp. strain CL190 and its corresponding gene (hmgr) had been cloned (S. Takahashi, T. Kuzuyama, and H. Seto, J. Bacteriol. 181:1256-1263, 1999). Sequence analysis of the flanking regions of the hmgr gene revealed five new open reading frames, orfA to -E, which showed similarity to those encoding eucaryotic and archaebacterial enzymes for the mevalonate pathway. Feeding experiments with [1-(13)C]acetate demonstrated that Escherichia coli JM109 harboring the hmgr gene and these open reading frames used the mevalonate pathway under induction with isopropyl beta-D-thiogalactopyranoside. This transformant could grow in the presence of fosmidomycin, a potent and specific inhibitor of the nonmevalonate pathway, indicating that the mevalonate pathway, intrinsically absent in E. coli, is operating in the E. coli transformant. The hmgr gene and orfABCDE are thus unambiguously shown to be responsible for the mevalonate pathway and to form a gene cluster in the genome of Streptomyces sp. strain CL190.
87 citations
TL;DR: It was found that a 6-fold increase in FPPS activity compared with that of the wild-type strain FL100 did not cause significant changes in HMG-CoA reductase activity, while the amounts of synthesized dolichols and ergosterol increased by 80 and 32%, respectively.
55 citations
TL;DR: It is demonstrated for the first time that COC can synthesize cholesterol from mevalonate and accumulateFF-MAS in the presence of AY9944-A-7, indicating that FF-MAS, and possibly other sterol intermediates of the cholesterol synthesis pathway, play a central role in stimulating mouse oocytes to resume meiosis.
Abstract: Two sterols of the cholesterol biosynthetic pathway induce resumption of meiosis in mouse oocytes in vitro The sterols, termed meiosis-activating sterols (MAS), have been isolated from human follicular fluid (FF-MAS, 4,4-dimethyl-5 alpha-cholest-8,14,24-triene-3 beta-ol) and from bull testicular tissue (T-MAS, 4,4-dimethyl-5 alpha-cholest-8,24-diene-3 beta-ol) FF-MAS is the first intermediate in the cholesterol biosynthesis from lanosterol and is converted to T-MAS by sterol delta 14-reductase An inhibitor of delta 7-reductase and delta 14 reductase, AY9944-A-7, causes cells with a constitutive cholesterol biosynthesis to accumulate FF-MAS and possibly other intermediates between lanosterol and cholesterol The aim of the present study was to evaluate whether AY9944-A-7 added to cultures of cumulus-oocyte complexes (COC) from mice resulted in accumulation of MAS and meiotic maturation AY9944-A-7 stimulated dose dependently (5-25 mumol l-1) COC to resume meiosis when cultured for 22 h in alpha minimal essential medium (alpha-MEM) containing 4 mmol hypoxanthine l-1, a natural inhibitor of meiotic maturation In contrast, naked oocytes were not induced to resume meiosis by AY9944-A-7 When cumulus cells were separated from their oocytes and co-cultured, AY9944-A-7 did not affect resumption of meiosis, indicating that intact oocyte-cumulus cell connections are important for AY9944-A-7 to exert its effect on meiosis Cultures of COC with 10 mumol AY9944-A-7 l-1 in the presence of [3H]mevalonic acid, a natural precursor for steroid synthesis, resulted in accumulation of labelled FF-MAS, which had an 11-fold greater amount of radioactivity incorporated per COC compared with the control culture without AY9944-A-7 In contrast, incorporation of radioactivity into the cholesterol fraction was reduced 30-fold in extracts from the same oocytes The present findings demonstrate for the first time that COC can synthesize cholesterol from mevalonate and accumulate FF-MAS in the presence of AY9944-A-7 Furthermore, AY9944-A-7 stimulated meiotic maturation dose dependently, indicating that FF-MAS, and possibly other sterol intermediates of the cholesterol synthesis pathway, play a central role in stimulating mouse oocytes to resume meiosis The results also indicate that oocytes may not synthesize steroids from mevalonate
50 citations
TL;DR: It is found that mammalian GGPP synthase synthesizes not only GGPP but also its metabolic precursor farnesyl diphosphate, which might be a factor determining the ability of the cells to respond to hormonal stimulation requiring both Ras-related small GTPases and trimeric G protein-coupled receptors.
Abstract: We have recently reported that skeletal muscle of the ob/ob mouse, an animal model of genetic obesity with extreme insulin resistance, exhibits alterations in the expression of multiple genes. Analysis and cloning of a full-length cDNA of one of the overexpressed mRNAs revealed a 300-amino-acid protein that could be identified as the mouse geranylgeranyl diphosphate synthase (GGPP synthase) based on its homology to proteins cloned from yeast and fungus. GGPP synthase catalyzes the synthesis of all-trans-geranylgeranyl diphosphate (GGPP), an isoprenoid used for protein isoprenylation in animal cells, and is a branch point enzyme in the mevalonic acid pathway. Three mRNAs for GGPP synthase of 4.3, 3.2, and 1.7 kb were detected in Northern blot analysis. Western blot analysis of tissue homogenates using specific antipeptide antibodies revealed a single band of 34.8 kDa. Expression level of this protein in different tissues correlated with expression of the 4.3- and 3.2-kb mRNAs. GGPP synthase mRNA expression was increased 5- to 20-fold in skeletal muscle, liver, and fat of ob/ob mice by Northern blot analysis. Western blot analysis also showed a twofold overexpression of the protein in muscle and fat but not in liver, where the dominant isoform is encoded by the 1.7-kb mRNA. Differentiation of 3T3-L1 fibroblasts into adipocytes induced GGPP synthase expression more than 20-fold. Using the immunoprecipitated protein, we found that mammalian GGPP synthase synthesizes not only GGPP but also its metabolic precursor farnesyl diphosphate. Thus, the expression of GGPP synthase is regulated in multiple tissues in obesity and is induced during adipocyte differentiation. Altered regulation in the synthesis of isoprenoids for protein prenylation in obesity might be a factor determining the ability of the cells to respond to hormonal stimulation requiring both Ras-related small GTPases and trimeric G protein-coupled receptors.
32 citations
TL;DR: Kinetic studies indicated an ordered sequential mechanism of action, in which mevalonate was the first substrate to bind and ADP was the last product to leave the enzyme, and a broad pH optimum between pH 7 and 10, with a maximum at about pH 8.9.
29 citations
TL;DR: Western- and Northern-blot analyses indicate that this activation of the gene coding for HMG-CoA reductase is apparently performed via post-transcriptional control, and a better understanding of the role of this enzyme in trypanosomatids is achieved.
Abstract: In eukaryotes the enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase catalyses the synthesis of mevalonic acid, a common precursor to all isoprenoid compounds. Here we report the isolation and overexpression of the gene coding for HMG-CoA reductase from Leishmania major. The protein from Leishmania lacks the membrane domain characteristic of eukaryotic cells but exhibits sequence similarity with eukaryotic reductases. Highly purified protein was achieved by ammonium sulphate precipitation followed by chromatography on hydroxyapatite. Kinetic parameters were determined for the protozoan reductase, obtaining K m values for the overall reaction of 40.3‡5.8 lM for (R,S)-HMG-CoA and 81.4‡5.3 lM for NADPH; V max was 33.55‡1.8 units[mg’". Gel-filtration experi
TL;DR: Patients with recurrent episodes of unexplained high fever with the associated features of hyperimmunoglobulinaemia D and periodic fever syndrome are reported in whom a minimally increased mevalonate excretion during febrile episodes appeared to be related to meValonate kinase (MK) deficiency resulting from mutations in the gene encoding mevalonic aciduria.
Abstract: Mevalonic aciduria is an inborn error of cholesterol and nonsterol isoprene biosynthesis due to mevalonate kinase deficiency (MKD; McKusick 251170). Urinary excretion of mevalonate is massively increased. Clinical manifestations include psychomotor retardation, hypotonia, dysmorphic features, failure to thrive, cataracts and hepatosplenomegaly. In addition to the multisystemic symptoms, patients present recurrent febrile attacks accompanied by adenopathy, arthralgias, rash and diarrhoea. These recurrent episodes of unexplained high fever with the associated features are also a characteristic finding of hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), a relatively benign condition in which elevated immunoglobulin D (IgD) itself appears not to be causative. The febrile episodes in HIDS have an average duration of 24 h to 7 days, varying frequency, and a tendency to decrease in both numbers and severity of the attacks with age. We report 12 HIDS patients in whom a minimally increased mevalonate excretion during febrile episodes appeared to be related to mevalonate kinase (MK) deficiency resulting from mutations in the gene encoding mevalonate kinase. (Less)
TL;DR: In this article, the effect of topical mevalonic acid on the murine epidermal permeability barrier function, comparing it with that of cholesterol, was investigated, and the results indicated that topical application of MEV enhances barrier recovery in aged mice, which is accompanied by not only acceleration of cholesterol synthesis from MEV but also stimulation of the whole cholesterol biosynthesis.
TL;DR: In most SLOS patients in vivo HMG-CoA reductase is not stimulated in spite of blocked cholesterol biosynthetic pathway and reduced plasma and hepatic cholesterol concentrations, suggesting in vivo regulation of the cholesterol biosynthesis pathway in SLOS.
Abstract: The Smith–Lemli–Opitz syndrome (SLOS) is a recessively inherited birth disorder caused by a defect in 7-dehydrocholesterol (3β-hydroxysteroid) Δ7-reductase, the final enzyme in cholesterol biosynthesis. To investigate in vivo regulation of the cholesterol biosynthetic pathway in SLOS, we measured hepatic microsomal sterol concentrations and activities of several key enzymes in the pathway, including HMG-CoA synthase, HMG-CoA reductase, squalene synthase and 7-dehydrocholesterol Δ7-reductase in liver specimens from a patient with SLOS and 11 controls. Hepatic microsomal 7-dehydrocholesterol Δ7-reductase activity in the patient was less than 1% of the control mean, and decreased cholesterol concentration and markedly increased 7- and 8-dehydrocholesterol concentrations were observed in the patient's microsomes. HMG-CoA synthase and squalene synthase activities in the patient were upregulated to 149% and 532%, respectively, while the activity of HMG-CoA reductase, the rate-limiting enzyme in the pathway, was reduced to 39% of the control mean. Downregulation of HMG-CoA reductase activity in SLOS was supported by measuring plasma levels of mevalonic acid, the immediate product of HMG-CoA reductase. The levels in SLOS patients (n=9) were significantly low compared with age-matched controls (n=8) (12±2 vs 28±6 nmol/L, p<0.05). These results suggest that in most SLOS patients in vivo HMG-CoA reductase is not stimulated in spite of blocked cholesterol biosynthetic pathway and reduced plasma and hepatic cholesterol concentrations.
TL;DR: In this paper, branch-specific inhibitors of the cytosolic isoprenoid pathway downstream from mevalonic acid (MVA) were used to study their capacity to block cell cycle progression.
Abstract: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR), which catalyzes the formation of mevalonic acid (MVA), can be specifically blocked by mevinolin. Inhibition of HMGR in vivo leads to an arrest in cell cycle progression in tobacco (Nicotiana tabacum L. Bright Yellow 2) cells. As MVA in plants is the common precursor of a myriad of isoprenoid products synthesized in the cytosol and mitochondria, it is difficult to identify among such MVA-dependent molecules those whose lack may lead to cell cycle arrest. In an attempt to do so, branch-specific inhibitors of the cytosolic isoprenoid pathway downstream from MVA were used to study their capacity to block cell cycle progression. The effects of squalestatin (sterol biosynthesis inhibitor), chaetomellic acid A and patulin (protein prenyltransferase (PT) inhibitors) and tunicamycin (inhibitor of dolichol-dependent protein glycosyl transferase, thus mimicking the effect of an absence of dolichol) were compared to those induced by mevinolin. In this way, squalestatin and chaetomellic acid were identified as behaving like true cell cycle inhibitors, in that they led to a specific arrest in the cell cycle. However, they did not exactly mimic the mevinolin-induced effects. Patulin proved to be of high general toxicity, which suggests that it may affect other reactions besides blockage of protein isoprenylation. Finally, tunicamycin efficiently blocked growth of cell suspension cultures, but did not arrest the cells in a specific phase of the cell cycle. Results are discussed in the context of a better understanding of the essential implication of isoprenoids in plant cell cycle progression.
TL;DR: It is believed that statins and other substances, for example, plant isoprenoids in the diet, have ben eficial antithrombotic properties arising through the in hibition of anIsoprenoid product other than cholesterol, and that this isopranoid product has cell regulatory functions upregulated by thrombin stimulation.
Abstract: Statins inhibit 3-hydroxy-3-methyl-glutaryl coenzyme A (HMGCoA) reductase, which synthesizes mevalonic acid in the isoprenoid pathways. These pathways lead to squalene and subsequently to cholesterol and related products (e.g., steroids, vitamin D, bile salts, lipopro teins) and have major branches producing cell regulatory substances (e.g., farnesyl- and geranylgeranyl conjugated proteins) (1,2). Although cholesterol reduc tion in blood has been widely believed to be beneficial (e.g., less available for accumulation by foam cells in atherosclerotic plaques), the ability of cholesterol reduc tion to mitigate the incidence and severity of cardiovas cular diseases has recently been questioned. Like others (3-10), we (11) believe that statins and other substances, for example, plant isoprenoids in the diet (12), have ben eficial antithrombotic properties arising through the in hibition of an isoprenoid product other than cholesterol. However, unlike others, we also believe that this isopren oid product has c...
TL;DR: The results suggest that lovastatin deserves further study as an agent for ex vivo marrow purging, and a differential effect on leukemia and normal progenitor cells could be detected in a clonogenic assay.
Abstract: Lovastatin reduces the isoprenylation of p21ras via suppression of mevalonic acid generation. Lovastatin has been shown to reduce tumor cell proliferation in a dose-dependent manner. Here,
TL;DR: It is concluded that the absorption of dietary mevalonic acid and alcohol-induced mevalony acid synthesis affects the urinary excretion and serum concentration of this cholesterol precursor, and studies using mevalonal acid as a marker of cholesterol synthesis must be carefully monitored regarding dietary meValonic acid intake and alcohol consumption.
Abstract: The influence of 2 different alcoholic beverages containing an equal amount of alcohol (48 g), 1 with mevalonic acid (beer) and 1 without (vodka), on the urinary excretion and serum concentration of mevalonic acid was investigated in 7 healthy subjects. Drinking 1 L of beer at night containing 608 μg/L mevalonic acid more than doubled the urinary excretion of mevalonic acid the following 12 hours, on average from 103 ± 15 μg/12 h to 211 ± 17 μg/12 h ( P am to 7 pm ) after ingestion of both alcoholic beverages. Serum concentrations of mevalonic acid were significantly increased the following morning after ingestion of beer (from 3.22 ± 0.20 ng/mL to 6.79 ± 0.58 ng/mL) or vodka (from 3.23 ± 0.37 ng/mL to 5.36 ± 0.55 ng/mL, P 13 C 2 ] mevalonic acid at night, 20% ± 0.7% of the dose was excreted in urine the following 12 hours, and only trace amounts thereafter. No [ 13 C 2 ] mevalonic acid could be detected in serum the following morning. We conclude that the absorption of dietary mevalonic acid and alcohol-induced mevalonic acid synthesis affects the urinary excretion and serum concentration of this cholesterol precursor. Therefore, studies using mevalonic acid as a marker of cholesterol synthesis must be carefully monitored regarding dietary mevalonic acid intake and alcohol consumption.
Journal Article•
TL;DR: Recently, the gene for HIDS was discovered by two independent groups using positional and functional cloning methods and there was a decreased enzyme activity due to missense mutations in the mevalonate kinase gene.
Abstract: Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is a rare autosomal recessive disorder. Patients suffer from recurrent attacks (3-6 days) with fever, abdominal distress, lymphadenopathy, skin lesions and arthralgias. Patients display a constantly elevated serum IgD which serves as a biological marker of the disease. Recently, the gene for HIDS was discovered by two independent groups using positional and functional cloning methods. One group used linkage analysis (positional cloning) and was able to locate the gene for HIDS on the long arm of chromosome 12 (12q24). Mevalonate kinase was an interesting candidate gene because patients with a near complete absence of this enzyme (mevalonic aciduria) do exhibit attacks of fever. Indeed subsequent data showed that there was a decreased enzyme activity due to missense mutations in the mevalonate kinase gene. The other group detected slightly elevated urinary excretion of mevalonic acid during attacks in a HIDS patient (functional cloning). The enzyme activity of mevalonate kinase was lower in cultured cells and sequence analysis identified several missense mutations in cDNA encoding for mevalonate kinase. Mevalonate kinase is a key enzyme in the cholesterol synthesis pathway and it is rather surprising that a defect in the cholesterol metabolism can cause a periodic inflammatory disease such as HIDS.
Journal Article•
TL;DR: In this article, the authors used linkage analysis (positional cloning) and functional cloning methods to locate the gene for HIDS on the long arm of chromosome 12 (12q24) and showed that there was a decreased enzyme activity due to missense mutations in the mevalonate kinase gene.
Abstract: Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is a rare autosomal recessive disorder. Patients suffer from recurrent attacks (3-6 days) with fever, abdominal distress, lymphadenopathy, skin lesions and arthralgias. Patients display a constantly elevated serum IgD which serves as a biological marker of the disease. Recently, the gene for HIDS was discovered by two independent groups using positional and functional cloning methods. One group used linkage analysis (positional cloning) and was able to locate the gene for HIDS on the long arm of chromosome 12 (12q24). Mevalonate kinase was an interesting candidate gene because patients with a near complete absence of this enzyme (mevalonic aciduria) do exhibit attacks of fever. Indeed subsequent data showed that there was a decreased enzyme activity due to missense mutations in the mevalonate kinase gene. The other group detected slightly elevated urinary excretion of mevalonic acid during attacks in a HIDS patient (functional cloning). The enzyme activity of mevalonate kinase was lower in cultured cells and sequence analysis identified several missense mutations in cDNA encoding for mevalonate kinase. Mevalonate kinase is a key enzyme in the cholesterol synthesis pathway and it is rather surprising that a defect in the cholesterol metabolism can cause a periodic inflammatory disease such as HIDS
01 Jan 2000
TL;DR: The best-studied routes of isoprenoid biosynthesis are those of vertebrates, where terpenes and terpenoids are generally produced via the mevalonate metabolism, and this book will refer to it as the meValonate-dependent route (MAD route).
Abstract: The best-studied routes of isoprenoid biosynthesis are those of vertebrates, where terpenes and terpenoids are generally produced via the mevalonate metabolism. Throughout this book we will refer to it as the mevalonate-dependent route (MAD route). The biosynthesis of mevalonic acid, which is their precursor, is governed by at least four different enzymes: acetyl-CoA thiolase, HMG-CoA synthase, HMG-CoA cyclase and HMG-CoA reductase. The latter enzyme that reduces s-hydroxy-s-methylglutaryl CoA to mevalonic acid (MVA) (Box 2.1) is a key enzyme in the production of MVA and isoprenoid groups.
01 Jan 2000
TL;DR: A relationship between HMGR activity, isoprenoid biosynthesis, sugar metabolism of both C6 and C7 sugars, and AOS production is shown in the form of an hypothesis/scheme in an attempt to show the relationship between these various factors.
Abstract: Studies have shown that isoprenoid metabolism plays an essential role in normal fruit growth and development. Thus in an attempt to examine the metabolic events that contribute to the appearance of the Hass small-fruit phenotype, isoprenoid metabolism has been studied in detail in both normal and small-fruit phenotypes. 3-hydroxy-3methylglutaryl-coenzyme A reductase (HMGR; EC 1.1.1.34) catalyses the formation of mevalonic acid (MVA) from 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), which is the committed step in isoprenoid biosynthesis. The small-fruit phenotype is characterised by reduced HMGR and cell division cycle activity, and increased levels of abscisic acid (ABA) metabolic activity (which is associated with increased active oxygen species (AOS) production). The small-fruit phenotype also has reduced total C6 soluble sugar content and increased glucose content. Work carried out thus far shows a relationship between HMGR activity, isoprenoid biosynthesis, sugar metabolism of both C6 and C7 sugars, and AOS production. Results are concluded in the form of an hypothesis/scheme in an attempt to show the relationship between these various factors.
Patent•
15 Dec 2000
TL;DR: In this paper, a histamine release inhibitor consisting of mevalonic acid was proposed. But this inhibitor was not suitable for practical uses and it was not safe to use in clinical applications.
Abstract: PROBLEM TO BE SOLVED: To obtain a histamine release inhibitor having excellent antiallergic actions and safely applicable to practical uses. SOLUTION: This histamine release inhibitor comprises mevalonic acid.
01 Jan 2000
TL;DR: A deficiency of sterol-∆8-isomerase can cause a chondrodysplasia punctata phenotype ranging from mild Conradi-hunermann to a lethal chondrohodosplasia as discussed by the authors.
Abstract: Only four of over 30 possible defects of cholesterol biosynthesis have been described. Mevalonic aciduria due to mevalonate kinase deficiency is situated at the beginning of the pathway and compromises the production of nonsterol isoprenes in addition to cholesterol. Patients with this enzyme defect show a wide range of symptoms, particularly dysmorphic features, hypotonia, developmental delay, enteropathy, hepatosplenomegaly, and recurrent febrile crises. At the end of the pathway, a defect of 3β- hydroxysterol-∆7-reductase could be delineated as the cause of Smith-Lemli-Opitz syndrome (SLOS), an important multiple malformation syndrome. Amongst these malformations are a characteristic facial appearance and syndactyly of toes 2–3. Deficiency of sterol-∆8-isomerase can cause a chondrodysplasia punctata phenotype ranging from mild Conradi-Hunermann to a lethal chondrodysplasia. One child with a malformation syndrome different from SLOS and generalized accumulation of desmosterol can be assumed to have suffered from a deficiency of 3β-hydroxysterol-∆24-reductase. Further defects are likely to be unraveled in due course and Table 29.1 summarizes indications for the two available tests: determination of mevalonic acid by urinary organic acid analysis and sterol analysis by gas chromatography-mass spectrometry (GCMS).