The Pentose Phosphate Pathway and Its Involvement in Cisplatin Resistance
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Oxidative Pentose Phosphate Pathway Enzyme 6-Phosphogluconate Dehydrogenase Plays a Key Role in Breast Cancer Metabolism
biology Article Oxidative Pentose Phosphate Pathway Enzyme 6-Phosphogluconate Dehydrogenase Plays a Key Role in Breast Cancer Metabolism Ibrahim H. Polat 1,2,3 ,Míriam Tarrado-Castellarnau 1,4 , Rohit Bharat 1, Jordi Perarnau 1 , Adrian Benito 1,5 , Roldán Cortés 1, Philippe Sabatier 2 and Marta Cascante 1,4,* 1 Department of Biochemistry and Molecular Biomedicine and Institute of Biomedicine (IBUB), Faculty of Biology, Universitat de Barcelona, Av Diagonal 643, 08028 Barcelona, Spain; [email protected] (I.H.P.); [email protected] (M.T.-C.); [email protected] (R.B.); [email protected] (J.P.); [email protected] (A.B.); [email protected] (R.C.) 2 Equipe Environnement et Prédiction de la Santé des Populations, Laboratoire TIMC (UMR 5525), CHU de Grenoble, Université Grenoble Alpes, 38700 CEDEX La Tronche, France; [email protected] 3 Department of Medicine, Hematology/Oncology, Goethe-University Frankfurt, 60590 Frankfurt, Germany 4 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28001 Madrid, Spain 5 Division of Cancer, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London W12 0NN, UK * Correspondence: [email protected] Simple Summary: Cancer cells alter their metabolism to maintain their high need for energy, produce Citation: Polat, I.H.; enough macromolecules for biosynthesis, and preserve their redox status. The investigation of Tarrado-Castellarnau, M.; Bharat, R.; cancer cell-specific metabolic alterations has vital importance to identify targets to be exploited for Perarnau, J.; Benito, A.; Cortés, R.; therapeutic development. The pentose phosphate pathway (PPP) is often highly activated in tumor Sabatier, P.; Cascante, M. -
Pentose PO4 Pathway, Fructose, Galactose Metabolism.Pptx
Pentose PO4 pathway, Fructose, galactose metabolism The Entner Doudoroff pathway begins with hexokinase producing Glucose 6 PO4 , but produce only one ATP. This pathway prevalent in anaerobes such as Pseudomonas, they doe not have a Phosphofructokinase. The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt) is a biochemical pathway parallel to glycolysis that generates NADPH and pentoses. While it does involve oxidation of glucose, its primary role is anabolic rather than catabolic. There are two distinct phases in the pathway. The first is the oxidative phase, in which NADPH is generated, and the second is the non-oxidative synthesis of 5-carbon sugars. For most organisms, the pentose phosphate pathway takes place in the cytosol. For each mole of glucose 6 PO4 metabolized to ribulose 5 PO4, 2 moles of NADPH are produced. 6-Phosphogluconate dh is not only an oxidation step but it’s also a decarboxylation reaction. The primary results of the pathway are: The generation of reducing equivalents, in the form of NADPH, used in reductive biosynthesis reactions within cells (e.g. fatty acid synthesis). Production of ribose-5-phosphate (R5P), used in the synthesis of nucleotides and nucleic acids. Production of erythrose-4-phosphate (E4P), used in the synthesis of aromatic amino acids. Transketolase and transaldolase reactions are similar in that they transfer between carbon chains, transketolases 2 carbon units or transaldolases 3 carbon units. Regulation; Glucose-6-phosphate dehydrogenase is the rate- controlling enzyme of this pathway. It is allosterically stimulated by NADP+. The ratio of NADPH:NADP+ is normally about 100:1 in liver cytosol. -
Enzyme Characterisation and Kinetic Modelling of the Pentose Phosphate
1 Enzyme characterisation and kinetic modelling of the pentose 2 phosphate pathway in yeast 1;2 3 Hanan L. Messiha Edward Kent 1;3;4 Naglis Malys 1;2;6 Kathleen M. Carroll 1;5 Neil Swainston 1;4 s 1;4;7;∗ t Pedro Mendes 1;4 n Kieran Smallbone i r P 1Manchester Centre for Integrative Systems Biology e r 2Faculty of Life Sciences 3 P Doctoral Training Centre in Integrative Systems Biology 4School of Computer Science 5School of Chemistry University of Manchester, M13 9PL, UK. 6School of Life Sciences, Gibbet Hill Campus, University of Warwick, Coventry, UK. 7Center for Quantitative Medicine and Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA. 4 Abstract 5 We present the quantification and kinetic characterisation of the enzymes of the pentose 6 phosphate pathway in Saccharomyces cerevisiae. The data are combined into a mathematical 7 model that describes the dynamics of this system and allows us to predict changes in metabo- 8 lite concentrations and fluxes in response to perturbations. We use the model to study the 9 response of yeast to a glucose pulse. We then combine the model with an existing glycolysis 10 model to study the effect of oxidative stress on carbohydrate metabolism. The combina- 11 tion of these two models was made possible by the standardised enzyme kinetic experiments 12 carried out in both studies. This work demonstrates the feasibility of constructing larger 13 network-scale models by merging smaller pathway-scale models. ∗To whom correspondence should be addressed at [email protected] PeerJ PrePrints | http://dx.doi.org/10.7287/peerj.preprints.146v4 | CC-BY 3.0 Open Access | received: 10 Apr 2014, published: 10 Apr 2014 1 14 Introduction 15 The pentose phosphate pathway (PPP) is a central and widely conserved metabolic pathway of car- 16 bohydrate metabolism which, in eukaryotic cells, is located in the cytoplasm (see Figure 1). -
Lecture 7 - the Calvin Cycle and the Pentose Phosphate Pathway
Lecture 7 - The Calvin Cycle and the Pentose Phosphate Pathway Chem 454: Regulatory Mechanisms in Biochemistry University of Wisconsin-Eau Claire 1 Introduction The Calvin cycle Text The dark reactions of photosynthesis in green plants Reduces carbon from CO2 to hexose (C6H12O6) Requires ATP for free energy and NADPH as a reducing agent. 2 2 Introduction NADH versus Text NADPH 3 3 Introduction The Pentose Phosphate Pathway Used in all organisms Glucose is oxidized and decarboxylated to produce reduced NADPH Used for the synthesis and degradation of pentoses Shares reactions with the Calvin cycle 4 4 1. The Calvin Cycle Source of carbon is CO2 Text Takes place in the stroma of the chloroplasts Comprises three stages Fixation of CO2 by ribulose 1,5-bisphosphate to form two 3-phosphoglycerate molecules Reduction of 3-phosphoglycerate to produce hexose sugars Regeneration of ribulose 1,5-bisphosphate 5 5 1. Calvin Cycle Three stages 6 6 1.1 Stage I: Fixation Incorporation of CO2 into 3-phosphoglycerate 7 7 1.1 Stage I: Fixation Rubisco: Ribulose 1,5- bisphosphate carboxylase/ oxygenase 8 8 1.1 Stage I: Fixation Active site contains a divalent metal ion 9 9 1.2 Rubisco Oxygenase Activity Rubisco also catalyzes a wasteful oxygenase reaction: 10 10 1.3 State II: Formation of Hexoses Reactions similar to those of gluconeogenesis But they take place in the chloroplasts And use NADPH instead of NADH 11 11 1.3 State III: Regeneration of Ribulose 1,5-Bisphosphosphate Involves a sequence of transketolase and aldolase reactions. 12 12 1.3 State III: -
RESPIRATION Pentose Phosphate Pathway Or Hexose Monophosphate Pathway
RESPIRATION Pentose Phosphate Pathway or Hexose Monophosphate Pathway Pentose phosphate pathway or hexose monophosphate pathway (HMP pathway) is the other common pathway to break down glucose to pyruvate and operates in both aerobic and anaerobic conditions. This pathway produces NADPH, which carries chemical energy in the form of reducing power and is used almost universally as the reductant in anabolic (energy utilization) pathways (e.g., fatty acid biosynthesis, cholesterol biosynthesis, nucleotide biosynthesis) and detoxification pathways (e.g., reduction of oxidized glutathione, cytochrome P450 monooxygenases). Also, the pentose phosphate pathway generates pentose sugar ribose and its derivatives, which are necessary for the biosynthesis of nucleic acids (DNA and RNA) as well as ATP, NADH, FAD, and coenzyme A. In this way, though the pentose phosphate pathway may be a source of energy in many microorganisms, it is more often of greater importance in various biosynthetic pathways. Pentose phosphate pathway consists of two phases: the oxidative phase and the non-oxidative phase. Oxidative Phase: The oxidative phase of the pentose phosphate pathway initiates with the conversion of glucose 6- phosphate to 6-Phosphogluconate. NADP+ is the electron acceptor yielding NADPH during this reaction. 6-Phosphogluconate, a six-carbon sugar, is then oxidativelydecarboxylated to yield ribulose 5-phosphate, a five-carbon sugar. NADP+ is again the electron acceptor yielding NADPH. In the final step of oxidative phase, there is isomerisation of ribulose 5-phosphatc to ribose 5- phosphate by phosphopentose isomerase and the conversion of ribulose 5-phosphate into its epimerxylulose 5-phosphate by phosphopentose epimerase for the transketolase reaction in non- oxidative phase. -
Carbohydrates: Structure and Function
CARBOHYDRATES: STRUCTURE AND FUNCTION Color index: . Very important . Extra Information. “ STOP SAYING I WISH, START SAYING I WILL” 435 Biochemistry Team *هذا العمل ﻻ يغني عن المصدر المذاكرة الرئيسي • The structure of carbohydrates of physiological significance. • The main role of carbohydrates in providing and storing of energy. • The structure and function of glycosaminoglycans. OBJECTIVES: 435 Biochemistry Team extra information that might help you 1-synovial fluid: - It is a viscous, non-Newtonian fluid found in the cavities of synovial joints. - the principal role of synovial fluid is to reduce friction between the articular cartilage of synovial joints during movement O 2- aldehyde = terminal carbonyl group (RCHO) R H 3- ketone = carbonyl group within (inside) the compound (RCOR’) 435 Biochemistry Team the most abundant organic molecules in nature (CH2O)n Carbohydrates Formula *hydrate of carbon* Function 1-provides important part of energy Diseases caused by disorders of in diet . 2-Acts as the storage form of energy carbohydrate metabolism in the body 3-structural component of cell membrane. 1-Diabetesmellitus. 2-Galactosemia. 3-Glycogen storage disease. 4-Lactoseintolerance. 435 Biochemistry Team Classification of carbohydrates monosaccharides disaccharides oligosaccharides polysaccharides simple sugar Two monosaccharides 3-10 sugar units units more than 10 sugar units Joining of 2 monosaccharides No. of carbon atoms Type of carbonyl by O-glycosidic bond: they contain group they contain - Maltose (α-1, 4)= glucose + glucose -Sucrose (α-1,2)= glucose + fructose - Lactose (β-1,4)= glucose+ galactose Homopolysaccharides Heteropolysaccharides Ketone or aldehyde Homo= same type of sugars Hetero= different types Ketose aldose of sugars branched unBranched -Example: - Contains: - Contains: Examples: aldehyde group glycosaminoglycans ketone group. -
1. Nucleotides A. Pentose Sugars – 5-Carbon Sugar 1) Deoxyribose – in DNA 2) Ribose – in RNA B. Phosphate Group C. Nitroge
1. Nucleotides a. Pentose sugars – 5-Carbon sugar 1) Deoxyribose – in DNA 2) Ribose – in RNA b. Phosphate group c. Nitrogenous bases 1) Purines a) Adenine b) Guanine 2) Pyrimidines a) Cytosine b) Thymine 2. Types of Nucleic Acids a. DNA 1) Locations 2) Functions b. RNA 1) Locations 2) Functions E. High Energy Biomolecules 1. Adenosine triphosphate a. Uses 1) Active transport 2) Movement 3) Biosynthesis reactions b. Regeneration 1) ADP + Pi + Energy → ATP 4. Classes of proteins a. Structural – ex. Collagen, keratin b. Transport – Hemoglobin, many β-globulins c. Contractile – Actin and Myosin of muscle tissue d. Regulatory - Hormones e. Immunologic - Antibodies f. Clotting – Thrombin and Fibrin g. Osmotic - Albumin h. Catalytic – Enzymes 1) Characteristics of enzymes • Proteins (most); ribonucleoproteins (few/ribozymes) • Act as organic catalysts • Lower the activation energy of reactions • Not changed by the reaction • Bind to their substrates o Lock-and-key model of enzyme activity o Induced-fit model • Highly specific • Named by adding -ase to substrate name; e.g., maltose/maltase • May require cofactors which may be: o Nonprotein metal ions such as copper, manganese, potassium, sodium o Small organic molecules known as coenzymes. The B vitamins like thiamine (B1) riboflavin (B2) and nicotinamide are precursors of coenzymes. • May require activation; e.g., pepsinogen pepsin in stomach chief cells 4. Factors Affecting Enzyme Action • pH o pepsin (stomach) @ pH = 2; trypsin (small int.) @ pH = 8 • Temperature o Denatured by high temp’s. • Enzyme inhibitors o Competitive inhibitors o Noncompetitive inhibitors • Effect of substrate concentration and reversible reactions and the Law of Mass D. -
Chemoenzymatic Synthesis of Novel, Structurally Diverse Compounds
Chemoenzymatic synthesis of novel, structurally diverse compounds A Thesis Submitted for the Degree of Doctor of Philosophy to the University of London Lydia G Coward Department of Biochemical Engineering University College London 1 I, Lydia Grace Coward confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 For my fantastic family. 3 Abstract The use of Diels Alder cycloaddition chemistries to access a diverse range of useful cyclic structures is well established throughout literature. However, the value of the product may be enhanced further still by linking this reaction with subsequent (biocatalytic) steps to create novel, structurally demanding, optically pure compounds. This project investigates the linking of Diels Alder (DA) chemistry to the enzyme, transketolase (TK) as a model integration pathway of a chemical syntheses and a biological transformation. The two-step process aims to provide a framework to synthesise small structurally diverse compounds with high enantiomeric excess. The demand for optically pure compounds is becoming a necessity due to the adverse affects frequently introduced by racemic compounds and the cost implications of the material possessing often only 50% active compound. Recombinant wild type Eschericha coli transketolase (EC 2.2.1.1) (WT-TK) was overexpressed in E. coli for the biocatalytic step of this two step synthesis. A substrate walking approach whereby a range of sequentially linked cyclic aldehydes, were applied to wild type transketolase and potential activity detected. Transketolase mutants, previously constructed based on information derived from the structural position within the active site of the dimeric enzyme were subsequently screened for activity with the cycloadduct of the Diels Alder reaction as aldehyde acceptor substrate for TK. -
PENTOSE PHOSPHATE PATHWAY — Restricted for Students Enrolled in MCB102, UC Berkeley, Spring 2008 ONLY
Metabolism Lecture 5 — PENTOSE PHOSPHATE PATHWAY — Restricted for students enrolled in MCB102, UC Berkeley, Spring 2008 ONLY Bryan Krantz: University of California, Berkeley MCB 102, Spring 2008, Metabolism Lecture 5 Reading: Ch. 14 of Principles of Biochemistry, “Glycolysis, Gluconeogenesis, & Pentose Phosphate Pathway.” PENTOSE PHOSPHATE PATHWAY This pathway produces ribose from glucose, and it also generates 2 NADPH. Two Phases: [1] Oxidative Phase & [2] Non-oxidative Phase + + Glucose 6-Phosphate + 2 NADP + H2O Ribose 5-Phosphate + 2 NADPH + CO2 + 2H ● What are pentoses? Why do we need them? ◦ DNA & RNA ◦ Cofactors in enzymes ● Where do we get them? Diet and from glucose (and other sugars) via the Pentose Phosphate Pathway. ● Is the Pentose Phosphate Pathway just about making ribose sugars from glucose? (1) Important for biosynthetic pathways using NADPH, and (2) a high cytosolic reducing potential from NADPH is sometimes required to advert oxidative damage by radicals, e.g., ● - ● O2 and H—O Metabolism Lecture 5 — PENTOSE PHOSPHATE PATHWAY — Restricted for students enrolled in MCB102, UC Berkeley, Spring 2008 ONLY Two Phases of the Pentose Pathway Metabolism Lecture 5 — PENTOSE PHOSPHATE PATHWAY — Restricted for students enrolled in MCB102, UC Berkeley, Spring 2008 ONLY NADPH vs. NADH Metabolism Lecture 5 — PENTOSE PHOSPHATE PATHWAY — Restricted for students enrolled in MCB102, UC Berkeley, Spring 2008 ONLY Oxidative Phase: Glucose-6-P Ribose-5-P Glucose 6-phosphate dehydrogenase. First enzymatic step in oxidative phase, converting NADP+ to NADPH. Glucose 6-phosphate + NADP+ 6-Phosphoglucono-δ-lactone + NADPH + H+ Mechanism. Oxidation reaction of C1 position. Hydride transfer to the NADP+, forming a lactone, which is an intra-molecular ester. -
Questions with Answers- Nucleotides & Nucleic Acids A. the Components
Questions with Answers- Nucleotides & Nucleic Acids A. The components and structures of common nucleotides are compared. (Questions 1-5) 1._____ Which structural feature is shared by both uracil and thymine? a) Both contain two keto groups. b) Both contain one methyl group. c) Both contain a five-membered ring. d) Both contain three nitrogen atoms. 2._____ Which component is found in both adenosine and deoxycytidine? a) Both contain a pyranose. b) Both contain a 1,1’-N-glycosidic bond. c) Both contain a pyrimidine. d) Both contain a 3’-OH group. 3._____ Which property is shared by both GDP and AMP? a) Both contain the same charge at neutral pH. b) Both contain the same number of phosphate groups. c) Both contain the same purine. d) Both contain the same furanose. 4._____ Which characteristic is shared by purines and pyrimidines? a) Both contain two heterocyclic rings with aromatic character. b) Both can form multiple non-covalent hydrogen bonds. c) Both exist in planar configurations with a hemiacetal linkage. d) Both exist as neutral zwitterions under cellular conditions. 5._____ Which property is found in nucleosides and nucleotides? a) Both contain a nitrogenous base, a pentose, and at least one phosphate group. b) Both contain a covalent phosphodister bond that is broken in strong acid. c) Both contain an anomeric carbon atom that is part of a β-N-glycosidic bond. d) Both contain an aldose with hydroxyl groups that can tautomerize. ___________________________________________________________________________ B. The structures of nucleotides and their components are studied. (Questions 6-10) 6._____ Which characteristic is shared by both adenine and cytosine? a) Both contain one methyl group. -
8| Nucleotides and Nucleic Acids
8| Nucleotides and Nucleic Acids © 2013 W. H. Freeman and Company CHAPTER 8 Nucleotides and Nucleic Acids Key topics: – Biological function of nucleotides and nucleic acids – Structures of common nucleotides – Structure of double‐stranded DNA – Structures of ribonucleic acids – Denaturation and annealing of DNA – Chemistry of nucleic acids; mutagenesis Functions of Nucleotides and Nucleic Acids • Nucleotide Functions: – Energy for metabolism (ATP) – Enzyme cofactors (NAD+) –Signal transduction (cAMP) • Nucleic Acid Functions: – Storage of genetic info (DNA) – Transmission of genetic info (mRNA) –Processing of genetic information (ribozymes) –Protein synthesis (tRNA and rRNA) Nucleotides and Nucleosides • Nucleotide = – Nitrogeneous base –Pentose – Phosphate • Nucleoside = – Nitrogeneous base –Pentose • Nucleobase = – Nitrogeneous base Phosphate Group •Negatively charged at neutral pH • Typically attached to 5’ position – Nucleic acids are built using 5’‐triphosphates •ATP, GTP, TTP, CTP – Nucleic acids contain one phosphate moiety per nucleotide •May be attached to other positions Other Nucleotides: Monophosphate Group in Different Positions Pentose in Nucleotides • ‐D‐ribofuranose in RNA • ‐2’‐deoxy‐D‐ribofuranose in DNA •Different puckered conformations of the sugar ring are possible Nucleobases •Derivatives of pyrimidine or purine • Nitrogen‐containing heteroaromatic molecules •Planar or almost planar structures •Absorb UV light around 250–270 nm Pyrimidine Bases • Cytosine is found in both DNA and RNA •Thymineis found only in DNA -
De Novo Nucleic Acids: a Review of Synthetic Alternatives to DNA and RNA That Could Act As † Bio-Information Storage Molecules
life Review De Novo Nucleic Acids: A Review of Synthetic Alternatives to DNA and RNA That Could Act as y Bio-Information Storage Molecules Kevin G Devine 1 and Sohan Jheeta 2,* 1 School of Human Sciences, London Metropolitan University, 166-220 Holloway Rd, London N7 8BD, UK; [email protected] 2 Network of Researchers on the Chemical Evolution of Life (NoR CEL), Leeds LS7 3RB, UK * Correspondence: [email protected] This paper is dedicated to Professor Colin B Reese, Daniell Professor of Chemistry, Kings College London, y on the occasion of his 90th Birthday. Received: 17 November 2020; Accepted: 9 December 2020; Published: 11 December 2020 Abstract: Modern terran life uses several essential biopolymers like nucleic acids, proteins and polysaccharides. The nucleic acids, DNA and RNA are arguably life’s most important, acting as the stores and translators of genetic information contained in their base sequences, which ultimately manifest themselves in the amino acid sequences of proteins. But just what is it about their structures; an aromatic heterocyclic base appended to a (five-atom ring) sugar-phosphate backbone that enables them to carry out these functions with such high fidelity? In the past three decades, leading chemists have created in their laboratories synthetic analogues of nucleic acids which differ from their natural counterparts in three key areas as follows: (a) replacement of the phosphate moiety with an uncharged analogue, (b) replacement of the pentose sugars ribose and deoxyribose with alternative acyclic, pentose and hexose derivatives and, finally, (c) replacement of the two heterocyclic base pairs adenine/thymine and guanine/cytosine with non-standard analogues that obey the Watson–Crick pairing rules.