Metabolism, Transport, and Signaling PDF

Chemical Composition of Life SPH EH 710 Jesse D. Moreira-Bouchard, PhD “From the Ground Up” Atoms: unit of matter that makes up all chemical substances Element: a type of atom with differing numbers of fundamental sub- atomic particles Subatomic Particles...

Chemical Composition of Life SPH EH 710 Jesse D. Moreira-Bouchard, PhD “From the Ground Up” Atoms: unit of matter that makes up all chemical substances Element: a type of atom with differing numbers of fundamental sub- atomic particles Subatomic Particles 2D 3D Subatomic Particles 1. Proton – positive charge, one of two types of particles which forms the nucleus of an atom 2. Neutron – no charge, one of two types of particles which forms the nucleus of an atom 3. Electron – negative charge, particle that forms pairs in the electron cloud surrounding a nucleus of an atom Atoms Each atomic element contains a unique number of protons, which determines its atomic number and distinguishes it from other elements Atomic mass is expressed in atomic mass units or “AMUs” and is defined as the number of protons plus the number of neutrons, as electrons don’t really have mass Usually, the # of protons = # of neutrons When the number of neutrons is more or less than protons, this is called an isotope because while it is still the same element, its atomic mass will have changed Radioisotopes are usefully clinically because we can track them in the body Radioisotopes in Cancer Diagnostics Positron Emission Tomography – a radiolabeled glucose tracer is injected and then visualized in the body Anatomic structures are visualized and ones that glow, which don’t normally uptake large amounts of glucose, can be identified as likely pathological Ions and Charge Ions are an element that does not have a full outer shell of electrons, meaning the electron and proton number are not balanced These frequently occur in nature and mean that most elements do have net electrical charges When an electron is gained, there is a net negative charge, and the ion is called an anion When an electron is lost, there is a net positive charge, and the ion is called a cation  Covalent Bonds Bonds that occur between elements whereby they share electrons in their outer shell (valence electrons) Denoted in chemical diagrams as lines between a central atom and surrounding bonded atoms Strongest type of bond in the body and generally require heat to disrupt Polarity and Bonds Electronegativity Electronegativity and Bond Classification Nonpolar bonds generally occur when the difference in electronegativity between the two atoms is less than 0.5 Polar bonds generally occur when the difference in electronegativity between the two atoms is roughly between 0.5 and 2.0 Ionic bonds generally occur when the difference in electronegativity between the two atoms is greater than 2.0 Ionic Bonds Ionic Bonds form when positive and negatively charges ions attract Dissolution can occur when an ionic bonded molecule enters a polar solvent, and the ions composing it are attracted to opposite ends of the polar solvent Hydrogen Bonds Electrical attraction between charged elements of polar molecules that hold them closely together Molecules Molecules are made up of atoms bonded together, and are the building blocks of life The major elements in living systems that make up molecules are: Carbon Hydrogen Nitrogen Oxygen Phosphorus Sulfur “CHNOPS” Molecules Molecules can ionize, and often do, resulting in their ability to attract or repel one another based on charge Molecules Molecules can also, based on polarity, attract or repel water Hydrophobic: repel water Hydrophilic: attract water Amphipathic: Molecules that have a polar end and a nonpolar end These will occur naturally and are evolutionary useful as they allow for complex structures to form, such as the lipid membrane of cells Organic Molecules Organic molecules contain carbon as a central element Carbohydrates Sugars, largely speaking, that are composed of fundamental units of saccharides Monosaccharides: singular/monomers in sugars, with one ring of hydrocarbons Carbohydrates Disaccharides: two monomers in sugars combined by a chemical reaction, with two rings of hydrocarbons Carbohydrates Polysaccharides: many monomers in sugars combined by a chemical reaction, with multiple adjoined rings of hydrocarbons Lipids Molecules composed of hydrocarbons that are generally nonpolar and hydrophobic, and account for 40% of organic matter in the body There are 4 classes 1. Fatty Acids – long chains of lipids which are a source of energy for high ATP yield and usually get stored Lipids - triglycerides Lipids that are glycerol combined with three fatty acids, stored as energy preserved in adipose and released during stress or energy demand Lipids - phospholipids Lipids that are similar to triglycerides but in which case the third hydroxyl group of glycerol is linked to phosphate Used in membranes and signaling Lipids - steroids Lipids that are unique with four rings of hydrocarbons as their base in all cases Examples include cholesterol, cortisol, and estrogens Often used as signaling molecules Proteins Molecules that serve a plethora of functions and account for 50% of the organic material in the body Composed of carbon, hydrogen, nitrogen, and oxygen, as well as sulfur Polypeptides are formed when amino acids, the subunits of proteins, are linked together via dehydration reactions at the ribosome Proteins Protein Structure Protein Structure Tertiary structure: result of five bonding forces  Protein Structure Functional proteins often contain elements or regions called domains which serve specific functions of the given protein “-binding domains” “enzymatic domains”  Nucleic Acids Only account for 2% of body weight Composed of nucleotides Critically important for storing information and expressing that information to create functional proteins Nucleic Acid Structure DNA and Bonding Bases linked to one another by H-bonds Broken enzymatically during DNA handling processes  Eukaryotic Cells Fundamental unit of life Cells possess the ability to: 1. store information 2. express that information 3. undergo metabolism to generate energy 4. replicate independently, and 5. interact with signals from the environment  Eukaryotic Cells - Compartmentalization Interior: Divided into 2 regions 1. Nucleus 2. Cytoplasm 1. Cytosol: fluid part of cytoplasm Eukaryotic Cells - Compartmentalization Membranes: phospholipids that divide compartments, as well as surround the whole cell semi-permeable Filled with proteins “fluid mosaic model” Eukaryotic Cells – Subcellular Organelles Mitochondria Mitochondria: co-evolved with eukaryotic cells, theory of endosymbiosis Double membrane enveloped Matrix contains enzymes for cellular respiration “oxidative phosphorylation” Contain their own genome, the mtDNA, where enzymes for OXPHOS are encoded Central Dogma of Molecular Biology Central Dogma of Molecular Biology Ribosomal Translation Regulating Gene Transcription Binding Specificity Most ligand-receptor binding events have “lock-in-key” fit Chemical interactions and weak bonds transiently hold the ligand at the binding site to induce some sort of effect If a receptor, conformational changes occur that will either open a channel, activate enzymatic activity, or induce a signal cascade whereby the receptor activates a subsequent protein Enzymes and Catalysis Determinants of chemical reactions Reactant concentration Temperature Presence of a catalyst Activation energy Enzymes and catalysis Modulation of Enzymatic Activity Physiological Mechanisms of Health and Disease Week 2 Metabolism, membrane transport, cell signaling Energy Adenosine triphosphate – ATP Adenosine Ribose 3 phosphates Metabolic Pathways 3 main pathways Glycolysis Tricarboxylic acid cycle (TCA) – other names: Citric Acid Cycle, Krebs cycle Oxidative phosphorylation Glycolysis Glucose + 2 ADP + 2Pi + 2 NAD+ → 2 pyruvate + 2 ATP + 2 NADH + 2H + + 2 H2O Anaerobic Occurs in cytosol 2 phases Energy investment Energy generation End products 2 pyruvate 4 ATP** 2 NADH Anaerobic Pathway Without the presence of oxygen, NADH++ must be oxidized (removal of hydrogens) outside the mitochondria NAD = Nicotinamide adenine dinucleotide Glycolysis requires NAD to accept hydrogen atoms Lactic Acid Pathway Hydrogen is added to pyruvic acid to form lactic acid Anaerobic Pathways 1 – Phosphorylation using ATP and enzyme hexokinase 2 – Rearrangement 3 – Phosphorylation using enzyme phosphofructokinase and ATP Anaerobic Pathways 4 – Fructose 1,6-bisphosphate split into 2 sugars – G3P 5 – NAD oxidizes G3P followed by phosphorylation Enzyme – glyceraldehyde 3-phosphate dehydrogenase to produce NADH++ and BPG 6 – Phosphoglycerate kinase transfers phosphate group from BPG to ADP to form ATP and 3PG Anaerobic Pathways 7 – Phosphate moved from 3rd carbon to 2nd carbon, 3PG → 2PG 8 – H2O removed, 2PG now PEP 9 – Pyruvate kinase transfers phosphate from PEP to ADP to form ATP and pyruvic acid Anaerobic Pathways Glycolysis Products: 2 NADH++ 4 ATP Cost 2 ATP Net gain: 2 ATP 2 Pyruvates (ionized form of pyruvic acid) In preparation for Krebs cycle  Tricarboxylic Acid Cycle (TCA) Primary function – to remove H+ Seen in formation of NADH and FADH Other products: Guanosine triphosphate (GTP) Carbon dioxide (CO2) Steps of Krebs Cycle 1 – Acetyl CoA joins with oxaloacetate to form citrate 2 – Citrate is rearranged to form isocitrate 3 – Isocitrate is oxidized by NAD+ & enzyme isocitrate dehydrogenase to produce NADH+ H+ & ⍺-ketoglutarate 4 – ⍺-ketoglutarate is oxidized by NAD+ & ⍺-KG dehydrogenase to produce NADH+ H+ & succinyl-CoA Steps of Krebs Cycle 5 – Succinyl-CoA synthesis removes CoA to form succinate, energy is released used to make guanosine triphosphate 6 – Succinate oxidized by FAD & enzyme succinate dehydrogenase to produce FADH2 & fumarate 7 – Fumarate hydrated to form malate 8 – Malate oxidized by NAD+ & malate dehydrogenase to form NADH+ H+ & oxaloacetate  Net Reaction of Krebs cycle Acetyl CoA + 3NAD+ + FAD + GDP + Pi + 2H2O → 2CO2 + CoA + 3NADH + 3H+ + FADH2 + GTP Coenzyme products Waste products ATP production ** Can only operate under aerobic conditions ** Why? Oxidative Phosphorylation – Electron Transport Chain ½O2 + NADH + H+ → H2O + NAD+ + Energy Passage of electrons (e-) through a series of complexes Occurs in inner membrane of mitochondria Generates a proton gradient in the intermembrane space Electron Transport Chain Complex I Oxidizes NADH Passes e- to coenzyme Q Pumps 4 H+ Electron Transport Chain Complex II Oxidizes FADH Passes e- Electron Transport Chain Complex III Receives e- from CoQ Becomes charged Pumps 4 H+ Passes e- to cytochrome C Electron Transport Chain Complex IV Receives e- from cytochrome c Hydrolyzes oxygen to form H20 Enzyme: cytochrome oxidase Pumps 2 H+ Chemiosmosis ATP Synthase Macronutrients and their roles Three classes of energy yielding nutrient molecules Carbohydrates Fats Proteins  Carbohydrate Metabolism Catabolism Carbohydrate Metabolism Glycogen synthesis occurs when there is an excess of glucose Glycogen stored in liver and skeletal muscle Low glucose state Glycogenolysis – breaks down glycogen into glucose Gluconeogenesis – glucose synthesis from glycerol and amino acids (non carbohydrate precursors) Fat Metabolism ~80% of the body’s stored energy is in fat Triglycerides consist of three fatty acids bound to glycerol Stored largely in adipocytes Fat Metabolism Beta-Oxidation Protein Metabolism Proteins are long chains of amino acids Amino acids can be metabolized for energy Broken down into intermediates that can enter glycolysis or Krebs cycle Ammonia produced (NH3) is toxic to cells in high concentrations Passes through membrane to enter blood stream Liver combines ammonia with CO2 to form urea which is later excreted by the kidneys Protein/Amino Acid Metabolism Movement of Solutes and Water Diffusion Mediated-transport systems Osmosis Endocytosis Exocytosis Epithelial transport Diffusion Molecules are in constant random motion Movement along concentration gradient Factors Affecting Diffusion Temperature Mass of molecule Surface area of separation Medium molecules are moving through Distance Membrane permeability to molecule Diffusion of Ions Through Ion Channels Mediated Transport Systems Requires transporter protein to undergo conformational change to move substance through membrane Dependent by: Solute concentration Affinity of transporters for solute Number of transporters in membrane Rate conformational change occurs Active Transport Transporters used energy to pump solutes across a membrane against a gradient Ex. Na+/K+ pump Osmosis Net diffusion of water across a membrane Water diffuses through plasma membranes through membrane proteins called aquaporins Amount of and type of aquaporins dictate how permeable to water a given membrane is Osmosis follows a concentration gradient Amount of solute to water in a solution creates the gradient  Endo- and Exocytosis Molecules are carried via vesicles into or outside of a cell Pinocytosis “cell drinking” Phagocytosis Receptor mediated Endo- and Exocytosis Molecules are carried via vesicles into or outside of a cell Phagocytosis Epithelial Transport Cellular Communication through Signaling Along cell membrane are embedded receptors Chemical messengers are used to communicate a change but are specific to the receptor that they fit into – specificity Increased affinity of a ligand to it’s receptor increases chance of binding Antagonists can compete with chemical messengers and take the available binding location Signal Transduction Once binding occurs there is a conformational change to the receptor Cell then responds to create change through: Altering permeability or transport properties Metabolism Secretory activity Rate of proliferation and differentiation Examples