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Markedly Inhibited 7-Dehydrocholesterol-Delta 7-Reductase Activity in Liver Microsomes from Smith-Lemli-Opitz Homozygotes
Markedly inhibited 7-dehydrocholesterol-delta 7-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes. S Shefer, … , T C Chen, M F Holick J Clin Invest. 1995;96(4):1779-1785. https://doi.org/10.1172/JCI118223. Research Article We investigated the enzyme defect in late cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome, a recessively inherited developmental disorder characterized by facial dysmorphism, mental retardation, and multiple organ congenital anomalies. Reduced plasma and tissue cholesterol with increased 7-dehydrocholesterol concentrations are biochemical features diagnostic of the inherited enzyme defect. Using isotope incorporation assays, we measured the transformation of the precursors, [3 alpha- 3H]lathosterol and [1,2-3H]7-dehydrocholesterol into cholesterol by liver microsomes from seven controls and four Smith-Lemli-Opitz homozygous subjects. The introduction of the double bond in lathosterol at C- 5[6] to form 7-dehydrocholesterol that is catalyzed by lathosterol-5-dehydrogenase was equally rapid in controls and homozygotes liver microsomes (120 +/- 8 vs 100 +/- 7 pmol/mg protein per min, P = NS). In distinction, the reduction of the double bond at C-7 [8] in 7-dehydrocholesterol to yield cholesterol catalyzed by 7-dehydrocholesterol-delta 7- reductase was nine times greater in controls than homozygotes microsomes (365 +/- 23 vs 40 +/- 4 pmol/mg protein per min, P < 0.0001). These results demonstrate that the pathway of lathosterol to cholesterol in human liver includes 7- dehydrocholesterol as a key intermediate. In Smith-Lemli-Opitz homozygotes, the transformation of 7-dehydrocholesterol to cholesterol by hepatic microsomes was blocked although 7-dehydrocholesterol was produced abundantly from lathosterol. -
Annotation-1 Annotation-1
Annotation-1 Baseline Resuscitation Normal Saline Resuscitation PFP Shock Annotation-1 Aminoacids Arginine and proline metabolism Carnitine and fatty acid metabolsim Glutamate metabolism Glycerophospholipid biosynthesis Glycolysis and sugars GSH homeostasis GSH homeostasis/Glyoxlate Hexosamine Indole and Tryptophan Nucleotides Other Panthothenate metabolism Pentose Phosphate Pathway Serine biosynthesis and one-carbon metabolism Signaling Sulfur metabolism TCA cycle urea cycle relative row min row max Baseline_14 Baseline_16 Baseline_13 Baseline_15 Baseline_22 Baseline_2 Baseline_12 Baseline_3 Baseline_4 Baseline_9 Baseline_7 Baseline_8 Shock_13 Shock_12 Shock_15 Shock_22 Shock_14 Shock_16 Shock_2 Shock_3 Shock_7 Shock_4 Shock_8 Shock_9 Res_NS_14 Res_NS_13 Res_NS_16 Res_NS_12 Res_NS_22 Res_NS_15 Res_PFP_2 Res_PFP_3 Res_PFP_7 Res_PFP_4 Res_PFP_8 Res_PFP_9 Annotation-1 Annotation-1 Annotation Annotation-1 L-Arginine Aminoacids L-Isoleucine Aminoacids Leucine Aminoacids L-Cysteine Aminoacids L-Alanine Aminoacids L-Aspartate Aminoacids L-Glutamate Aminoacids L-Glutamine Aminoacids L-Histidine Aminoacids L-Lysine Aminoacids L-Methionine Aminoacids L-Tyrosine Aminoacids L-Asparagine Aminoacids L-Threonine Aminoacids L-Cystine Aminoacids L-Serine Aminoacids L-Proline Aminoacids L-Valine Aminoacids L-Tryptophan Aminoacids Glycine Aminoacids L-Kynurenine Aminoacids L-Phenylalanine Aminoacids CMP Nucleotides 6-Hydroxynicotinate Nucleotides 5-6-Dihydrouracil Nucleotides AMP Nucleotides dAMP Nucleotides GMP Nucleotides Guanine Nucleotides 2-5-Dihydroxypyridine -
35 Disorders of Purine and Pyrimidine Metabolism
35 Disorders of Purine and Pyrimidine Metabolism Georges van den Berghe, M.- Françoise Vincent, Sandrine Marie 35.1 Inborn Errors of Purine Metabolism – 435 35.1.1 Phosphoribosyl Pyrophosphate Synthetase Superactivity – 435 35.1.2 Adenylosuccinase Deficiency – 436 35.1.3 AICA-Ribosiduria – 437 35.1.4 Muscle AMP Deaminase Deficiency – 437 35.1.5 Adenosine Deaminase Deficiency – 438 35.1.6 Adenosine Deaminase Superactivity – 439 35.1.7 Purine Nucleoside Phosphorylase Deficiency – 440 35.1.8 Xanthine Oxidase Deficiency – 440 35.1.9 Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency – 441 35.1.10 Adenine Phosphoribosyltransferase Deficiency – 442 35.1.11 Deoxyguanosine Kinase Deficiency – 442 35.2 Inborn Errors of Pyrimidine Metabolism – 445 35.2.1 UMP Synthase Deficiency (Hereditary Orotic Aciduria) – 445 35.2.2 Dihydropyrimidine Dehydrogenase Deficiency – 445 35.2.3 Dihydropyrimidinase Deficiency – 446 35.2.4 Ureidopropionase Deficiency – 446 35.2.5 Pyrimidine 5’-Nucleotidase Deficiency – 446 35.2.6 Cytosolic 5’-Nucleotidase Superactivity – 447 35.2.7 Thymidine Phosphorylase Deficiency – 447 35.2.8 Thymidine Kinase Deficiency – 447 References – 447 434 Chapter 35 · Disorders of Purine and Pyrimidine Metabolism Purine Metabolism Purine nucleotides are essential cellular constituents 4 The catabolic pathway starts from GMP, IMP and which intervene in energy transfer, metabolic regula- AMP, and produces uric acid, a poorly soluble tion, and synthesis of DNA and RNA. Purine metabo- compound, which tends to crystallize once its lism can be divided into three pathways: plasma concentration surpasses 6.5–7 mg/dl (0.38– 4 The biosynthetic pathway, often termed de novo, 0.47 mmol/l). starts with the formation of phosphoribosyl pyro- 4 The salvage pathway utilizes the purine bases, gua- phosphate (PRPP) and leads to the synthesis of nine, hypoxanthine and adenine, which are pro- inosine monophosphate (IMP). -
Clinical Symptoms of Defects in Pyrimidine Metabolism
ClinicalClinical symptomssymptoms ofof DefectsDefects inin pyrimidinepyrimidine metabolismmetabolism Birgit Assmann Department of General Pediatrics Universtiy Children‘s Hospital Düsseldorf, Germany Overview • Biosynthesis: UMP Synthase • Degradation: –– PyrimidinePyrimidine 55‘‘--Nucleotidase(UMPNucleotidase(UMP--Hydrolase)Hydrolase) – [Thymidine-Phosphorylase, mitochondrial] –– DihydropyrimidineDihydropyrimidine DehydrogenaseDehydrogenase –– DihydropyrimidinaseDihydropyrimidinase –– UreidopropionaseUreidopropionase HCO3+gluNH2 carbamoyl-P orotic acid OMP OPRT UMP OD UMPS UMPSUMPS == uridinemonophosphateuridinemonophosphate synthasesynthase Bifunctional enzyme (one gene): a) Orotate phosphoribosyl transferase (OPRT) b) Orotidine decarboxylase (OD) UMPS deficiency • = Hereditary orotic aciduria Hallmarks:Hallmarks: - MegaloblasticMegaloblastic anemiaanemia inin infantsinfants >> IfIf untreateduntreated:: FailureFailure toto thrivethrive PsychomotorPsychomotor retardationretardation • Therapy: uridine (≥100-150 mg/kg/d) Defects of pyrimidine degradation • Pyrimidine 5‘-Nucleotidase deficiency - chronic hemolytic anemia + basophilic stippling of erythrocytes • Thymidine phosphorylase deficiency = MNGIE=Mitoch. NeuroGastroIntestinal Encephalomyopathy Mitochondrial disorder with elevatedelevated urinaryurinary thymidinethymidine excretionexcretion HCO3+gluNH2 carbamoyl-P orotic acid OMP TMP UMP UMPS thymidine cytosolic 5‘- uridine Thym. Nucleotidase phosphor ylase thymine uracil Pyrimidine 5‘-Nucleotidase- SuperactivitySuperactivity • Existence -
1 AMINO ACIDS Commonly, 21 L-Amino Acids Encoded by DNA Represent the Building Blocks of Animal, Plant, and Microbial Proteins
1 AMINO ACIDS Commonly, 21 L-amino acids encoded by DNA represent the building blocks of animal, plant, and microbial proteins. The basic amino acids encountered in proteins are called proteinogenic amino acids 1.1). Biosynthesis of some of these amino acids proceeds by ribosomal processes only in microorganisms and plants and the ability to synthesize them is lacking in animals, including human beings. These amino acids have to be obtained in the diet (or produced by hydrolysis of body proteins) since they are required for normal good health and are referred to as essential amino acids. The essential amino acids are arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. The rest of encoded amino acids are referred to as non-essential amino acids (alanine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine). Arginine and histidine are classified as essential, sometimes as semi-essential amino acids, as their amount synthesized in the body is not sufficient for normal growth of children. Although it is itself non-essential, cysteine (classified as conditionally essential amino acid) can partly replace methionine, which is an essential amino acid. Similarly, tyrosine can partly replace phenylalanine. 1.1 The glutamic acid group 1.1.1 Glutamic acid and glutamine Free ammonium ions are toxic to living cells and are rapidly incorporated into organic compounds. One of such transformations is the reaction of ammonia with 2-oxoglutaric acid from the citric acid cycle to produce L-glutamic acid. This reaction is known as reductive amination. Glutamic acid is accordingly the amino acid generated first as both constituent of proteins and a biosynthetic precursor. -
Sample Thesis Title with a Concise And
DESIGN, SYNTHESIS AND STUDIES OF GUANIDINIUM-BASED INHIBITORS FOR ISOPRENOID BIOSYNTHETIC PATHWAY ENZYMES by Walid Abdelmagid MChem., The University of Liverpool, 2011 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Doctor of Philosophy in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) October 2019 © Walid Abdelmagid, 2019 i The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: DESIGN, SYNTHESIS AND STUDIES OF GUANIDINIUM-BASED INHIBITORS FOR ISOPRENOID BIOSYNTHETIC PATHWAY ENZYMES submitted by Walid Abdelmagid in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry Examining Committee: Martin Tanner Supervisor Stephen Withers Supervisory Committee Member Glenn Sammis Supervisory Committee Member Kathryn Ryan University Examiner David Chen University Examiner Additional Supervisory Committee Members: Supervisory Committee Member Supervisory Committee Member ii Abstract In this thesis an inhibition strategy was developed to target enzymes that utilize allylic diphosphates. Positively-charged inhibitors that mimic the transition states/intermediates formed with these enzymes were synthesized. In chapter two, inhibitor 2 containing a guanidinium moiety appended to a phosphonylphosphinate was designed to mimic the transition state for the dissociation of dimethylallyl diphosphate into an allylic carbocation-pyrophosphate ion-pair. To test for the effectiveness of incorporating a guanidinium functionality into inhibitors of human farnesyl diphosphate synthase, inhibitors 3 and 4 were also prepared. Inhibitor 3 has a positive charge localized onto one atom, and inhibitor 4 is isosteric to inhibitor 2, but lacks positive charge. The inhibitors displayed IC50 values that were significantly higher than the substrate Km value, indicating that the positive charge did not result in tight binding to the enzyme. -
The Effects of Phytosterols Present in Natural Food Matrices on Cholesterol Metabolism and LDL-Cholesterol: a Controlled Feeding Trial
European Journal of Clinical Nutrition (2010) 64, 1481–1487 & 2010 Macmillan Publishers Limited All rights reserved 0954-3007/10 www.nature.com/ejcn ORIGINAL ARTICLE The effects of phytosterols present in natural food matrices on cholesterol metabolism and LDL-cholesterol: a controlled feeding trial X Lin1, SB Racette2,1, M Lefevre3,5, CA Spearie4, M Most3,6,LMa1 and RE Ostlund Jr1 1Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA; 2Program in Physical Therapy, Washington University School of Medicine, St Louis, MO, USA; 3Pennington Biomedical Research Center, Baton Rouge, LA, USA and 4Center for Applied Research Sciences, Washington University School of Medicine, St Louis, MO, USA Background/Objectives: Extrinsic phytosterols supplemented to the diet reduce intestinal cholesterol absorption and plasma low-density lipoprotein (LDL)-cholesterol. However, little is known about their effects on cholesterol metabolism when given in native, unpurified form and in amounts achievable in the diet. The objective of this investigation was to test the hypothesis that intrinsic phytosterols present in unmodified foods alter whole-body cholesterol metabolism. Subjects/Methods: In all, 20 out of 24 subjects completed a randomized, crossover feeding trial wherein all meals were provided by a metabolic kitchen. Each subject consumed two diets for 4 weeks each. The diets differed in phytosterol content (phytosterol-poor diet, 126 mg phytosterols/2000 kcal; phytosterol-abundant diet, 449 mg phytosterols/2000 kcal), but were otherwise matched for nutrient content. Cholesterol absorption and excretion were determined by gas chromatography/mass spectrometry after oral administration of stable isotopic tracers. -
Lathosterol Oxidase (Sterol C-5 Desaturase) Deletion Confers Resistance to Amphotericin B and Sensitivity to Acidic Stress in Leishmania Major
Washington University School of Medicine Digital Commons@Becker Open Access Publications 7-1-2020 Lathosterol oxidase (sterol C-5 desaturase) deletion confers resistance to amphotericin B and sensitivity to acidic stress in Leishmania major Yu Ning Cheryl Frankfater Fong-Fu Hsu Rodrigo P Soares Camila A Cardoso See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Authors Yu Ning, Cheryl Frankfater, Fong-Fu Hsu, Rodrigo P Soares, Camila A Cardoso, Paula M Nogueira, Noelia Marina Lander, Roberto Docampo, and Kai Zhang RESEARCH ARTICLE Molecular Biology and Physiology crossm Downloaded from Lathosterol Oxidase (Sterol C-5 Desaturase) Deletion Confers Resistance to Amphotericin B and Sensitivity to Acidic Stress in Leishmania major Yu Ning,a Cheryl Frankfater,b Fong-Fu Hsu,b Rodrigo P. Soares,c Camila A. Cardoso,c Paula M. Nogueira,c http://msphere.asm.org/ Noelia Marina Lander,d,e Roberto Docampo,d,e Kai Zhanga aDepartment of Biological Sciences, Texas Tech University, Lubbock, Texas, USA bMass Spectrometry Resource, Division of Endocrinology, Diabetes, Metabolism, and Lipid Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA cFundação Oswaldo Cruz-Fiocruz, Instituto René Rachou, Belo Horizonte, Minas Gerais, Brazil dCenter for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia, USA eDepartment of Cellular Biology, University of Georgia, Athens, Georgia, USA ABSTRACT Lathosterol oxidase (LSO) catalyzes the formation of the C-5–C-6 double bond in the synthesis of various types of sterols in mammals, fungi, plants, and pro- on September 14, 2020 at Washington University in St. -
The Pennsylvania State University the Graduate School College Of
The Pennsylvania State University The Graduate School College of Health and Human Development EFFECTS OF DIETS ENRICHED IN CONVENTIONAL AND HIGH-OLEIC ACID CANOLA OILS COMPARED TO A WESTERN DIET ON LIPIDS AND LIPOPROTEINS, GENE EXPRESSION, AND THE GUT ENVIRONMENT IN ADULTS WITH METABOLIC SYNDROME FACTORS A Dissertation in Nutritional Sciences by Kate Joan Bowen © 2018 Kate Joan Bowen Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy December 2018 The dissertation of Kate Joan Bowen was reviewed and approved* by the following: Penny Kris-Etherton Distinguished Professor of Nutritional Sciences Dissertation Advisor Chair of Committee Gregory Shearer Associate Professor of Nutritional Sciences Sheila West Professor of Biobehavioral Health Peter Jones Distinguished Professor of Human Nutritional Sciences and Food Sciences University of Manitoba Special Member Lavanya Reddivari Assistant Professor of Food Science Purdue University Laura E. Murray-Kolb Associate Professor of Nutritional Sciences Professor-in-Charge of the Graduate Program *Signatures are on file in the Graduate School ii ABSTRACT The premise of this dissertation was to investigate the effects of diets that differed only in fatty acid composition on biomarkers for cardiovascular disease (CVD) in individuals with metabolic syndrome risk factors, and to explore the mechanisms underlying the response. In a multi-site, double blind, randomized, controlled, three period crossover, controlled feeding study design, participants were fed an isocaloric, prepared, weight maintenance diet plus a treatment oil for 6 weeks with washouts of ≥ 4 weeks between diet periods. The treatment oils included conventional canola oil, high-oleic acid canola oil (HOCO), and a control oil (a blend of butter oil/ghee, flaxseed oil, safflower oil, and coconut oil). -
Lc and Lc-Free Mass Spectrometry Applications in Non-Targeted Metabolomics for Disease Detection and Early Prediction
LC AND LC-FREE MASS SPECTROMETRY APPLICATIONS IN NON-TARGETED METABOLOMICS FOR DISEASE DETECTION AND EARLY PREDICTION A Dissertation Presented to The Academic Faculty by Xiaoling Zang In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the School of Chemistry and Biochemistry Georgia Institute of Technology August 2018 COPYRIGHT © 2018 BY XIAOLING ZANG LC AND LC-FREE MASS SPECTROMETRY APPLICATIONS IN NON-TARGETED METABOLOMICS FOR DISEASE DETECTION AND EARLY PREDICTION Approved by: Dr. Facundo M. Fernández, Advisor Dr. Ronghu Wu School of Chemistry and Biochemistry School of Chemistry and Biochemistry Georgia Institute of Technology Georgia Institute of Technology Dr. María E. Monge, Co-advisor Dr. Matthew Torres Centro de Investigaciones en School of Biology Bionanociencias (CIBION) Georgia Institute of Technology Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Dr. Julia Kubanek Dr. Mark Styczynski School of Chemistry and Biochemistry School of Chemical and Biomolecular Georgia Institute of Technology Engineering Georgia Institute of Technology Date Approved: July 23, 2018 Never give up on what you really want to do. The person with big dreams is more powerful than one with all the facts. -Albert Einstein, The World as I See It1 ACKNOWLEDGEMENTS There are many people who have helped and supported me a lot during my 6-year Ph.D. life at Georgia Tech. First of all, I want to express my deepest gratitude to my advisor, Dr. Facundo M. Fernández, for his guidance, support, patience and encouragement during my whole Ph.D. study. Under his mentorship over the last 6 years, I have gained so much knowledge and experience in mass spectrometry and have grown to become more independent and capable in handling the research projects. -
Behavior of Activities of Thymidine Metabolizing Enzymes in Human Leukemia-Lymphoma Cells1
[CANCER RESEARCH 49. 1090-1094. March I, 1989] Behavior of Activities of Thymidine Metabolizing Enzymes in Human Leukemia-Lymphoma Cells1 Taiichi Shiotani, Yasuko Hashimoto, Terukazu Tanaka, and Shozo Irino First Department of Internal Medicine, Kagawa Medical School, Ikenobe, Miki, Kagawa, 761-07, Japan ABSTRACT 7). These observations indicate the importance of this catabolic enzyme for dThd utilization. Thymidylate, an important pre The behavior of the activities of thymidine metabolizing enzymes, cursor of DNA synthesis, also may be produced by the de novo dihydrothymine dehydrogenase (EC 1.3.1.2) and thymidine phosphoryl- pathway through dTMP synthase. The correlation between cell ase (EC 2.4.2.4) for thymidine degradation, thymidine kinase (EC proliferation and dThd kinase (3, 4, 6, 8, 9) or dTMP synthase 2.7.1.75) and thymidylate synthase (EC 2.1.1.45) for DNA synthesis, was elucidated in cytosolic extracts from normal human lymphocytes and (8, 10, 11) has been demonstrated. The enhanced capacity for 13 human leukemia-lymphoma cell lines. In the normal human lympho the salvage pathway in leukemia (12, 13) appears to limit the cytes, the activities of dihydrothymine dehydrogenase, thymidine phos- antitumor effectiveness of antimetabolites of de novo pyrimidine phorylase, thymidine kinase, and thymidylate synthase were 6.88, 796, biosynthesis. The enzymic capacities of the de novo and salvage 0.30, and 0.29 nmol/h/mg protein, respectively. In leukemia-lymphoma pathways and dThd catabolism have not been determined si cell lines, the activities of synthetic enzymes, thymidine kinase, and multaneously in human leukemia-lymphoma cells. Therefore, thymidylate synthase, increased two- to 79-fold and 22- to 407-fold of the elucidation of the behavior of the enzymic capacities in the the normal lymphocyte values. -
Steroidal Triterpenes of Cholesterol Synthesis
Molecules 2013, 18, 4002-4017; doi:10.3390/molecules18044002 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Review Steroidal Triterpenes of Cholesterol Synthesis Jure Ačimovič and Damjana Rozman * Centre for Functional Genomics and Bio-Chips, Faculty of Medicine, Institute of Biochemistry, University of Ljubljana, Zaloška 4, Ljubljana SI-1000, Slovenia; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +386-1-543-7591; Fax: +386-1-543-7588. Received: 18 February 2013; in revised form: 19 March 2013 / Accepted: 27 March 2013 / Published: 4 April 2013 Abstract: Cholesterol synthesis is a ubiquitous and housekeeping metabolic pathway that leads to cholesterol, an essential structural component of mammalian cell membranes, required for proper membrane permeability and fluidity. The last part of the pathway involves steroidal triterpenes with cholestane ring structures. It starts by conversion of acyclic squalene into lanosterol, the first sterol intermediate of the pathway, followed by production of 20 structurally very similar steroidal triterpene molecules in over 11 complex enzyme reactions. Due to the structural similarities of sterol intermediates and the broad substrate specificity of the enzymes involved (especially sterol-Δ24-reductase; DHCR24) the exact sequence of the reactions between lanosterol and cholesterol remains undefined. This article reviews all hitherto known structures of post-squalene steroidal triterpenes of cholesterol synthesis, their biological roles and the enzymes responsible for their synthesis. Furthermore, it summarises kinetic parameters of enzymes (Vmax and Km) and sterol intermediate concentrations from various tissues. Due to the complexity of the post-squalene cholesterol synthesis pathway, future studies will require a comprehensive meta-analysis of the pathway to elucidate the exact reaction sequence in different tissues, physiological or disease conditions.