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Fausto G Hegardt - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA synthase: a control enzyme in ketogenesis
Biochemical Journal, 1999Co-Authors: Fausto G HegardtAbstract:Cytosolic and mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) synthases were first recognized as different chemical entities in 1975, when they were purified and characterized by Lane's group. Since then, the two enzymes have been studied extensively, one as a control site of the cholesterol biosynthetic pathway and the other as an important control site of ketogenesis. This review describes some key developments over the last 25 years that have led to our current understanding of the physiology of mitochondrial HMG-CoA synthase in the HMG-CoA pathway and in ketogenesis in the liver and small intestine of suckling animals. The enzyme is regulated by two systems: succinylation and desuccinylation in the short term, and transcriptional regulation in the long term. Both control mechanisms are influenced by nutritional and hormonal factors, which explains the incidence of ketogenesis in diabetes and starvation, during intense lipolysis, and in the foetal-neonatal and suckling-weaning transitions. The DNA-binding properties of the peroxisome-proliferator-activated receptor and other transcription factors on the nuclear-receptor-responsive element of the mitochondrial HMG-CoA synthase promoter have revealed how ketogenesis can be regulated by fatty acids. Finally, the expression of mitochondrial HMG-CoA synthase in the gonads and the correction of auxotrophy for mevalonate in cells deficient in cytosolic HMG-CoA synthase suggest that the mitochondrial enzyme may play a role in cholesterogenesis in gonadal and other tissues.
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Regulation of the expression of the mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA synthase gene. Its role in the control of ketogenesis.
Biochemical Journal, 1992Co-Authors: Nuria Casals, José Ayté, Gabriel Gil-gómez, N Roca, M Guerrero, Carlos J. Ciudad, Fausto G HegardtAbstract:We have explored the role of mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) synthase in regulating ketogenesis. We had previously cloned the cDNA for mitochondrial HMG-CoA synthase and have now studied the regulation in vivo of the expression of this gene in rat liver. The amount of processed mitochondrial HMG-CoA synthase mRNA is rapidly changed in response to cyclic AMP, insulin, dexamethasone and refeeding, and is greatly increased by starvation, fat feeding and diabetes. We conclude that one point of ketogenic control is exercised at the level of genetic expression of mitochondrial HMG-CoA synthase.
Nuria Casals - One of the best experts on this subject based on the ideXlab platform.
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structural βα 8 tim barrel model of 3 hydroxy 3 methylglutaryl coenzyme a lyase
Journal of Biological Chemistry, 2003Co-Authors: Nuria Casals, Juan Pié, Cecilia Mir, Ramón Roca, Beatriz Puisac, Rosa Aledo, Josep Clotet, Sebastián Menao, Paulino Gomezpuertas, Dolors SerraAbstract:Abstract This study describes three novel homozygous missense mutations (S75R, S201Y, and D204N) in the 3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) lyase gene, which caused 3-hydroxy-3-methylglutaric aciduria in patients from Germany, England, and Argentina. Expression studies in Escherichia coli show that S75R and S201Y substitutions completely abolished the HMG-CoA lyase activity, whereas D204N reduced catalytic efficiency to 6.6% of the wild type. We also propose a three-dimensional model for human HMG-CoA lyase containing a (βα)8 (TIM) barrel structure. The model is supported by the similarity with analogous TIM barrel structures of functionally related proteins, by the localization of catalytic amino acids at the active site, and by the coincidence between the shape of the substrate (HMG-CoA) and the predicted inner cavity. The three novel mutations explain the lack of HMG-CoA lyase activity on the basis of the proposed structure: in S75R and S201Y because the new amino acid residues occlude the substrate cavity, and in D204N because the mutation alters the electrochemical environment of the active site. We also report the localization of all missense mutations reported to date and show that these mutations are located in the β-sheets around the substrate cavity.
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Regulation of the expression of the mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA synthase gene. Its role in the control of ketogenesis.
Biochemical Journal, 1992Co-Authors: Nuria Casals, José Ayté, Gabriel Gil-gómez, N Roca, M Guerrero, Carlos J. Ciudad, Fausto G HegardtAbstract:We have explored the role of mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) synthase in regulating ketogenesis. We had previously cloned the cDNA for mitochondrial HMG-CoA synthase and have now studied the regulation in vivo of the expression of this gene in rat liver. The amount of processed mitochondrial HMG-CoA synthase mRNA is rapidly changed in response to cyclic AMP, insulin, dexamethasone and refeeding, and is greatly increased by starvation, fat feeding and diabetes. We conclude that one point of ketogenic control is exercised at the level of genetic expression of mitochondrial HMG-CoA synthase.
Victor W Rodwell - One of the best experts on this subject based on the ideXlab platform.
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Structures of lovastatin, a statin drug that competitively inhibits HMGR, and of HMG-CoA
2011Co-Authors: Jon A Friesen, Victor W RodwellAbstract:Copyright information:Taken from "The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases"Genome Biology 2004;5(11):248-248.Published online 1 Nov 2004PMCID:PMC545772.Copyright © 2004 BioMed Central Ltd It can be seen that the portion of the drug shown here at the top resembles the HMG portion of HMG-CoA
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The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases
Genome Biology, 2004Co-Authors: Jon A Friesen, Victor W RodwellAbstract:The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyzes the conversion of HMG-CoA to mevalonate, a four-electron oxidoreduction that is the rate-limiting step in the synthesis of cholesterol and other isoprenoids. The enzyme is found in eukaryotes and prokaryotes; and phylogenetic analysis has revealed two classes of HMG-CoA reductase, the Class I enzymes of eukaryotes and some archaea and the Class II enzymes of eubacteria and certain other archaea. Three-dimensional structures of the catalytic domain of HMG-CoA reductases from humans and from the bacterium Pseudomonas mevalonii , in conjunction with site-directed mutagenesis studies, have revealed details of the mechanism of catalysis. The reaction catalyzed by human HMG-CoA reductase is a target for anti-hypercholesterolemic drugs (statins), which are intended to lower cholesterol levels in serum. Eukaryotic forms of the enzyme are anchored to the endoplasmic reticulum, whereas the prokaryotic enzymes are soluble. Probably because of its critical role in cellular cholesterol homeostasis, mammalian HMG-CoA reductase is extensively regulated at the transcriptional, translational, and post-translational levels.
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substrate induced closure of the flap domain in the ternary complex structures provides insights into the mechanism of catalysis by 3 hydroxy 3 methylglutaryl coa reductase
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Lydia Tabernero, Victor W Rodwell, Daniel A Bochar, Cynthia V StauffacherAbstract:3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) reductase is the rate-limiting enzyme and the first committed step in the biosynthesis of cholesterol in mammals. We have determined the crystal structures of two nonproductive ternary complexes of HMG-CoA reductase, HMG-CoA/NAD+ and mevalonate/NADH, at 2.8 A resolution. In the structure of the Pseudomonas mevalonii apoenzyme, the last 50 residues of the C terminus (the flap domain), including the catalytic residue His381, were not visible. The structures of the ternary complexes reported here reveal a substrate-induced closing of the flap domain that completes the active site and aligns the catalytic histidine proximal to the thioester of HMG-CoA. The structures also present evidence that Lys267 is critically involved in catalysis and provide insights into the catalytic mechanism.
Thomas J. Bach - One of the best experts on this subject based on the ideXlab platform.
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the specific molecular architecture of plant 3 hydroxy 3 methylglutaryl coa lyase
Journal of Biological Chemistry, 2019Co-Authors: Andrea Hemmerlin, Alexandre Huchelmann, Denis Tritsch, Hubert Schaller, Thomas J. BachAbstract:3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) lyase (HMGL) is involved in branched-chain amino acid catabolism leading to acetyl-CoA production. Here, using bioinformatics analyses and protein sequence alignments, we found that in Arabidopsis thaliana a single gene encodes two HMGL isoforms differing in size (51 kDa, HMGL51 and 46 kDa, HMGL46). Similar to animal HMGLs, both isoforms comprised a C-terminal type 1 peroxisomal retention motif, and HMGL51 contained a mitochondrial leader peptide. We observed that only a shortened HMGL (35 kDa, HMGL35) is conserved across all kingdoms of life. Most notably, all plant HMGLs also contained a specific N-terminal extension (P100) that is located between the N-terminal mitochondrial targeting sequence TP35 and HMGL35 and is absent in bacteria and other eukaryotes. Interestingly, using HMGL enzyme assays, we found that rather than HMGL46, homodimeric recombinant HMGL35 is the active enzyme catalyzing acetyl-CoA and acetoacetate synthesis when incubated with (S)-HMG-CoA. This suggested that the plant-specific P100 peptide may inactivate HMGL according to specific physiological requirements. Therefore, we investigated whether the P100 peptide in HMGL46 alters its activity, possibly by modifying the HMGL46 structure. We found that induced expression of a cytosolic HMGL35 version in A. thaliana delays germination and leads to rapid wilting and chlorosis in mature plants. Our results suggest that in plants, P100-mediated HMGL inactivation outside of peroxisomes or mitochondria is crucial, protecting against potentially cytotoxic effects of HMGL activity while it transits to these organelles.
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Outline of isoprenoid biosynthesis pathways in plants.
2014Co-Authors: Pan Liao, Hui Wang, Mingfu Wang, An-shan Hsiao, Thomas J. Bach, Mee-len ChyeAbstract:Enzymes are shown in bold. Pathway inside the mitochondria and plastid are boxed. Arrows between cytosolic and plastid compartments represent metabolic flow between them (greater arrow for more flux). Abbreviations: ABA, abscisic acid; AACT, acetoacetyl-CoA thiolase; BR6OX2, brassinosteroid-6-oxidase 2; CYP710A1, sterol C-22 desaturase; CYP85A1, cytochrome P450 monooxygenase; DMAPP, dimethylallyl diphosphate; DWF1, delta-24 sterol reductase; DXR, 1-deoxy-D-xylulose 5-phosphate reductoisomerase; DXS, 1-deoxy-D-xylulose 5-phosphate synthase; FPP, farnesyl diphosphate; GA-3-P, glyceraldehyde-3-phosphate; FPPS, farnesyl diphosphate synthase; GAs, gibberellins; GGPP, geranylgeranyl diphosphate; GGPPS, geranylgeranyl diphosphate synthase; GPP, geranyl diphosphate; HMG-CoA, 3-Hydroxy-3-Methylglutaryl-CoA; HMGS, 3-Hydroxy-3-Methylglutaryl-CoA synthase; HMGR, 3-Hydroxy-3-Methylglutaryl-CoA reductase; IPP, isopentenyl diphosphate; IPPI, isopentenyl/dimethylallyl diphosphate isomerase; Q10, coenzyme Q10; SMT, sterol methyltransferase; SQS, squalene synthase. HMGS is marked in red colour. The expression levels of enzymes analysed in this work are marked in blue colour.
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overexpression of brassica juncea wild type and mutant hmg coa synthase 1 in arabidopsis up regulates genes in sterol biosynthesis and enhances sterol production and stress tolerance
Plant Biotechnology Journal, 2012Co-Authors: Hui Wang, Thomas J. Bach, Dinesh A Nagegowda, Reetika Rawat, Pierrette Bouviernave, D Guo, Mee-len ChyeAbstract:Summary Brassica juncea 3-Hydroxy-3-Methylglutaryl-CoA synthase (HMGS) is encoded by four isogenes (BjHMGS1-BjHMGS4). In vitro enzyme assays had indicated that the recombinant BjHMGS1 H188N mutant lacked substrate inhibition by acetoacetyl-CoA (AcAc-CoA) and showed 8-fold decreased enzyme activity. The S359A mutant demonstrated 10-fold higher activity, while the H188N ⁄ S359A double mutant displayed a 10-fold increased enzyme activity and lacked inhibition by AcAc-CoA. Here, wild-type and mutant BjHMGS1 were overexpressed in Arabidopsis to examine their effects in planta. The expression of selected genes in isoprenoid biosynthesis, isoprenoid content, seed germination and stress tolerance was analysed in HMGS overexpressors (OEs). Those mRNAs encoding enzymes 3-Hydroxy-3-Methylglutaryl-CoA reductase (HMGR), sterol methyltransferase 2 (SMT2), delta-24 sterol reductase (DWF1), C-22 sterol desaturase (CYP710A1) and brassinosteroid-6-oxidase 2 (BR6OX2) were up-regulated in HMGS-OEs. The total sterol content in leaves and seedlings of OE-wtBjHMGS1, OE-S359A and OE-H188N ⁄ S359A was significantly higher than OE-H188N. HMGS-OE seeds germinated earlier than wild-type and vector-transformed controls. HMGS-OEs further displayed reduced hydrogen peroxide (H2O2)–induced cell death and constitutive expression of salicylic acid (SA)-dependent pathogenesis-related genes (PR1, PR2 and PR5), resulting in an increased resistance to Botrytis cinerea, with OE-S359A showing the highest and OE-H188N the lowest tolerance. These results suggest that overexpression of HMGS up-regulates HMGR, SMT2, DWF1, CYP710A1 and BR6OX2, leading to enhanced sterol content and stress tolerance in Arabidopsis.
Luqi Huang - One of the best experts on this subject based on the ideXlab platform.
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cloning and characterisation of the gene encoding 3 hydroxy 3 methylglutaryl coa synthase in tripterygium wilfordii
Molecules, 2014Co-Authors: Yujun Zhao, Meng Zhang, Xiujuan Wang, Ping Su, Xianan Zhang, Luqi HuangAbstract:Tripterygium wilfordii is a traditional Chinese medical plant used to treat rheumatoid arthritis and cancer. The main bioactive compounds of the plant are diterpenoids and triterpenoids. 3-Hydroxy-3-Methylglutaryl-CoA synthase (HMGS) catalyses the reaction of acetoacetyl-CoA to 3-Hydroxy-3-Methylglutaryl-CoA, which is the first committed enzyme in the mevalonate (MVA) pathway. The sequence information of HMGS in Tripterygium wilfordii is a basic resource necessary for studying the terpenoids in the plant. In this paper, full-length cDNA encoding HMGS was isolated from Tripterygium wilfordii (abbreviated TwHMGS, GenBank accession number: KM978213). The full length of TwHMGS is 1814 bp, and the gene encodes a protein with 465 amino acids. Sequence comparison revealed that TwHMGS exhibits high similarity to HMGSs of other plants. The tissue expression patterns revealed that the expression level of TwHMGS is highest in the stems and lowest in the roots. Induced expression of TwHMGS can be induced by MeJA, and the expression level is highest 4 h after induction. The functional complement assays in the YML126C knockout yeast demonstrated that TwHMGS participates in yeast terpenoid biosynthesis.
