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by: Mr. Bria Rosenbaum

InorganicChemistry CHEM332

Mr. Bria Rosenbaum
GPA 3.67


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This 281 page Class Notes was uploaded by Mr. Bria Rosenbaum on Sunday October 11, 2015. The Class Notes belongs to CHEM332 at Eastern Michigan University taught by Staff in Fall. Since its upload, it has received 13 views. For similar materials see /class/221485/chem332-eastern-michigan-university in Chemistry at Eastern Michigan University.


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Date Created: 10/11/15
Bioinorganic Chemistry Essential Metals Deficiencies and Toxicity CHEM332 3 Bioinorganic Chemistry Metals although they constitute a fraction of the mass of living organisms they play key roles in practically all the biological processes that keep living cells alive DNA replication essential for cell reproduction needs the element calcium Iron is needed to transport oxygen thought the human body Nickel although its exact chemical role is not well understood is essential to all CHEM332 w vertebrates Metal Containing Biomolecules Hm 39 50 A Urease Biological Active Metals Bioinorganic periodic table Major essential element Essential trace element Drugs or probes Essential for some species possibly for humans Radioactive element Bioinorganic Chemistry Key Concept Occurrence of metals in biological systems is widespread The roles of the metals in biomolecules fall into two classes 0 Active where they are right at the active center of the biomolecule and they are involved directly on the chemical processes 0 Passive where the metal plays a structural role and they affect the conformation of the biomolecule but the metal is not directly involved in the chemical processes a if innin ntii w Bioinorganic Chemistry Key Concept Metal centers include 0 Atomic ions in aqueous solution 0 Coordination complexes metal ligand 0 Organometallic compounds metal carbon bonds 0 Metallic Clusters metal metal bonds Bioinorganic Chemistry Key concept Chemical activity depends on 0 Possible ionic states of the metals 0 Equilibria between metals and their ligands which depend on thermodynamic factors 0 Kinetics of the metal ligand systems 0 Electron transfer processes lead to oxidation reduction processes Essential Elements Key Concept There are essential elements needed in living organisms in different amounts these amounts can be classified into the following groups 0 Bulk 0 Macro 0 Trace and 0 Ultra trace amounts Essential Elements 0 Bulk Covalent H C N O P S 0 Atomic Ions Ht 0239 5392 0 Molecular Ions 02 022 Note there are no metals at the bulk level Essential Elements 0 Macro Atomic Ions Na K Mgz Ca2 Cl 0 Molecular Ions P0433 8042 Note there are metals and non metals at the macro level Essential Elements 0 Trace 0 Covalent Fe Zn Cu 0 Atomic ions Zn2 o Multivalent atomic ions 0 Pet Fe3 Fe4 CuCu2Cu3 Note there are only metals at the trace level Essential Elements 0 Ultra trace 0 Covalent non metals F 1 Se Si 0 Covalent metals Mn Mo Co Cr V Ni Sn 0 Non metal Atomic ions F39 Iquot Sez39 Si4 0 Metallic Monovalent ions Cd2 Pb Lit Note the multivalent atomic ions MnII 111 IV MoIVVVI 001111 CrIIIVI VIIIIV Ni1 11 111 SnIIIV Essential Elements Essential Elements criteria Physiological negative effects appear when these elements are removed completely from the diet 0 Symptoms disappear when the element is re introduced into the diet in the proper dose Specific biological activity is known to depend on the specific element Their relative amounts usually correlate to the normal availability of these elements in the food and water DoseResponse Curve 0 Every essential element has a dose response curve 0 At doses lower than normal the health of the organisms is impaired 0 At higher doses than normal toxicity is observed and deleterious health effects are evident 0 Daily doses range from a few micrograms to a few grams depending on the specific element Essentiality IA L I r DefICIency Excess Healthww I 5quot Zone x i of a Health I I I E Zone E I Of I Disease 5 Conflict 5 I l I I II II I I I I Zone I i I 0f Decreasing 39 39 39 Health Death 39 Intake e I I Severe Possible I Healthy Possible Severe Deficiency Deficiencyi State EExcess Toxicity Health Disease 5quot Death Examples of Metal Functions Metals in living organisms have many functions such as 0 Charge Carriers Metals are involved in charge maintenance osmotic balance 81 nerve impulses 0 Structural Elements Metals influence protein structure they can act as protein activity triggers 0 Electron Transfer Metals are central to the enzymatic processes like in nitrogen fixation 0 Dioxygen Transfer Metals bind and carry molecular oxygen like in hemocyanin myoglobin Metal Functions Groups amp II Group I and Group II metals usually operate 0 in the maintenance of osmotic balance 0 in the electric potential across cell membrane maintenance of s 0 as structural elements in the conformation and folding of protein chains Transition Metal Functions Oxidation States Transition metals exhibiting a single stable oxidation state 0 can act as triggers for changes in protein conformation and biological activity where the metals act as structural elements in the stabilization and folding of protein chains Transition Metal Functions Oxidation States Transition metals exhibiting multiple stable oxidation states multivalent can function as 0 electron carriers 0 facilitators of oxygen transfer 0 catalytic centers in enzyme activity Metal Functions In general the possible functions of metals depend on 0 their location distribution and ease of transport within the living organism affinity for protein binding Metals usually bind to the lone pairs in N O or S atoms present within proteins 0 the number of possible stable stabilized oxidation states the metal can exhibit Essential Metals 0 Main Group Metals 0 Macro Na K Mg and Ca 0 Transition Metals 0 Trace Fe Cu Zn 0 Ultra trace V Cr Mn Co Ni Zn Mo Sn Pb and Cd where the metals in red are the multivalent elements N Deficiencies and Toxicity of Metals Iron in the Body 0 65 to 70 of all the iron in the human body is found in 6 chain 39g39 a chain hemoglobin pawsstzazpsazme IITFZN pH 77 0 Iron is transported inside the body by the protein transferrin 0 Iron is stored in the body by the protein ferritin Iron Deficiency Absence of iron in a diet causes a 0 decrease in the hemoglobin count in blood decrease in the number of red blood cells a condition knows as anemia 0 Which results in a decrease in the oxygen delivery to tissues resulting in the poor oxygenation of tissues Iron Toxicity Iron toxicity can be caused by 0 Ingestion of excessive amount of iron pill supplements 0 Cooking and storing acidic foods in iron containers Treatment 0 Removal of iron by chelating compounds such as the siderophore desferrioxamine a naturally occurring polypeptide with a great specific affinity to ironlll Zinc in the Body 0 The average human adult has about 2 g of zinc 0 15 mg to 20 mg daily intake are needed 0 The understanding of the roles of zinc in the human body are not able to explain all the observed effects associated with zinc deficiency 0 Most of the zinc in the skin and bones Zinc Defficienacy 0 It is not a very common event 0 An unbalanced diet can lead to Zn deficiency 0 Certain foods can prevent zinc absorption 0 It can lead to growth retardation testicular atrophy skin lesions loss of appetite and loss of body hair 0 It affects the enzyme activities of 0 alkaline phosphatase removes phosphate groups caI39b OXYP eptidase cleaves peptide bonds on the C end of proteins kinase involved in DNA synthesis Zinc Toxicity Zinc toxicity is rare Zinc toxicity results in deficiencies of other essential metals such as 0 Calcium 0 Iron 0 Copper A CIDIOer in the Boy Copper is found in 0 the liver 0 the heart and 0 the brain Copper is stored in the liver as copper thionein a cysteine thiolrich 30 protein Copper is released from the liver for transport as 0 ceruloplasmin the major copper carrying protein or 0 a serum albumin complex Copper Deficiency It can occur because of lack of it in the diet or because of a diet that prevents copper from being absorbed It can lead to 0 brain disease in infants 0 anemia since copper is needed in the productions of red blood cells 0 heart disease Copper Toxicity 0 It leads to 0 Liver disease 0 Neurological damage 0 Green or brown rings around the cornea Wilson s disease is a genetic metabolic syndrome where people with this genetic defect cannot tolerate the normal amount of copper in the body and exhibit copper toxicity symptoms Copper Toxicity Chelate Treatment of patients with chelating agents such as CaNa2EDTA can effectively reduce the amount of copper However it also reduces the amounts of other metals which are also chelated as EDTA enter into the human body EDTA chelated metals are readily processed by the liver and eliminated through the kidneys Patients undergoing EDTA treatment for copper are given doses of the other metals to compensate for their loss from the Chelate Treatment Bioinorganic Chemistry Essential Metals Deficiencies and Toxicity i CHEM332 Bioinorganic Chemistry Electronic Structure and the JahnTeller Effect CHEM332 Octahedral Fell d6 A I Weak Field Strong Field LL Elctronic Structure if 7 Electronic Structure The ligand field determines the magnetic properties of Fe2 complexes A strong eld results in a low spin complex and a diamagnetic substance quotquotquotquotquotquotquotquotquotquotquotquotquotquotquotquotquotquotquotquotquotquot barycenter tt p Fe3920e2 FeCN6439 EID electron pairing energy A weak eld results in a high spin complex and a paramagnetic that interacts strongly with a magnetic field Electronic Structure Ligand Field Stabilization Energy LFSE represents the net stability gained through the d orbital splitting by the speci c ligand eld geometry as compared to the d orbitals preserving the degeneracy in an equivalent eld with a spherical geometry Electronic Structure Ligand Field Stabilization Energy Orbital splitting takes place because of the speci c geometry of the incoming ligands towards the central metal Further orbital splitting can happen through distortion Jahn Teller effect In either case the energy of the system metal plus ligands decreases to give a less energetic more stable metal complex A Quantifying the Stabilization Energy Ligand Field Stabilization Energy octctll mdnil th Cmtstml eld splitting Key concept E 3 J52 ulxz1 The center of gravity or barycenter is preserved upon orbital splitting Quantifying the Stabilization Energy tetrahedral de crysml eld splitting l WC Cri stt l eld SP it l lg Relative energy Changes upon splitting into the different geometries Quantifying the Stabilization Energy Ligand Field Stabilization Energy LFSE for an octahedral geometry can be calculated using the following equation LFSE 25e in tzg th 35e39 in eg th 06w quot The JahnTeller Effect IahnTeller Distortions The JahnTeller effect involves the distortion of an octahedral geometry by the relative elongation or compression of two trans ligands along the zaxis of the molecule This type of distortions result in the further splitting of the d orbitals and it is observed only when it results in a lower energy state and a further stabilization of the metal complex The JahnTeller Effect IahnTeller Distortions There is a way of predicting whether the distortion is possible or not based on the further splitting of the d orbitals Key Concept When the JahnTeller effect can be predicted the metal complex might or might not show the actual distortion The JahnTeller Effect ngyzfnh H quot39 52 23 2 2 2 2 u i t Xjf z uu 1031 22 T X2F2 i NBC 1 KY 36 r IahnTeller 1 93 W l uquot Xy XE Y an o c quotan Distortions X3 5 3 g5 axial elongation Oh axial compression L L Lfbfhli 1 ng L2 I EI M i Liquot L L L Light LI 1 r Ligand Field Theoy IahnTeller Distortion 1339 t29 1 ya x y H z elongation z compression 2 short 4 long 2 long 4 short Ligand Field Theory IahnTeller Distortion Min 1 1quot 1f 1 S i 3zh H m 4 3 For the following octahedral complexes predict whether the Jahn Teller distortion could be expected Questionl F9L63 A Yes B No Questionz CrL6 A Yes B No 3 W j q Jr s Liand Field Theoy f Iahn Teller Effect eg and tzg barycenters are preserved 9 g NiH2062 no JT distortion oI quotquotquot w quotoakq aoo JahnTeller Distortion All six NiO bonds equal at 205 A 39 i CuO bonds 2A5A two long axial 39 7 four short inplane 39 l CuO bonds CuiH20612 23900 A JT distortion lengthens axial CuO s W Bioinorganic Chemistry Electronic Structure and the JahnTeller Effect L CHEM332 four short inplane CuO bonds 200 A Long axial CuO bonds 245 A LCuH2062 I quot The Jahn Teller J T theorem states that in molecules ions that have a degenerate ground state the molecule ion will distort to remove the degeneracy This is a fancy way of saying that when orbitals in the same level are occupied by different numbers of electrons this will lead to distortion of the molecule For us what is important is that if the two orbitals of the 6 level have different numbers of electrons this will lead to J T distortion Cull with its d9 configuration is degenerate and has J T distortion Highspin Ni only one way of filling the eg level Cu two ways of filling eg level it is not degenerate no JT degenerate and has JT distortion distortion d9 energy 1 1 d8 ii 1 LE e 6g 6g g gilt 11111 11111 Ni 2g tZg tZg N The CF View of the splitting of the d orbitals is that those aligned with the two more distant donor atoms along the z coordinate experience less repulsion and so drop in energy d d and dzz while those Closer to the in plane xz yz t donor atoms l i grg zli iiii w H 1 of the splitting is that energy eg the dx2y2 in l 1 d particular overlaps 2 more strongly with the dxy ligand donor orbitals 12g i 1 1 and so is raised in energy Note that all Cua I in regular octa 1 1 d d d orbitals with a Z in hed ral environment x W the SUbSCFiPt drop in Cu after JT distortion energy v r L 2711 13 distortio magma water long axial Cu O bonds of 260 A Shon inplane CuN bonds of 203 A ethylenediamine CCDAZAREY long axial CuN bonds of 270 A Sho inplane Cu N bonds of 207 A CCDITEDZEI 94 If1vin39 quotquot 39 r l rrr kij a 16 L J log K1 en as a function of no of d electrons extra stabiliz Cum ation due 12 l to JT distortion 10 double CFSE E 8 7 humped 3 curve a 2 2 4 7 l a rising baseline 2 Ca MN dueto ionic 1quot a 39 contraction 0 i i i i 0 1 2 3 4 5 6 7 8 9 10 no of delectrons d4 highspin d7 lowspin d8 lowspin d9 Cr Co Co Ni Pd Cu Mnll Ni RhPtlAul Agl Square planar complexes JahnTeller distortion leads to tetragonal distortion of the octahedron with the extreme of tetragonal distortion being the complete loss of axial ligands and formation of a squareplanar complex Tetragonal distortion is the stretching of the axial ML bonds and shortening of the inplane bonds Cull is usually tetragonally distorted while lowspin Nil is usually square planar long ax39a39 Axial ligands L M L bonds L Removed entirely all ML L I L L l L LN L bondsthe M39 gt M39 gt M same LL L L L L length L L regular octahedron tetragonal square plane distortion All highspin d8 metal ions are octahedral or tetrahedral but the lowspin d8 metal ions are all square planar Important examples dxzyz of squareplanar lowspin d8 metal energy e t t Ions are NiI Pd g Pt Au Co Rh and r At dzz left is seen the H d splitting of the H 1 xy d subshell in Ni tzg lowspin square 1 planar complexes Highspin Ni in dxz regular octahedral environment LOW39Sp39n N39 squareplanar after JT distortion in d8 metal ions Rare Oxidn states 4 DCDZ CDZDI39HFUOZ Obviously the group 9 WI ions the group 10 W ions and the group 11 Will ions are d8 metal ions d8 metal ions must be lowspin to become square planar Since A increases down groups in the periodic table it is larger for the heavier members of each group Thus all Pt complexes are lowspin and squareplanar while for Ni most are highspin octahedral except for ligands high in the spectrochemical series so that NiCN4239 is square planar Because of increasing A down groups most Nill complexes are high spin octahedral whereas Virtually all Ptll complexes are lowspin square planar For Pdll the only high spin complex is PdF6439 and Psz which has Pd in an octahedron of bridging F groups while all others are low spin square planar Some examples are 2 2 2 NCNNVCN Clx Cl I F CIN Cl I Pd r NC CN CI CI F39Pt F CI39AU CI Ni Pd Pt Au CO 2 m 2 Phst Ix co N N CI39Rh PPh Rh Pd L Pd 1 N N H2 H2 Rh Rh Pd Pdl energy 1 l lowspin d8 ion eg Nill Pdll The filled d22 orbital occupies two coordination sites in the VSEPR view and so the four donor atoms occupy the plane 2 NC CN NiCN4239 The structure of NiCN4239 can be compared to that of square planar IF439 where from VSEPR two lone pairs occupy the axial sites if 7 V View of d8 square planar a v air 7 quot Ttrahedral complexes Tetrahedral complexes are favored with metal ions that have a low CFSE which is particularly true for d10 Znll which has CFSE zero Ligands that are very low in the spectrochemical series also tend to produce tetrahedral complexes such as Cl Brquot and 139 Thus Nill that has high CFSE 12 A is very reluctant to form tetrahedral complexes but it forms tetrahedral complexes such as NiCl4239 and Nil 4 239 If we look at the spectrochemical series in relation to the geometry of complexes of Nill we have I39 lt Br39 lt Cl39 lt F39lt H20 lt NH3 lt CN39 tetrahedral octahedral square planar low CFSE high CFSE Splitting of the dorbitals in tetrahedral WLEA G s in tetrahedral coordination do not overlap well with the metal dorbitals so that Atet is much smaller than Acct in octahedral complexes with the same ligands eg CoNH342 versus CoNH362 Calculation suggests Atet z 49 Acct in that situation Note the lack of a g in the subscripts t2 e because Td complexes do not have a center of symmetry energy l tetrahedral complex ion in the gasphase octahedral complex Bioinorganic Chemistry Protein Function and Metallic Cofactors CHEM332 Protein Function 1 d There are many different ways to Classify the roles that proteins play in living organisms nucleic proteins amds enzymes regulator transport 31131111818 5T1quot mural catalysis proteins storage proteins pores proteins E e eollaoen small molecules e g Perm g silk b substratesi metal ions 39 39 ewstallin coiactors electrons 39 Protein Disco very The rate of discovery of new proteins far outweighs our ability to characterize them functionally Functional discovery of new proteins has implications 1n Drug discovery and design Biomarker identi cation Understanding of biological processes Identi cation of disease states and treatment reg1mes Many others it Metaboiisyh 3 Signal transgigtlon Examples for glqracenmar many protems roles within my Euk t39 a 0 1C 11 FY lt Vacuole CE S quotmgrquot Pifgt i 39 39 destination and s39tqrage Physiology Cell Biology Migratory Sensors Ventricular c Modeling Heart mm Electron c gt Microscopy Proteomics Genomics Medicinal Chemistry Structure 8 Sequence Kmay Crystallography Protease Protein Inhibitor Docking Protein Research Genome rapid increase in sequenced genomes pr0V1des new raw materlal Proteome large increase in the number of 3D structures highlights new functions Interactome identi cation of a binding partner points to a new function Metabolome isolation of a protein within a metabolic pathway Cell localization points to function Organ gene expression in heart tissue points to function Organism different physiology observed in species can be related to protein functions Biomolecules 1 nnn JUI39II39 a myoglobin b hemoglobin c lysozyme d transfer RNA e antibodies f viruses 9 actin h the nucleosome DNAJproteins i myosin j ribosome RNAderoteins I d nuc BIC acn S Protein FUthth Enzymes SUBSTRATE REACTION TYPE 1 Enzymes given ase suffix 2 Substrate rst then reaction type Example f 7 Product is an aldehyde Substrate is alcohol Reactian removes hydrogen atoms Protein Functiona i 1 Oxidoreductases oxidationreduction reactions of all types acting on C H OH ga oup of substrates requires NAD or NADP 1 as hydrogen acceptor speci c substrate is ethyl alcohol Transfer group to substrate ICHZOH HO C H A HO C H ADP CHZOH H2 Glycerol Glycerol phosphate Cleave bonds with H20 CHZOH HO C H CH20H H20 gt Glycerol phosphate Glycerol split C X without water reverse forms I bond without a need for energy IZIQOPOS CO Hog H Dillydroxyacetone phosphate 6550 H OH HZoPO3 Glyceraldehydes phosphate Fructose 16 bisphosphate Higg i1lil i1l f JE39IL change groups around 00M FDOH d H E w 7 7 CH 20H 3phosp hoglyce rate 2phosphoglyceurate glucose 6phoslpha1ce ru ctose 6Phosphate N Metalloenzymes Metalloenzymes 0 Metalloenzymes contain a metal ion directly bound to the protein structure The metal center in addition to the protein bond has a readily available coordination site 0 The cavity where the metals is found within the protein is crucial to the activity of the enzyme as it brings the substrate in the correct orientation and electronic state to undergo the specific chemical transformation etalloenzymes 0 Small changes in structure can lead to inactivation of the enzyme 0 The metal inside the cavity is capable of performing chemical changes while the free ion is not capable of doing on its own 0 The protein cavity plays an important role in the activation and orientation of the substrate 11 i lVIetalloenzymes Examples 0 carbonic anhydrase contain Zn co2 H20 HZCO3 0 nitrogenase contain Mo Fe S N2 16 MgATP 86 9 2NH3 16 MgADP 16 Pi H2 0 superoxide dismutase contain Cu or Ni 34 Oxidation Mm 02 gt Mn 02 Reduction 1V1n 02 2H gt Mm HZO2 Overall 2 O 2 H gt 02 H202 biology dismutation chemistry disproportionatio n N Enzyme Cofactors Enzyme Cofactors Cofactors can be Coenzymes are not tightly bound cofactors Prosthetic Groups are tightly bound cofactors Cofactors can be Organicz Vitamin E 1norganic metallic such as Cu2 or FeS clusters Some enzymes require more than one cofactors Cofactors turn on and off the activity of the enzyme Cofactors are used to regulate enzyme activity C H3 H0 I V CH5 HC39 0 CH3 H5 Q HQ Vitamin E uTocuphernl Vitamin D Calciferul I D I Vltal I Ith39 Dr anlc Cofactors g HO H 3 o gt57CH20H CHIC D71 H3C l l NKO H0 OH Kit CH3 H Vitamin 85 CH2 Vitamin C Vitamin 33 Vitamin Ba Pantothenate H OH Ascorbic acid Niacin Pyridoxine H OH H OH CHZOH Vitamin B Riboflavin Cobalamin BlZ B12 is converted into two coenzymes in the body 539 deoxyadenosylcobalamin methylcobalamin B12 Catalyzes three reaction types Intramolecular rearrangements Reductions of ribonucleotides to deoxyribonucleotides Methyl group transfers assisted by tetrahydrofolate Cobalamin BlZ 0 B12 X ray structure was determined in 1961 by Dorothy Hodgkin at the time it was the most complicated structure ever elucidated by X ray diffraction and she won a Nobel prize in 1964 o Cobalamin is needed in the maturation of red blood cells and is used in carbohydrate metabolism and DNA synthesis B12 is only found in animal products and is not made by plants Vjtamin smaremprecu rso rs of cofa AWM CtO rs I Vitamin Coenzyme Typical reaction type Consequences of deficiency Thiamine B1 Thiamine pyrophosphate Aldehyde transfer Beriberi weight loss heart problems neurological dysfunction Ribo avin B2 Flavin adenine Oxidationereduction Cheliosis and angular dinucleotide FAD stomatitus lesions of the mouth dermatitis Pyridoxine B0 Pyridoxal phosphate Group transfer to or from Depression confusion Nicotinic acid niacin Pantothenic acid Biotin Folic acid B12 C ascorbic acid Nicotinamide adenine dinucleotide NAD Coenzyme A Biotinelysine complexes biocytin Tetrahydrofolate S Deoxyadenosyl cobalamin amino ac1 s Oxidation reduction Acylgroup transfer ATPdependent carboxylation and carboxyl group transfer Transfer of one carbon components thymine synthesis Transfer of methyl groups intramolecular rearrangements Antioxidant convulsxons Pellagra dermatitis depression diarrhea Hypertension Rash about the eyebrows muscle pain fatigue rare Anemia neuraltube defects in development Anemia pernicious anemia methylmalonic acidosis Scurvy swollen and bleeding gums subdermal hemorrhages Cofactors Other cofactors 0 One electron transfers FAD NAD 0 Two electron transfers NAD Liponamid FAD FMN Cofactors Amino acid oxidase FAD Overall reaction o H N H 3 CH3 CH3 H2O 012 l NH4 H202 055 0 D O Tasks Proton abstraction or hydride at C 1 and oxidation at C 1 24 Cofactors K 1 D Amino acid oxidase FAD The proton from the substrate ends up on N 1 of FAD but only after 143 OH reduction of the aVin because the H C NK m 0 oxidized aVin is no base a The electrons are transferred Via a HgNggOH covalent intermediate to C 4a K H H3C 1 NYC H3CEL NH H3C7FCOOH FlaVinH2 oxidized pKa ltlt 0 FlaVinH2 reduced pKa 63 N H x 9 H 2 93 25 Metal Cofactors Transition row metal ions are often involved in redox reactions Mn Fe Co Ni Cu There are mononuclear sites Clusters with and without small ligands SZ 02 and cations as part of larger cofactors tetrapyrrols MoCo Metal Cofactors o Single metal sites I o mostly structural sites Ca2 Zn2 0 metal active sites Cu2 0 Metal Clusters 0 FeS Fe4S Fe 0 FeMoCo 0 Mn 4 an Cuz mixed metal Clusters 0 Organometallic cofactors 0 Porphyrins 4 o Cobalamin Single Metal Site Structural Zn2 Alcohol dehydrogenase Overall reaction RlRZCHOH NAD gt RlRZCO NADHH Single Metal Site Alcohol dehydrogenase H N o H 002 2 2 o The an39 mcreases the 9312900 acidity of the alcohol caN R 39 63b1 but is not involved in the 6 redox reaction H401 Q HzN o H QEDA 2 H H 26 3 quot RKOQ zn G O N G N H Single Metal Site Alcohol hose dehydrogenase Path of the HN NO 89 p alcohol abstracted proton 3 H00 HCC z The His is in contact serine Zn2 to the bulk solvent ribose Burst k1net1cs ShOW a J pKa Of 39gt H A H90 His N N Eb gt 34 0H t serine Zn2 4 239 Single Metal Site Alcohol dehydrogenase H N o H 002 2 2 o The an39 mcreases the 9312900 acidity of the alcohol caN R 39 63b1 but is not involved in the 6 redox reaction H401 Q HzN o H QEDA 2 H H 26 3 quot RKOQ zn G O N G N H Single Metal Site Alcohol hose dehydrogenase Path of the HN NO 89 p alcohol abstracted proton 3 H00 HCC z The His is in contact serine Zn2 to the bulk solvent ribose Burst k1net1cs ShOW a J pKa Of 39gt H A H90 His N N Eb gt 34 0H t serine Zn2 4 239 Metal cofactors ingle metal sites 0 mostly structural sites Ca2 Zn2 0 exceptions Cu2 I 0 Metal clusters I 0 FeS Fe4S4 Fe 0 FeMoCo 0 Mn 4 an Cuz mixed metal clusters 0 Organometallic cofactors 0 Porphyrins 0 Cobalamin Superoxide dismutase SOD Overall reaction 2 0239 2 H gt 02 H202 1k ZnCu SOD Crystallographic structure of the tetrameric extracellular human SOD3 enzyme complexed with copperorange and zinc gray cations 35 Superoxide dismutase G EZu2 NN 2112 Cu square planar I I e Hquot pale blue C NquotN L Cu trigonal pyramidal U 397 zri colorless 36 Cu2OON N9 eri A H B 2395 275 H H O H T I H M H N Nv H 16 023 05 Hymn Ona H H H H 227 l OZFLHH Ava vngr Argus I 31H e ox1dlzed H H Vo square planar f 1 V htquot HESS gtW Hio39 r4202 0 Hgo C H H 225 33 H H Ho H l H m HN NH Pa 0 C ON I H H A a H H 27 o A w om H 9 4 0774 399 H n 226 A D NH V1653 4 CU 23912 reduced 05 tetrahedral Hzobzs 38 Metal Chelation by amino acids Ligands are determined by electronic affinity and geometrical constraints Small hard metals prefer hard ligands eg Ca2 OOC R Asp Glu Large soft metals prefer soft ligands eg Hg2 S R Cys Iron and copper in between eg Fe2 Nlt His Metal cofactors 0 Single metal sites 0 mostly structural sites Ca2 Zn2 0 exceptions Cu2 0 Metal clusters 0 FeS Fe 4S 4 Fe 0 FeMoCo 0 Mn 4 an Cuz mixed metal clusters 390 Organometallic cofactors I 0 Porphyrins 0 Cobalamin 7 39 V 6m r C h l 0 390 p I 1 pnmmin 9 a 2amp5 Mac 1 III 55l4 5U h X j Stroma xxx l i d 23 g ll T 40 I Thylakoid m Membrane M J 92a 6 65quot cEs 1FIJ Lu men photosystem I contains 100 chlorophyll molecules three different types of Fe S clusters and phylloquinones 0 porphyrin pyrrole ring 0 iron prefers hexacoordination 0 5th coordinate position protein amino acid usually His 0 6th coordinate substrate binding or protein binding a P h aquot I Bioinorganic Chemistry Protein Function and Metallic Cofactors CHEM332 N MichaelisMenten Bioinorganic Chemistry Protein Shape and Function DNA Transcription CHEM332 Proteln Functlons Functions Catalysis enzymes Binding and transport active passive Protein DNA RNA binding histones transcription factors Protein protein interactions antibodies lysozymes Protein fatty acid binding apolipoproteins lipid transport in lymph and blood Protein small molecules drug interaction and transport Protein Functions Functions 39 Structural component y crystallin Regulation roles in transcription replication signaling Immune system response Motor proteins actin myo sin Proteln Functions Protein functions are so varied that they are difficult to categorize Example yscrystallin eye lens protein needs to stay stable and transparent for a lifetime very little turnover in the eye lens Protein Function Evolution Function and speci city can stay the same Function stays same but specificity changes Change to some similar function e g somewhere else in metabolic system Change to a completely new function Protein Functions Arriving at a given function can happen through 0 Divergent Evolution 0 homologous proteins proteins have same structure and same ish function 0 Convergent Evolution 0 analogous proteins different structure but similar function Proteln Functions How do proteins evolve 0 By addition of domains at either end of protein sequence or at loop sites see next slides 0 Often through gene duplication followed by divergence 0 Multi domain proteins are a result of gene fusion where multiple genes end up in a single Open Reading Frame of protein coding 0 Repetitions of the same domain in a single protein occur frequently this results from gene duplication followed by gene fusion Protein Modifications Protein structure modification Insertion deletion of secondary structural elements can easily be eztv done at loop sites These sites are normally at th surface of a protein Protein Modifi ations Protein structure modification Insertion deletion of whole structural domains can easily be done at loop sites quot w lt Proteln Modlflcatlons Protein structure modification h Active site Active C ymotrypsm c6mbination of Site 39 I I I I quot ancestral active site 0 coupling Putative ancestral Modern 2 barrel structure barrel structure Activity woo 10000 times enhanced rotein Modficatins Protein Domains The basic functional unit of a protein is a domain Compact semi independent unit Richardson 1981 Stable unit of a protein structure that can fold autonomously Wetlaufer 1973 Recurring functional and evolutionary modules Bork 1992 Proteln Modlflcatlons Protein Domains Understanding domains is important for Obtaining high resolution structures X ray N MR Sequence analysis Multiple sequence alignment methods Prediction algorithms SS Class secondary tertiary structure Fold recognition and threading Elucidating the evolution structure and function of a protein family Structural functional genomics Cross genome comparative analysis Prntein Dnma ng Pyruvate kinase ADP ATP Phosphotransferase contains a manganese ion B barrel regulatory domain ocB barrel catalytic substrate binding domain ocB nucleotide binding domain l2 1 A US 6 2132M 331 3 N IHHWH H 0 Domain 1 2 4l 335 529 3 40 50 5B 0 Domain 2 42 5 2l9 384 3 2 20 60 9 Domain 3 lLSZLE 240 070 Protein Domains Complex protein functions are a result of multiple domains and often synergistic domains 0 An example is the so called swivelling domain in pyruvate phosphate dikinase Herzberg et al 1996 which brings an intermediate enzymatic product over about 45 A from the active site of one domain to that of another 0 This enhances the enzymatic activity delivery of intermediate product not by a diffusion process but by active transport dramatically improves enzymatic rates l J rxw c1c33h quotJ The DEATH Domain m m Present in a variety of EukaryotiC proteins involved with cell death D m l W Six helices enclose a tightly packed hydrophobic core Some DEATH domainsform homotypic and heterotypic dimers DAF K N FKB p 391 GIG MGF R p75 http www mshrionca1awson Fens N DNA Transcription Molecular Visualization of DNA DNA Replication DNA Transcription into RNA RNA translation into Proteins http wwwyoutubeComwatchv4PKj onumYo A Transcriptin Transcription 0 RNA polymerases 0 RNA polymerase I II and Ill 0 RNA transcription Regulatory Elements promoters enhancers Transcription Factors gene specific and general factors Motifs helixturnheliX helixloophelix zincfingers and leucine zippers 0 Post transcriptional processes Heterogeneous nuclear RNA mature transcript RNA Introns and exons selfsplicing RNA DNA Transcription RNA Polymerases RNA Pol There are three known types 0 RNA Pol I synthesizes rRNA 0 RNA Pol II synthesizes formation of mRNA 0 RNA Pol III synthesizes tRNA and other small RNA RNA polymerases do not work alone they need the help of regularors such as promoters and enhancers They also need several transcription factors DNA Transcription Transcription Regulators The transcription process has many control mechanisms Protein DNA interactions play a central role in these mechanisms DNA itself has regulator sites called promoters and enhancers There are also smaller proteins called transcription factors that regulate the transcription process Regulators Promoters and Enhancers Promoters Consist of specific ciS acting nucleotide sequences that regulate the RNA polymerase binding and starting point for transcription Transcription Promoters Control RNA polymerase Control transcription initial binding starting point p Transcnptlon Proximal Region C079 R9930 Region GC Box AAT Box TATA Box ma u gift Tv f f 39 gene 110 bp 70 to 80 bp 25 to 30 bp 0 bp There can be several GC and CAAT boxes for a given gene Transcription Ini EMA laneamt Enhancers RNA 551 Consist of speci c nucleotide sequences that regulate RNA polymerase activity i I transcription factor Activator proteins They can be thousands of bp away on either direction Activator Enhancer from the gene They interact by folding of the DNA which brings them into the proximity They interact with the RNA polymerase through a protein transcription factor They are not specific to a particular gene L 3 2 if Regulators Transcription Factors TF These are DNA binding proteins and they determine the different many activities of the genes in multiple chromosomes In eukaryotic cells RNA polymerases are not able to recognize promoter sequences themselves they require transcription factors It is the gene speci c factors that attract general cofactors and RNA polymerase itself RNA transcription animation Transcription Factors General factors Gene specific factors TBP TATA Binding Protein DNA Transcription Transcription Factors and Enhancers Activators t0 and Repremrs exact positioning of the RNA polymerase at the site of initiation is V L accomplished by some quotquot wfquot u of the transcription factors As transcription starts Coding region transcrlptlon factors I Wm assoc1ated w1th positioning are released 0 V V TATA box Core promoter 39 Coactivators Basal factors Bioinorganic Chemistry Protein Shape and Function DNA Transcription i CHEM332 Bioinorganic Chemistry Erectron Transfer CHEM332 Electron Transfer Definition Electron transfer is the process by which electrons are transferred from one molecule or atom to another atom or molecule describes the mechanisms involved in the oxidation reduction process is involved in a large number of biological processes including respirations and photosynthesis Elctron Transfer f Complementary Electron Transfer Electron transfer is called complementary when the number of species being oxidized are equal to the number of species being reduced In complementary electron transfer reactions the ratio of the species being oxidized to the species being reduced is 1 to 1 Example CoNH35CI2 CrHZO62 9 NHE5C0H202 CICrHZO52 Elctron Transfer Noncomplementary Electron Transfer Electron transfer is called no ncomplementary when the number of species being oxidized is different than those of species being reduced In noncomple mentary electron transfer reactions the ratio of the species being oxidized to the species being reduced is not 1 to 1 Example PbCI6239 2 Craze PbC339 2 CrCI3 CI 1 Pb for evey 2 Cr Elctron Transfer f Outer Sphere Electron Transfer Outer sphere electron transfer reactions involve molecules atoms in the outer coordination sphere in the electron transfer process In outer sphere electron transfer reactions the inner sphere coordination remains unchanged Example CoN H363 RuN H3629 CoNH362 RuNH363 Electron Transfer InnerSphere Electron Transfer Inner sphere electron transfer reactions involve ligands in the inner coordination sphere Typically in inner sphere electron transfer reactions an inner Sphere ligand bridges the two species during the electron transfer process Example CrH2062 CONH35C29 9 CI39 H205ClCO N H354 electron transfer intermediate 9 9 CrNH35CI2 CoNH35H202 Process is accompanied by ligand exchange Elctron Transfer f Electron Transfer Centers There are three common types of electron transfer centers in biological systems involving 1 Cysteine dimer formation 2 Small organic molecules such as Nicotinamide adenine dinucleotide NAD Quinones FlaVin mononucleotide FMN 3 Metalloproteins such as in cytochromes Metal Centers in Electron Transfer Reactions Metal Centers in Biomolecules The active role of metals in biomolecules is greatly dependent on The stable oxidation states of the metal The ligands available from the amino acids that form the protein chains The geometry of the inner sphere ligands surrounding the metal atom The ability of substrates and other ligands and cofactor to reach the metal center Bioinorganic Chemistry Emectron Transfer L CHEM332 Elctron Transfer Electron Transferases The third type are also called electron transferases and they have the following characteristics They have associated cofactors acting as electron sources or sinks ie NADNADH There is enough space to allow the cofactor close enough for electron transfer A protein hydrophobic shell close to the cofactor Flexible enough chain to allow conformational changes to facilitate the electron transfer process Electron Transfer Electron Transferases An example of electron transferases are the large and varied family of cytochrome biomolecules They include Cytochromes four different ones are known in the electron transfer process in mitochondria Rubredoxin contain iron sulfur centers where the irons are ligated to four cysteine sulfurs Ferredoxin found in plants and animals an contain 2Fe ZS cluster centers Bioinorganic Chemistry Protein Binding to DNA CHEM332 77 DA Bin In Helixturrghelix Transcription Fa 44 u M 7 4 C 7 L Lj r Ctors J J quot fquot V T j 3151 139 the major grooves of the DNA double helix 39 demains allow for precise protein DNA f alignment 4 E 97 Notice that the binding of the proteln to the DNA causes the DNA to bend Major and Minor Groove H bonding The availability for hydrogen bonding between a protein and DNA is not the same for the major groove as it is for the minor grove Hydrogen bonding is more likely for proteins that interact through the more polar major groove major groove quot 7 w 391 gquot a I r l Wquot l a a 3T7 I 39 Y39 T V a 39339 139 i AdenineThymine Guanin ECytosine ThymineAdenine Cytosine Guanine I minor groove Hydrogen bonding between the protein residues and DNA base pairs 51 Rf git H Glutaminc 1 701 asparagine H CH M53C D 3fo CH3 Om f1 11 H 67 HT 13 lNx H f6 1 7n NW N O 39N Thymine Adenine R NampL1 C R Arginine fllg 1mg CH2 lelH H ITI 3 rumba H H I N H E H I I in Q N 3 x N NIHHH N 6 7 7 f xx N 0 H NL N 39 H Cytosine EGuanine D ENSTAPgtKLIVMWAGN Sequence WCPHKRLIVTLWX2gt STAV39LIVMSTACx VMFYH I LWMTAH P P LWMSR S fracture Function DNA Binding Example SCRO CysHis zinc nger C x24 Cx3 LWMFYWC x8 Ix35 H Lcucinn zipper Lx6Lx 6 L x6L 0 3 gt x DNA Binding ZDRP Leucine Zipper yeast PDB 1YSA RA RKLQRMKQLE DKVEE LLSKN YHLENEVARL A ZincFinger Proteins Zinc Fingers They consist of about 30 amino acid residues A single Zn2 ion binds to two cysteine and 2 histidine residues A zinc finger has a secondary structure consisting of antiparallel beta sheets and an alpha helix Zinc fingers can be specific or non specific to a DNA region They can also bind to RNA they are known to bind to mRNA to repress translation Zlnc Flnger DNA recognition Drosophila PDBZ ZDRP YRCKVCSRVY THISNFCRHY VTSH ZIncFmger Proteins Structure One of the most abundant DNA binding motifs Proteins may contain more than one nger in a single chain For example Transcription Factor TF3A was the first zinc nger protein discovered to contain 9 C2H2 zinc nger motifs tandem repeats Each motif consists of 2 antiparallel beta strands followed by by an alpha helix A single zinc ion is tetrahedrally coordinated by conserved histidine and cysteine residues stabilising the motif ch Fmger Proteins Binding Fingers bind to 3 base pair sub sites and speci c contacts are mediated by amino acids in positions 1 2 3 and 6 relative to the start of the alpha helix Contacts mainly involve one strand of the DNA Where proteins contain multiple ngers each nger binds to adjacent sub sites within a larger DNA recognition site thus allowing a relatively simple motif to speci cally bind to a wide range of DNA sequences This means that the number and the type of zinc ngers dictates the speci city of binding to DNA ZincFinger Proteins Zinc 1 S Usually neutral aromatic residues Example of zinc finger The interaction of a single zinc finger is relatively weak DNA binding proteins exhibit multiple zinc fingers in order to form stable DNA 0 bound structures Zinc Finger ZincFinger Function The DNA binding motif is found as part of transcription regulatory proteins D x ZincFinger DNA Binding Amino acid residues in the alpha helix make N 4 contact with the DNA in the major groove 39 The amino acid 39 l C residues in the zinc nger form weak DNA hydrogen bonds with bmdlng chfmger oalns the base pairs in the I N major groove 5 39 ACTGCCTACCG AGTGGATGAGTGT B 39 Each factor has 20 or more contact sites N Nuclease domain Bioinorganic Chemistry DNA Binding E CHEM332 Bioinorganic Chemistry Genetic Mutations CHEM332 Mutations Mutations are considered the driving force of evolution where less favorable or deleterious mutations are removed from the gene pool by natural selection while more favorable or bene cial mutations tend to accumulate leading to continuous evolution Neutral mutations are those that do not affect the organism39s chances of survival in its natural environment These mutations can accumulate over time and can result in what is known as punctuated equilibrium which result in non continuous evolution Mutations It should be noted that contrary to science ction the overwhelming majority of mutations have no real effect Mutations can cause permanent transmissible changes to the genetic material usually in DNA or RNA of a cell Mutations can be caused by 39 copying errors in the genetic material during cell division exposure to radiation chemicals or Viruses deliberately under cellular control during the processes such as meiosis or hypermutation Mutations In multicellular organisms mutations can be subdivided into germline mutations which can be passed on to progeny and somatic mutations which when accidental often lead to the malfunction or death of a cell and can lead to cancer DNA has so called recombination hotspots where mutations occur 100 to 1000 times more frequently than the normal mutation rate A hotspot is usually a region of 15 to 20 kb Abou 25000 hot spots have been identified in the human genome 4gt Sfra Mutations 0 Organisms have many ways of proofreading and repairing damaged or mutated DNA Most mistakes are repaired however some of them are not and may lead to genetic diseases 0 Mutation rates also vary across species Evolutionary Biologists have theorized that higher mutation rates may be bene cial in some situations because they allow organisms to evolve and therefore adapting faster to their changing environment Causes of mutation There are two classes of mutations 0 spontaneous mutations which are naturally occurring and 0 induced mutations caused by mutagens Spontaneous mutations At the molecular level include 0 Tautomerism enol 0H Guam 0 ketc Hx N o Keto 9 Enol 1 j l 9 H EN I H i R 1 I39I H H H O Ammo 9 lmlno sk NH 8 H La Mutatins Causes of mutation Spontaneous mutations 0 Deamination apsite Loss of A or G they occur 1000 times each day in mammals Deamination to base analogs is estimated to occur 100 times each day in mammals 0 Cytosine C 9Uracil U or 0 Adenine A 9 HypoxanthineHX NH2 0 H2 Cytosine I N Ogt EKNH Uracil 7NH3 NKO k N O H M utatlons 0 Transition a base pair substitution in which the orientation of the purine and pyrimidine bases on each DNA strand remain the same ie AT to GC TA to GC 0 Transversion a base pair substitution in which the purine pyrimidine orientation on each DNA strand is reversed ie AT to TA 0 Frameshift mutation always involves insertion or deletion never a substitution of one or more nucleotides usually through a polymerase error when copying repeated sequences it leads to a shift in the subsequent reading of the nucleotide triads 0 Oxidative damage caused by oxygen radicals M utatlorist Point Mutations Point mutations are usually caused by chemicals or malfunction of DNA replication and exchange of a single nucleotide for another Most common is the transition that exchanges a purine for another purine or a pyrimidine for a another pyrimidine A 9 G C 9 T A transition can be caused by nitrous acid base mispairing or mutagenic base analogs such as 5 bromo z deoxyuridine BrdU A transversion is less common it exchanges a purine for a pyrimidine or a pyrimidine for a purine C T 9 A G M utatn0 5r Point Mutations Although a point mutation is usually the change of a single nucleotide in DNA It can also be the deletion of a single nucleotide or just a few base pairs that affect the function of a single gene A point mutation can be reversed by another point mutation in which the nucleotide is changed back to its original state true reversion a second site reversion a complementary mutation elsewhere that results in regained gene functionality Balmaw trmslontiom AECDE II wx y un t imaman AB CD Mu Point Mutations There are several kinds of point mutations depending upon what the erroneous codon codes for 39 silent mutations codes for the same amino acid so it has no effect 39 missense mutations codes for a different amino acid in the protein and the protein function is affected nonsense mutations results in a stop codon which truncates the protein frameshift mutations causes a shift in the reading frame which introduces unrelated amino acids into the sequence and is usually followed by a stop codon tatins i First has in 56an Liam luau use J UGG Trp n EEG CV5 L EGG EGA EGU I a 39I39Il39lird base in nudnn First base UUU UUC UUA UUG Leucine CUU CUE CUA CUG AUU AUC soleucine AUA Leucine AUG Methionine start codon GUU VnIine GU G Phenylalanine UCU 39 UCC UCA UCG CCU quot CCC CCA CCG ACU 39 ACC ACA ACG GCU GCC GCA Second base Satin 39 Praline Threonine F Alanine GCG UAU Tvrmine UAC quot UAA Stop codnn UAG Stop codon Histidine Glutamine AAU A AAC Asparang AAA AAG Lysine GAU Aspartic GAC acid 6AA Glutamic GAG acid H 322 UGA Stop codou UGG Tryptoph39dn CGU Arginine CGG AGU AGC 39 Sauna Arginine GGU GGC GGA GGG Glycine U C A G 61gt a 9an panu Igntv asajmances mmm MF he Alrg Tm HIE Ala ASHI n a d 39 t J lllle Pomt I gTTT GSA mas Mutatmns NW mg mp Hannah by addir un GIST ACE 7 quot39 1 airm TEE quot NH Mg Trp39 ram lhi by da e um z N T 3 iquotwquotrquot39a Jfr39 39 z 1 Large Scale Mutations WWW Deletion remove one or more nucleotides from the DNA shortens the DNA These mutations are irreversible and they can alter the reading frame of the gene Duplication Duplication repeats a set of nucleotides from the original DNA resulting on a longer DNA Like insertions these mutations can alter the reading frame of the gene Inversion reverses a segment of nucleotides from the DNA it doesn t alter the length of the DNA These mutations alter the reading frame of the gene Large Scale Mutations Insertion ranges from one to thousands extra nucleotides into the DNA These nser m mutations are also called indels for 39 insertion deletion They are usually errors during replication of repeating elements eg AT repeats i 3 Chromosome 20 mmmowmn Chmmumme 4 39 When the number of nucleotides is a multiple of three they may result is less serious consequences Huntington s disease involves repeated trinucleotide CAG which inserts extra glutamins Gln to the encoded protein This causes increased level of a brain protein that causes apoptosis Large Scale Mutations Translocation Translocation transfer a piece of a ammonia chromosome to a different 7 39 chromosome Translocations are usually reciprocal they can be Viewed as an exchange or swap on non equivalent segments Mriw un Iquot Chmmmomo ZU They may affect gene expression destroy gene function produces a hybrid gene For example the Philadelphia chromosome is the result of translocation and it is often found in leukemic cells of patients with chronic myelogeneous leukemiaCML Types of mutation Deletion Duplication Inversion A Large Scale Mutations Reciprocal translocation generates the Ph1 gene associated with leukemia chromosome Phl Insertion Chmmumma 20 P 11 Chromosome 20 mmmowmu 4 c abl 9 Chmmommo 4 Translocation Derivative 2 Chmmommn 20 Chmmmnm 1 39quot Lgt Dwivn ru chmmnwmn 4 der 9 Reciprocal translocation between one i 9 and one 22 chromosome forms an exlIalong chromosome 9 39der 939 and the rmquot 39539 Phi 39 athe fused ab l bcr gene This is a schematic View representing metaphase chromosomes cnmmmm 4 Mutatins f Induced mutations These mutations at the molecular level can be caused by speci c but sometimes simple chemical substances Chemically induced mutations by 0 Nitrosoguanidine NTG 0 Base analogs eg BrdU 0 Simple chemicals eg acids 0 Alkylating agents eg N ethyl N nitrosourea ENU 0 Methylating agents e g ethane methyl sulfonate EMS 0 DNA intercalating agents e g ethidium bromide 0 DNA crosslinker eg platinum 0 Oxygen radicals tanns a 0 Polycyclic hydrocarbons eg benzopyrenes found in internal combustion engine exhaust and charbroiled food Benzoapyrene Radiation Induced Mutations Mutations can be caused by electromagnetic radiation 0 Ultraviolet radiation 0 High energy ionizing radiation such as from X rays and radioactive decay Bioinorganic Chemistry Genetic Mutations amp CHEM332 Bioinorganic Chemistry Metal Ligand Substitution Thermodynamic and Kinetic Factors CHEM332 N Thermodynamics Tylt w in Thermodynamics Ions in Aqueous Solution In aqueous solutions free metal ions are surrounded by molecules of water 39 C02aq being a positively charged attracts the negative side of the water molecules 2 2 H2 CO aq COH206 aq Hga aw Cobalt is surrounded by 6 molecules of water in an 20 I QHi octahedral geometry 0H3 w quot7 Thermodynamics Metal Ligand Bonding Interaction 0H2 Metal Complex 2 ai39v a H 00H2062 agoMIDH Metal Cobaltl ion Co2 Ligand Water molecule H20 Thermodynamics 3 The square brackets indicate who that is a single species a molecular substance with a Hlo charge of 2 The charge is not 2 only at the cobalt atom but COH2062aq distributed through the molecule The formula of the ligand is CO OH 2 sometimes modified to 26 aq emphasize the metalligand bonding interaction w 7 39 Thermodynamics The presence of a ligand can result in substitution COHZO62aq NH3 3 COH205NH32aq H20 C02aq NH3 3 CONH32aq M L 3 ML Equilibrium Constant K1 ML ML A Thermodynamics Multiple ligand substitution can be Viewed as sequential equilibria where M Cozaq NH3 L K formation constant M L 3 ML K1 ML ML ML L s ML21 K2 Min ML1L1 ML2 L ML31 K3 ML31 ML21L1 A Thermodynamics Each multiple ligand substitution can be Viewed as individual equilibria where M Cozy NH3 L stability constant M L 3 ML m ML V1L M 2L 3 MLZ 82 MLZ ML2 M 3L 3 ML3 83 ML3 ML3 w c Thermodynamics Factors affecting metal ligand substitution in biological systems are 0 The equilibrium constant or stability constant 0 Hard soft acids and bases effect 0 Protein ligand conformation e a Thermodynamics Factors affecting metal ligand substitution biological systems also include Local concentrations and availabilities determined by 0 permeability of metals through membranes 0 availability of binding proteins in their correct conformations 0 Competition from other metals and ligands having their own competing equilibrium constants Thermodynamics The Uptake Factor Key concept KMLX M A x M K x M ML L Besides the value of the formation and stability constants which are thermo dynamic factors concentration of the metal M also influence the uptake factor Typical concentrations of metals M K Na Ca2 Mg2 Zn2 Cu2 Fe2 M 101 M 1O3 M lt1O9 M lt1O12 M 1O17 M Thermodynamics The Uptake Factor 0 To be able to concentrate metals where they are needed ligands need to demonstrate a high selectivity and a inity for the metal ie high attraction for the specific metal 0 This selectivity is re ected in the value of uptake factor Typical concentrations IIH a M 10 1 M 10393 M lt1O399 M lt 0 12 M 10 17 M The Uptake Factor for selected ligands W7 w Ca2 M92quot 4 5132quot T 712 H Mquot 394quot iJ awg l nitrogen and sulfur ligands KMLX M lt01 lt01 gt10 oxygen donors in di and tri carboxylates KMLX M lt01 gt1o lt01 oxygen macrocycles Crown Ethers KMLX M gt10 lt01 lt01 N Kinetics Kinetics Kinetic studies of biological systems often involve the study of catalytic activity of enzymes Often when studying these systems pseudo order reaction are used This can be done by holding the enzymes concentration constant and varying the concentration of the substrate the enzyme is transforming This usually leads to a first order kinetics Kinetics Kinetic studies of biological systems often involve the study of catalytic activity of enzymes However if the concentration of the substrate being varied is above the saturation concentration for the enzyme then a zero order kinetics is observed Ligand Substitution Process L L L lt bulk of solution solvent solutes DH H 0 outer sphere ligands counter Ions L 2 4 wOH solvent molecules In a 39 Jaw weakly attracted it dquot Inner sphere ligands directl bondin H20 0H L y 9 DH L L L CoH20gt612aq in the presence of potential ligands 777 7 7 7 7 Ligand Substitution Process Substitution can take place through 0 An associative mechanism 8N2 0 ML6 L R1399 ML6 L m 9 MLS L I L ML4 n L R1399 ML4 L n a ML3 L n L Note thefirst step is the association ofthe incoming L are used to enclosed a short lived intermediate state In general associative mechanisms are not that common for ML6 complexes due mainly to steric crowding around the metal which needs to bind to 7 ligands simultaneously The associative mechanism is more common for ML4 complexes since there is generally not much steric crowding 777 e 7 7 7 Liga nd Su bstitution Process Substitution can take place through 0 A dissociative mechanism 8N1 ML6 n R1399 MLSr1 L L a MLS L n L Note that thefirst step is the dissociation ofthe outgoing L are used to enclosed a short lived intermediate state In general dissociative mechanisms are most common for ML6 complexes due mainly to steric crowding around the metal which makes the dissociation of L a favorable event The dissociative mechanism is not common for ML 4 complexes since there associative mechanism is much more energeticallythermodynamically favorable if 177277777 r 39 Ligand Substitution Process Experimental observations 0 Intermediates for dissociative mechanism are not usually detected 0 Factors affecting substitutions include 0 Size 0 Charge 0 Polarity 0 Hard soft nature of the metal and ligand 0 Coordination number V quot 7 if 7 7 r Ligand Substitution Process Experimental observations 0 Cotton Wilkinson and Gaus classified metals base on their rate for water exchanged MHZO6n Hz0 3 MH205 HzOn quotI20 Class I Rate gt 108 s1 essentially diffusion controlled 0 Class II 108 3391 gt Rate gt 104 S391 0 Class III 104 s1 gt Rate gt1 s1 0 Class IV 10393 3391 gt Rate gt 106 3391 From the kinetics point of View metals in Class I are termed labile while those Class IV are termed inert Ligand Substitution Process Interchange I or Stoichiometric Mechanism 0 These are intermediate processes between associative and dissociative mechanisms where the intermediates cannot be detected 0 These processes are called Interchange l and the mechanism is called sometimes stoichiometric mechanism 0 When the interchange reaction rate depends on both the metal complex and the incoming ligand the mechanisms is termed associative interchange I A 0 When the interchange reaction rate depends only on the metal complex the mechanisms is termed dissociative interchange ID Ligand Substitution Process Interchange I or Stoichiometric Mechanism Step 1 MLSS n L S MLSS L r1 Step 2 MLSS L r1 9 MLS L t S MLSS L m is the proposed outer sphere OS intermediate In interchange reactions the incoming ligand is presumed to become part of the outer sphere before the reaction proceeds to its activated complex For IA mechanisms the incoming ligand is strongly embedded into the coordination sphere while For ID mechanism the incoming ligand is more weakly embedded Bioinorganic Chemistry Metal Ligand Substitution 1 CHEM332 Bioinorganic Chemistry Amino Acids and Metal Binding CHEM332 Amino Acids General Structure N C C 0L Clarbon H H Amine GFOUP Carboxylic Acid Group Ammo Acnds There are 20 naturally H O occurring amino acids I that are involved in all N C C living organisms a iarbon known in our planet H OH They all Share a Amine Group H Carboxylic Acid Group common structure but differ in the R group The R group is unique to each amino acid R groups can be classified as nonpolar polar acidic and basic depending on the nature of the side chain 09 Am i no Acids At normal biological pH 7 amino acids are found a zwitterions that is they are found as molecules that although they are neutral as a whole they carry positive and negative Charges R H3N 0 COO ZWItterIon H ng 1 a can Iquot39llll lllll39I glycine Ely E H313 k Inng Haw g c m mn INN isuleucine Ila 09 Nngolar Hydrophoit Amiho Acids H3153 Yb fEHa 9H3 EH H3N mn WISH EE mn Ii Ilfl alanine Ala A walim Val V HEB EH3 Iii Km 5 I 6 Cr H1quot ng Inn g cm H3H u u cm nia n leucine Len L methionine Mat M 7 anolar Hydrophoic Amino Acids H2 x ill l1 H212 9H3 mam uni Ea mn H3HFEquot cm H in prunylalanine Phe F pmline Pm P Polar Amino Acids HZNI D H N 9 HEN D N c r HZ CH2 9 EH2 H3N COD H3NI hug1 E200 H3N i Em CUB Q i in asparagine Asn N mapmn Trp W glutamine Eln Q 39 O I I I39d W I I mnigumn 8 Q a IIIIlt39IIII D t 8 H0 CH3 KgH ifquot H3Nh H3NmnE 1i 20039 H3M p I39l I Sarina Ear S mrennine Thr T cysteine 35 C DiHZyU H 32quot man u d B U Illlll lllll I aspartin acid aspartate I glutamic acid glutamam Elur E 0H Hz H3Mb 1i SHOE IHllll lllll39 tymsine Tyr Y wmma gt330 gt29 2 z x a 2H M l mu H 2i 2 K2 Innis nuns In fuz llmll n3 in amul nun m m 3535 IE 1 553 as m 2 Mn fin E u run in llmll nun IIIIII Jain run I Example Glutamic acid glutamate Glu E I Common Metal Binding Modes for Amino Acids g h 39S I H21 gHg H3NbEf mo H3N1 E7 CHOD 4 F1 histidine Hisr H cysteine cys C ij PET m mar I39Illllll methionine Met M 0 e 0 y I M f H3mn auteur I IuIIIII aspartic acid aspartate Asp D oz 5 o C T Hgfll 33942 CH2 H3N FE dma H3N E mu H h glutamic acid glutamate Glur E tymsine Tyr Y 9 if aky Metal Binding Amino Acids OH39 OCH f CH3 EH2 EH H3Nh E1 EDD H3M E CUD 4 1 4 Serine Ser S thrennine Thrr T Bioinorganic Chemistry Amino Acids and Metal Binding L CHEM332 Bioinorganic Chemistry SiteDirected Mutagenesis Recombinant DNA CHEM332 Identification and isolation of desired segment in DNA Restriction endonucleases open the DNA in the vector DNA ligase inserts the gene and closes the DNA Recombinant DNA introduced into host cells Cell replication produces recombinant DNA and translated proteins AT TT T T TTA overhangs nATT I Am mlxmg DNA Iigase added seals overhangs mm Tm AATT recombinant bacterial DNA chromosone DNA introduced into bacterial cells l l l recombinant lm molecules replicate and cells divide clones 2002 Encyclopedia Britannica Inc Requirements for DNA cloning itedirected Mutagenesis 1 A selfreplicating segment of DNA it can be a Bacteriophage virus or a bacterial plasmid VECZ39Oi 2 A procedure to introduce foreign DNA into a functioning ce such as transfection 0r eectroporation 3 A procedure for selecting cells that have incorporated this DNA by using antbiotic re5Stance Sitedirected Mutagenesis Gene Cloning Procedure 1 Locate specific cleavage sites at the beginning and end of the gene of interest 2 Treat the vector and DNA with the same nucleases to create a compatible opening 3 Covalently couple the fragments using DNA ligase 4 Insert mutated DNA into cells to replicate transformation 5 Isolate desired DNA segments and the desired proteins for further studies and use Identification and isolation of desired segment in DNA Restriction endonucleases open the DNA in the vector DNA ligase inserts the gene and closes the DNA Recombinant DNA introduced into host cells Cell replication produces recombinant DNA and translated proteins AT TT T T TTA overhangs nATT I Am mlxmg DNA Iigase added seals overhangs mm Tm AATT recombinant bacterial DNA chromosone DNA introduced into bacterial cells l l l recombinant lm molecules replicate and cells divide clones 2002 Encyclopedia Britannica Inc selecting a vector The vector can be a bacteriophage Virus or a bacterial plasmid the second one being the most commonly used of the two 3 swam 439 Bacterial DNA plasmids The plasmid is an extra circular chromosomal DNA which is separate from the bacterial DNA and is replicated along with the bacterial DNA E Coli is a commonly used as the bacteria Sitedirected Mutagenesis cutting desired DNA segment DNA splicing Restriction endonucleases are enzymes that have become exceptional tools for cutting DNA at speci c nucleotide sequences These enzymes are able to cut both strands of DNA at specific palindrome sequence across the double helix Endonucleases Bam HI BStYI Palindrome 5GGATCC 3 5 RGATCY3 Whlire A G d y y y y 01 an Sequences 3 CCTAGG5 3 YCTAGR5 Y C or T Sitedirected Mutagenesis cutting the plasmid DNA segment Recognition site DNA splicing 539 7 EcoRf ms lc iun EWease E EITC 5391 5 339 III I I II II I I II I I le 39m39lquot Iiill39illlm I III 39 73quot 7 5 Restriction enzymes cleave DNA at speci c sites Sitedirected Mutagenesis restriction endonuclease Cleavage Restriction enzyme EcoRl is a metalloenzyme containing two catalytic manganese ions Cleavage occurs at the metallic centers as shown in the orange DNA backbone Sitedirecte Plasmiq DNA VNA molequl x eqvage d Maesis Use of nucleases to cleave DNA at specific recognition sites EcoR1 cleavage AA I TC 3 77 Sicdirected Mutagenesis gene insertion 2 4quot swam 2574 mm HgiEll 135 An artificial self replicating circular DNA vector Contains a selectable marker for ampicilin resistance Contains a polycloning site for gene insertion Sitedirected Mutagenesis inserting plasmid into host cell The modi ed plasmid is the inserted into the host cell E Coli is commonly Plasmid E W d h Hursl 38quot use asa ost Tmnsfurmed Call The plasmid is an extra circular chromosomal DNA which is separate from the bacterial DNA and is replicated independently and along with the bacterial DNA Identi cation and isolation of desired segment in DNA Restriction endonucleases open the DNA in the vector donor DNA vector and donor DNA d gested cleaved wit restnction enz me MTT MTT Y ATT A An Tm TT A y T MT I overhangs DNA ligase inserts the gene and closes the DNA Recombinant DNA introduced into host cells Cell replication produces recombinant DNA and translated proteins Am mixing L DNA Iigase added seals overhangs Am Tun AATT l recombinant bacterial DNA chromosone I39 DNA introduced into bacterial cells i i i recombinant DNA molecules replicate and c39elis divide Y Clones 2002 Encyclopedia Britannica Inc lnsecllcide gene created uslng recomblnant DNA technology 1 Genetlcally I died Modified 000 Genetically modified organism I vectors gmlng plant cells lake up insecticide gene from plasmid vectors r nim Oga s s insecticidal cells cells um for plant Insects that feed on propagation the plants will die v l 5 26 2009 Encyclupaedia Britannica Inc Recombinant DNA Technology Human Insulin Once the gene for human insulin was identi ed the segment that codes for insulin was cut from the chromosome and recombined with a cut circular DNA plasmid The plasmid is inserted into a suitable bacterium and production starts as the gene is expressed Human insulin was a great advancement human sell quotsliced up chmmgsume f gene respnnsible for suitable baahem mpmdu ctiun of bacteria plasmid is g r log 99 1m g 77 a 399 33 4 J 1 finL llpruduct ian 5 oiinsulin l7 Iasmids vf isolated Iprlssmid plasmid cut with enzyme plasmid with gene inserted in bacterium 16 Re combinant DNA Technology There are may applications of recombinant DNA technology For an overview of this technology consult Recombinant RNA technology For an overview of applications of this technology consult Applications of Recombinant RNA Technology estrlctlon Endonuclease Restriction endonuclease 39 cuts both the organisms a DNA and the vector to I I form two complementary Z 2 DNA segments that can Sim ends be joined and inserted 2 0 into a bacterium for the 1 gene replication and expression DNA Organism 2 Antibiotic Resistance It is not possible to have 100 of the bacteria containing the recombinant DNA Culture of cloning host after incubation with recombinant In order to avoid competition P39as39mid aameigwn Bacteria lack recorn 39 man a spec1 c ant1b10t1c IS used vim p39asm39d The recombinant DNA besides having the desired mriamying gene it has a gene that Plasmid makes the bacteria resistant to a speci c O O 39 Page culture ant1b10t1c A Sonia Ampicillin resistance gene Selective medium with ampicillin cloned gene Only colonies having the recombinant DNA survive and reproduce TABLE 9 Product Some Pharmaceutical Products of Genetic Engineering Alp liqinterferon Antitrypsin Betainterferon Bone morphogenic proteins Colonystimulating Factor CSTI Epidermal growth factor EGF Erythropaietin lEPOl Factor VIII Gammainterferon Hepatitis B vaccine Human growth hormone thGH Human insulin Comments Therapy for leukemia melanoma and hepatitis produced by E coii and Sacchoromyces cerevisiae lyeast Assists emphysema patients produced by genetically modi ed sheep Treatment for multiple sclerosis produced by mammalian cell culture Induces new bone formation useful in healing fractures and reconstructive surgery produced by mammalian cell culture Counteracts effects of chemotherapy improves resistance to infectious disease such as AIDS treatmenl of leukemia produced by E coli and 5 cerevlsiae Heals wounds burns ulcers produced by E coil Treatment of anemia produced by mammalian cell cullure Treatment of hemophilia improves clotting produced by mammalian cell culture Treatment of chronic granulamatous disease produced by E coil Produced by 5 cerevisiae lhat carries hepati tisrvirus gene on a plasmid Corrects growth deficiencies in children produced by E colt Therapy for diabetes better tolerated than insulin extracted from animals produced by Escherichia coli Genetic Engineering Genetic Engineering GE These are some cases of GE 0 Herbicide resistant plants 0 Bt cottoncom toxin gene from Bacillus thuringiensis that kills insects 0 Flavr Savr tomatoes 0 Golden rice beta carotene 0 Plant based vaccines 0 Human insulin Genetically Engineered Crops Case Bt Crops The main idea behind genetically engineered GE Bt crops is that incorporating the toxin produced by Bacillus thuringiensis Bt it eliminates the need to apply chemical pesticides which is better for the environment and cheaper for the farmer The natural toxin from the microorganism Bacillus thuringiensis is deadly to many pest species while it has low toxicity for most benign organisms beneficial predators and humans Genetically Engineered Crops Case Bt Crops Bacillus thuringiensis Bt is not new to agricultural practices Bt spray has been used for decades for pest control and has been a particularly important tool for organic farmers who use it as a natural pesticide Genetic engineers can embed the genetic characteristics of the Bt toxin directly into some plants primarily corn cotton and potatoes so that they become naturally resistant to pests 416 quotGenetica Iy Engineered Crops Case Bt Crops Farmers have used Bt in as needed basis and in combination with other insect control techniques The intermittent use has prevented insects from developing resistance to Bt With genetically engineered Bt corn and Bt cotton the insects are constantly exposed and it is thus inevitable for insects to develop resistance to Bt Resistance is not a phenomenon specific to Bt only insects develop resistance to all regularly applied chemical pesticides I 7r quot Gnetically Engineered Crops Case Bt Crops In addition because crops grow unevenly in nature39s differing conditions expression of the Bt gene is not uniform throughout the plant Uneven growth will cause pests to get a quotsub lethal dosequot of Bt toxin which facilitates the development of resistance in the same way that pathogenic bacteria become resistant when a patient fails to complete the full course of an antibiotic These problems are being studied although Bt crops could be implemented now they are not a reality yet Bioinorganic Chemistry SiteDirected Mutagenesis Recombinant DNA L CHEM332 Bioinorganic Chemistry Metal Ligand Binding Metal Coordination CHEM332 MetalLigand Bonding Metals are able to interact with certain atoms and molecules which are termed ligands because of their ability to ligate the metal 0 Metals Atoms usually having a positive charge attracted to available electron density in other molecules or atoms 0 Ligands Atoms or molecules having available negative charge usually in the form of non bonding electron pairs that seek positive charges MetalLigand Bonding Acid Base Definition by Lewis 0 Acids Atoms or molecules that might be neutral or positively charged that seek negative charge electron density They are said to be electrophilic 0 Bases Atoms or molecules that might be neutral or negatively charged that seek positive charge They are said to be nucleophilic MetalLigand Bonding Hard Soft Model definition for metals 0 Hard Metals are small and dense cores of positive charge 0 Soft Metals are larger and have less densely distributed positive Charge their electron Cloud is highly polarizable MetalLigand Bonding Hard Soft Model definition for ligands 0 Hard Ligands are composed of small electronegative atoms that have dense electron density and seek positive charge 0 Soft Ligands are larger and have diffuse electron density and are easily polarized Bioinorganic Chemistry Metal Ligand Binding Metal Coordination i CHEM332 uenc g m39r Bioinorganic Chemistry Cell Structure RNA and DNA CHEM332 s Nucleus control body of the cell contains the genetic material DNA Endoplasmic Reticulum Nucleus lt Golgi Body AnimaI Ribosome Ribosome site where proteins are made Nucleotide Chromosome Nucleic Acid There are 23 pairs of chromosomes in humans Histone 7 protein DNA is tightly coiled within each t chromosome DNA is wrapped tightly around histones and coiled tightly to form chromosomes DNA Chromosome Chromatids 10 coils long One coil 30 roserxes One rosette 6 hoops around nucrear afraid One loop 75 kbp 30 nm chromatin fihre Beadsonasmng chromatin bre wrapped around histones DNA Chomatin Histone DNA wawiba udeig Add x DNF 675 0 DNA rm a gimg human CCEM Ktcgrmdg rm a gimg thread Em a mwg c 2 mwtmrg Ming 9 Hit mmftams mfmmmiwm Equa m mmee 6 printed pageg f 090 wmrdls Qatah a Eibmry fabamf 11 mm hawks urrent Understanding Current Model Transcription Processing Translation DNA preRNA RNA Protein Replication l amp Repair folding DNA assembly processing 7 77 Which were the rst informational macromolecules A Proteins B DNA C RNA RNA is the only currently used macromolecule that is both a carrier of genetic information and an enzyme The RNA World Hypothesis 0 The RNA world hypothesis proposes that there was a stage early in the early evolution of life that was dominated by RNA 0 Moreover the functions of RNA in modern cells are only remnants of its previous roles Possible remnants of the RNA World WPP NT Selfsplicing introns RNAse P ribozyme that cleaves tRNA precursors Selfcleaving viral RNAs Peptidyl transferase in the ribosome Nucleotides ribo involved in metabolism eg ATP UTP NADH NADPH signaling CAMP cGMP GTP lTP assembly of complexes GTP and ATP 0 Energy for motility ion pumping etc ATP GTP M ajor Groove Strands are anti paral el Deoxyribonucleic acid DNA is the genetic material Stores genetic information in the form of a code a linear sequence of AT GC nucleotides Replicated by copying the strands using each as a template for the production of the complementary strand 3 Ways of Depicting DASrtrLI tue A annic d lislly 1111161 B Riblumuhl C Space lling mid Single Snandedm cbuble shandedDNA double S arxhdm 3 implullc EDNA CH2 0 G V 339 C EEC H ambledlde o 1 O 0 PK I g I N H O 0quot C If N A J 1 O H 539 L 539 1 V N H Hmplndmta 6 AC m v NH r W 7 N 0 H H N O O R Il sringis gtDOH DNA Nucleotide Phosphate building block N Nitrogenous base A G C or T Sugar deoxyribose 39 Nitrogenous B s s 39 PURINES 4 ring nitrogens 1 Adenine A 2 Guanine G 39 PYRIMIDIN ES 2 ring nitrogens 3 Thymine T 4 Cytosine C Nitrogen Bases Pyrrlmitllma The nitrogen bases in quotH 12 H v I I Hick f R I unclequot ands cunsmst 5 I nfthe H 3 3 quot N39 H n H I P ynmmmes C T minimum mum mm m and PM 1pm only mm mm and U Purina And purines A and NH 13 G i i I 5 H I A i 39 i H H H m M nhnol39 mnlna G11 WA Imw RNA um um FIRM The pentuse vewmrban sugar I In is ribnse I In INA is deoxyribose I Has carb n mums numbered with primes tn distinguish them fmm the nitrogen bases Penman sugars n FHA and DNA 539 5quot HUGH aw Human DH H Ha awnen 339 239 339 239 a DH a H mbandld Hibase ln EMA Dwxy bnse In DNA In this Eamon quotNh sm Qua z 1 354er twain 39rrkvfg s 1 nla rwe E HE39Z H Nucleosides of DNA Precursors to Nucleotides N C W CH3 THZ N N HN N H k gt k l gt O j 0amp0 MAN N 2 deoxy ADENOSINE 2 deoxy GUANOSINE 2 deoxy THYMTINE 2 deoxy CYTIDINE Nucleoside base sugar Sugar deoxyribose 5 carbons no OH on the 2nd or 2 carbon base is at mlmrq tn Parb n 1 A nucleotide Is a nucleoside that forms Illquot a phn sphate ester with a pggg EH the CSquot DH gmup of I H ribnse nr deuxyribnse quot I Is named using the name of the nucleaside folluwe by 5 quotman up aspharei O 239 deox adenosine 539 tri hos hate N N N y p p gt 239 deoxyguanosine 539 triphosphate HN w 3 o o o HZN N U U U o o o of io o oism H w G w oipioipioipio wz o o o A J g 239 deoxycytidine 539 triphosphate thymidine 539 triphosphate DNA and RNA Pho sphodiesters In DNA and RNA nucleotides are held together by ghosghodiester bonds 39OT OCHZ O O NH2 N I A C I N O OTO CH2 0 O NH2 Phosphodiester N bonds N lt J A quotE N N 0 0 2 1 0 3 hydroxy OH A U c G 239 OH 239 0H 239 0H 239 OH 3 339 3 3 p p p 1 H0 1 539 5 5 5


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