CHEMISTRY 646 BIOINORGANIC CHEMISTRY SPRING 2011 Instructor Dr
CHEMISTRY 646 BIOINORGANIC CHEMISTRY SPRING 2011 Instructor: Dr. Keith M. Davies. Office 410 Occoquan (PW 1) kdavies@gmu. edu 703 -993 -1075 Office Hours: Tu 1: 00 -3: 30; Th 1: 30 -2: 30 (326 B ST 1) or by appointment M, W, F at 410 Occoquan (PW 1). . Syllabus: http: //osf 1. gmu. edu/%7 Ekdavies/646 SYL-Spring-11. html
Examinations and Grading Mid-Term Exam Tues, March 8 th 30% Final Exam Tues, May 17 th, 40% 1 Student 30% Presentations 1 A class presentation of a “bioinorganic chemistry“ topic taken from journal articles in the "inorganic-biochemistry" literature and a 1 -2 page written summary.
Textbook: Biological Inorganic Chemistry, Structure and Reactivity H. B. Gray, E. I. Stiefel, J. S. Valentine and I. Bertini, University Science Books, 2007.
8 Course Material Introduction: Occurrence, availability and biological roles of inorganic elements. Classification of metallobiomolecules. Fundamentals of metal ion coordination chemistry. Protein structure and metal ion binding. Ligand field effects, magnetic and spectral properties of transition metal ions. Thermodynamic stability, redox potentials and electron transfer. Kinetics of metal ion substitution. Molecular orbital theory for diatomic molecules and coordination compounds. Bonding models for Π-unsaturated ligands, P-bonded organometallic systems: Metal carbonyls, P-alkenes, allyls and aromatic complexes: 16/18 -electron rule. Metal-metal bonds and metal atom clusters. Rationalization of cluster structures, Transport and storage of metal ions (Fe, Zn, Cu) in biology. Transferrin, ferritin, siderophores, metallothioneins, metallochaperones. Channels and carriers. Mossbauer, epr and IR/Raman vibrational spectroscopy. Inorganic Tutorial -----Mid-Term Exam- (Part A) In-Class / Part B (Take Home)------- 15 ---------------------Spring Break-------------------- 22 Mid-Term Exam Part B (Due) Dioxygen carriers, cooperativity O 2 and CO discrimination. Dioxygen transport in lower organisms. Inorganic model compounds. Dioxygen activation enzymes, oxygen atom transfer. Cyt-P 450, tyrosinase Dioxygen toxicity and detoxification enzymes. Superoxide dismutases, peroxidases and catalases. Electron transfer proteins: Metal cofactors. Iron cytochromes and iron sulfur proteins, copper proteins. Electron transfer through proteins. Jan 25 Feb 1 8 15 22 Mar 1 29 Apr 5 12 19 26 May 3 May 17 Text Chapter p 695 -699 p 675 -682 p 31 -41 p 700 -711 p 57 -77 p 139 -173 p 354 -385 p 388 -395 p 319 -352 p 43 -56 p 229 -253 p 261 -275 p 95 -105 Metals in Medicine: Cisplatin and analogues. Metal toxicity and metalrelated disease. Chelation therapy. Nitric Oxide Biochemistry. Physiological roles of nitric oxide. Nitric oxide p 647 -653 synthase enzymes. p 562 -572 Cobalamins: B 12 -dependant transformations. Redox cofactors: nitrogenases, hydrogenases. p 468 -485 p 443 -450 Hydrolytic chemistry: Metal-dependant (Zn, Ni, Fe) lyase and hydrolase p 175 -185 enzymes. Urease, aconitase p 198 -199 p 209 -212 Final Exam 4: 30 – 7: 15
Bioinorganic Texts in Johnson Center Library • Bertini, I. ; Gray, H. B. ; Lippard, S. J. ; Valentine, J. S. Bioinorganic Chemistry (University Science Books; 1994) • Kaim, W. and Schwederski, B. Bioinorganic chemistry : inorganic elements in the chemistry of life : an introduction and guide (Wiley, 1994) • Cowan, J. A. Inorganic Biochemistry: An Introduction (Wiley-VCH: New York, 1997) • Lippard, S. J. and Berg, J. M. Principles of Bioinorganic Chemistry (University Science Books; 1994). • Roat-Malone, R. M. Bioinorganic Chemistry: A Short Course (Wiley, 2002)
Course Outline and Objectives q Bioinorganic chemistry is concerned with the roles of inorganic elements in biological processes. q In CHEM 646, we will apply fundamental principles of inorganic chemistry, particularly transition metal coordination chemistry and ligand field theory, to understand the structure and function of metal ion sites in biomolecules. q We will also consider bioinorganic topics including metal toxicity, the use of metal complexes as drugs and the bioregulatory functions of nitric oxide.
The role of the metal center in biomolecules q Metal ions can have structural roles, catalytic roles, or both. q Metals that have catalytic roles will be present at the active site of the biomolecule which will likely be a metalloprotein (a metalloenzyme). q The reactivity of a metalloprotein is defined by the nature of the metal, particularly its electronic structure and oxidation state. q This, in turn, is determined by its coordination environment (ligand donor atoms) and molecular geometry, which is provided by the architecture of the protein surrounding the metal.
The importance of the electronic structure of the metal center q The electronic structure and spin state of a metal center defines its chemical reactivity as a redox center (i. e. it controls its efficiency at accepting or donating electrons) q The electronic structure of a metal center defines its chemical reactivity as a Lewis acid (electron-pair acceptor) which enables it to bind ligands (O 2, N 2, CO. . ) for transport, activation and reaction. q The electronic structure and spin state of a metal center permits investigation and characterization through electronic, Mossbauer and epr spectroscopy and through magnetic measurements.
Introduction • Occurrence, availability and biological roles of inorganic elements. Fundamentals of metal ion coordination chemistry. • Metal-ligand interactions, stability of metal complexes, chelation. Review of protein structure and metal ion binding in biomolecules. Ligand field theory • Magnetic and spectral properties of transition metal ions. Thermodynamic stability, redox potentials and Latimer diagrams. Molecular orbital theory • Diatomic oxygen species. Metal-ligand s and Π-interactions. Π-unsaturated ligands, organometallic structures, 18 -electron rule Biological transport and storage of metals • Iron transport by transferrin and storage in ferritin. Bacterial iron transport in siderophores. Zn and Cu transport in metallothionein and metallochaperones. .
Dioxygen Transport: O 2 carriers • Hemoglobin, hemerythrin and hemocyanin. Cooperativity in O 2 binding, O 2 and CO discrimination. Inorganic model compounds. Oxygen Metabolism: Dioxygen Activation • Oxygen atom transfer by cytochromes-P 450, tyrosinase. Dioxygen Reactivity and Toxicity • Toxicity of reduced oxygen species. Oxidative stress from ROS and detoxification enzymes. Electron transfer in Biology • Metal cofactors. Iron cytochromes and iron sulfur proteins. Marcus theory. Electron transfer in proteins. Redox Cofactors • Cobalamins, nitrogenases, hydrogenases.
Metals in Medicine • Cisplatin and 2 nd generation Pt anticancer drugs. • Metal toxicity and metal-related disease. Chelation therapy. Nitric Oxide Biochemistry • Physiological roles of NO in control of blood pressure, neuronal signaling and cytotoxicity. Nitric oxide synthase enzymes (NOS). Cobalamins • B 12 - coenzme dependant rearrangements. Hydrolytic Enzymes • Metal-dependant Zn hydrolase enzymes. Carbonic anhydrase, carboxypeptidase. , alcohol dehydrogenase. Aconitase, urease. Biological roles and Transport of Na+, K+, Ca 2+. • Na, K, Ca as biological messengers: membrane transport mechanisms. Ion channels
Occurrence, roles and classification of metallobiomolecules
Biologically Important Elements Which “inorganic” elements are important biologically? 99% of human body is comprised of 11 elements Bulk biological elements: H, C, N, O, P, S, Cl (as PO 43 -, SO 42 -, Cl-) Bulk metal ion nutrients: Na, Mg, K, Ca Essential elements for a wide range of bacteria/plants/animals Transition metals: V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Mo Non-Metals: (B), F, (Si), Se I, F.
Periodic Distribution of Biologically Important Elements
Evolution of biological roles for essential metals Why have certain elements been "selected" for use in biological systems? a. their abundance (availability in the earth’s crust or oceans) b. their basic fitness (intrinsic chemical suitability) c. evolutionary adaption to realize critically required specificity.
• Lighter elements are more abundant in general and therefore utilized more. 3 d metals, rather than 4 d, are used as catalytic centers in metalloenzymes. • Why has Mo (4 d) rather than Cr (3 d) been utilized more biologically? Although Mo is rare in the earth’s crust, Mo is the most abundant transition metal in sea water as Mo. O 4 has fairly high solubility in water. Better correlation exists between the abundance of elements in in human body and in sea water than between the human body and the earth's crust. Taken as evidence for the oceans as the site of evolution of life. • Despite the high abundance of Si, Al and Ti (the 2 nd, 3 rd and 10 th most abundant elements on earth). Why are they are not utilized biologically? • Because of the insolubility of their naturally occurring oxides (Si. O 2, Al 2 O 3, Ti. O 2) under physiological conditions. A lower oxidation state is unavailable for Si and Al and unstable for Ti in an aerobic environment and is readily oxidized to Ti(IV) at p. H 7. •
• Why has iron been used so widely in biology although Fe 3+, its most stable oxidation state, is highly insoluble at p. H 7 Complex biological mechanisms have been developed to accommodate the low solubility of Fe(OH)3 (Ksp = 1 x 10 38) ~ p. H 7, and take advantage of its high "availability". • Co 2+ and Zn 2+ have very similar coordination chemistry and ionic size and can be interchanged in many Zn enzymes without loss of activity. Why is Co not utilized more biologically? Zn is much more abundant and therefore has been utilized more. • Why has cobalt been given an essential role in cobalamins despite its very low availability? • The unique properties of cobalt (e. g. its oxidation states, redox potentials and coordination chemistry) is needed to achieve essential functions of B 12 coenzymes.
Indicators of Biologically Important Elements • Relative abundance of inorganic elements in earth's crust and in seawater. • Availability of elements from earth’s crust and sea water • Elemental composition of human body • Essential inorganic elements in food • Inorganic elements linked to deficiency symptoms
Elemental Composition of Human Body (70 kg adult) Element mass % _________________________________________________ Oxygen O 45. 5 kg 65. 0 Carbon C 12. 6 18. 0 Hydrogen H 7. 0 10. 0 Nitrogen N 2. 1 3. 0 Calcium Ca 1. 1 1. 5 Phosphorus P 0. 700 1. 0 Sulfur S 0. 175 0. 25 Potassium K 0. 140 0. 20 Chlorine Cl 0. 105 0. 15 Sodium Na 0. 105 0. 15 Magnesium Mg 35 g 0. 020 Iron Fe 4. 2 0. 0060 Zinc Zn 2. 3 0. 0033 Silicon Si 1. 4 0. 0020 Rubidium Rb 1. 1 0. 0016 Fluorine F 0. 8 0. 0011 Zirconium Zr 0. 3 4. 3 x 10 -4 Bromine Br 0. 2 2. 9 x 10 -4 Strontium Sr 0. 14 2. 0 x 10 -4 Copper Cu 0. 11 1. 6 x 10 -4 Aluminum Al 0. 10 1. 4 x 10 -4 Lead Pb 0. 080 1. 1 x 10 -4 Cadmium Cd 0. 030 Iodine I 0. 030 Manganese Mn 0. 02 Vanadium V 0. 02 Selenium Se 0. 02 Barium Ba 0. 02 Arsenic As 0. 01 Nickel Ni 0. 01 Chromium Cr 0. 005 Cobalt Co 0. 003 Molybdenum Mo < 0. 00 __________________________________________________
q Mammals are believed to use only 25 of the known elements. q Eleven non-transition elements that make up 99. 9% of the human body (O, C, H, N, Ca, P, S, K, Cl, Na, Mg), q Three transition metals, Fe, Zn and Cu are needed in significant amounts. q “Trace quantities” of many other transition elements are required to maintain proper physical functioning. q Other elements in the human body (e. g. Rb, Zr, Sr, Al, Pb, Ba) are not essential but incorporated inadvertently because they share chemical and physical properties with essential elements. q Other elements are added to the list of elements thought to be essential as our knowledge of the chemistry of living systems increases.
Essential Inorganic Elements in Adult Diet ______________________________ Recommended Daily Allowance (mg) ______________________________ K Na Ca Mg Zn Fe Mn Cu Mo Cr Co Cl PO 43 SO 42 I Se F 2000 - 5500 1100 - 3300 800 - 1200 300 - 400 15 10 - 20 2. 0 - 5. 0 1. 5 - 3. 0 0. 075 - 0. 25 0. 05 - 0. 2 ~ 0. 2 3200 800 - 1200 10 0. 15 0. 05 - 0. 07 1. 5 - 4. 0 _______________________________
Symptoms of Elemental Deficiency in Humans _____________________________ Ca Retarded skeletal growth Mg Muscle cramps Fe Anemia, immune disorders Zn Stunted growth, skin damage, retarded maturation Cu Liver disorders, secondary anemia Mn Infertility, impaired skeletal growth Mo Retarded cellular growth Co Pernicious anemia Ni Depressed growth, dermatitis Cr Diabetes symptoms Si Skeletal growth disorders F Dental disorders I Thyroid disorders Se Cardiac muscular weakness As Impaired growth (in animals) ____________________________
Biological Roles of Metallic Elements. Structural Skeletal roles via biomineralization Ca 2+, Mg 2+, P, O, C, Si, S, F as anions, e. g. PO 43 , CO 32. Charge neutralization. Mg 2+, Ca 2+ to offset charge on DNA - phosphate anions Charge carriers: Na+, K+, Ca 2+ Transmembrane concentration gradients ("ion-pumps and channels") Trigger mechanisms in muscle contraction (Ca). Electrical impulses in nerves (Na, K) Heart rhythm (K). Hydrolytic Catalysts: Zn 2+ , Mg 2+ Lewis acid/Lewis base Catalytic roles. Small labile metals. Redox Catalysts: Fe(II)/Fe(IV), Cu(I)/Cu(II), Mn(II)/Mn(III)/(Mn(IV), Mo(IV)/Mo(VI), Co(I)/Co(III) Transition metals with multiple oxidation states facilitate electron transfer - energy transfer. Biological ligands can stabilize metals in unusual oxidation states and fine tune redox potentials. Activators of small molecules. Transport and storage of O 2 (Fe, Cu) Fixation of nitrogen (Mo, Fe, V) Reduction of CO 2 (Ni, Fe) Organometallic Transformations. Cobalamins, B 12 coenzymes (Co), Aconitase (Fe-S)
Transition Metals in Biomolecules Iron. Most abundant metal in biology, used by all plants and animals including bacteria. Some roles duplicated by other metals, while others are unique to Fe. Iron use has survived the evolution of the O 2 atmosphere on earth and the instability of Fe(II) with respect to oxidation to Fe(III). Zinc. Relatively abundant metal. Major concentration in metallothionein (which also serves as a reservoir for other metals, e. g. Cd, Cu, Hg). Many well characterized Zn proteins, including redox proteins, hydrolases and nucleic acid binding proteins. Copper Often participatse together with Fe in proteins or has equivalent redox roles in same biological reactions. Reversible O 2 binding, O 2 activation, electron transfer, O 2 - dismutation (SOD). Cobalt. Unique biological role in cobalamin (B 12 -coenzymes) isomerization reactions. Manganese Critical role in photosynthetic reaction centers, and SOD enzymes. Molybdenum Central role in nitrogenase enzymes catalyzing N 2 NH 3, NO 3 NH 3 Chromium, Vanadium and Nickel Small quantities, uncertain biological roles. Sugar metabolism (Cr); Ni only in plants and bacteria (role in CH 4 production) and SOD enzymes.
Biochemical Classification of Metallobiomolecules Transport and storage proteins : O 2 binding/transport: Transferrin (Fe) Ferritin (Fe) Metallothionein (Zn) Myoglobin (Fe) Hemerythrin (Fe) Hemocyanin (Cu) Enzymes (catalysts) Hydrolases: Oxido-Reductases: Isomerases: Carbonic anhydrase (Zn) Carboxypeptidase (Zn) Alcohol dehydrogenase (Zn) Superoxide dismutase (Cu, Zn, Mn, Ni) Catalase, Peroxidase (Fe) Nitrogenase (Fe, Mo) Cytochrome oxidase (Fe, Cu) Hydrogenase (Fe, Ni) B 12 coenzymes (Co) Aconitase (Fe-S) Oxygenases: Cytochrome P 450 (Fe) Nitric Oxide Synthases (Fe) Electron carriers: Electron transferases Cytochromes (Fe) Iron-sulfur (Fe) Blue copper proteins (Cu) Non Proteins Transport Agents: Siderophores (Fe)
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