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True or false? Cyanide is poisonous because it binds more tightly

About Chemical Warfare Agents. The Singapore government gets it right: “ Blood Agents: Cyanide-containing compound, affect body functions by poisoning the enzymes, Cytochrome Oxidise. Hence preventing the normal utilization of oxygen by the cells and causing rapid damage to body tissues. ”.

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True or false? Cyanide is poisonous because it binds more tightly

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  1. About Chemical Warfare Agents The Singapore government gets it right: “Blood Agents: Cyanide-containing compound, affect body functions by poisoning the enzymes, Cytochrome Oxidise. Hence preventing the normal utilization of oxygen by the cells and causing rapid damage to body tissues.” True or false? Cyanide is poisonous because it binds more tightly to the iron in hemoglobin than does O2 and cause suffocation.

  2. False • Let’s do the calculation. • You have ~ 2g Fe in your body; about 1.5g of Fe is in your blood as hemoglobin. • 1.5 g Fe = 0.03 mol. • Toxicity of cyanide: The LD50 for ingestion is 50-200 milligrams, or 1-3 milligrams per kilogram of body weight, calculated as hydrogen cyanide. The LC50 for gaseous hydrogen cyanide is 100-300 parts per million. Inhalation of cyanide in this range results in death within 10-60 minutes, with death coming more quickly as the concentration increases. Inhalation of 2,000 parts per million hydrogen cyanide causes death within one minute. • So, if you weigh 60 kg, between 60-180 mg could be a toxic dose. • Or, 0.06-0.18g = 0.002-0.007 mol CN- (as HCN) vs 0.03 mol Fe • That amount of cyanide would block only ~10% of O2 binding sites in hemoglobin, not enough to kill you. • The toxicity of Cyanide is because of its strong binding to Fe in heme in other critical Heme-proteins.

  3. The Many Role of Hemes • oxygen carrier (hemoglobin) • electron transfer (cytochromes a,b,c, etc, in respiratory chain) • cytochrome oxidase (mitochondrial electron transport chain, • oxygen is terminal electron acceptor and is reduced to water) • detoxification (cytochrome P450, catalase) • hydroxylation (cytochrome P450 in hormone production)

  4. Respiration

  5. Complex III matrix Q HEME 1 QH2 2 Q HEME 2 2 x QH2 cytosol c1 HEME 3 c Cyt c HEME 4

  6. Complex IV – Cytochrome C Oxidase Fe(III) Fe(II) HEME 1 Cu(II)—Cu(I)Cu(I)—Cu(I) HEME 2 HEME 3 Cu(II)  Cu(I) HEME 4

  7. Using Iron Porphyrins as Models for Hemoglobin The system:

  8. Key Features of Hemes • Fe oxidation state • Fe spin state • porphyrin oxidation state • porphyrin • hydrophobicity

  9. How will the spin state of Fe(porphyrin) complexes change on binding imidazole? Intermediate Spin S = 3/2 n = 3 High Spin S = 5/2 n = 5 Low Spin S = 1/2 n = 1

  10. Sample for Evans’ Magnetic Susceptibility Method NMR tube Inside capillary: sample in CHCl3, 1) with imidazole 2) without imidazole Outside capillary: 99.5 %D CDCl3

  11. NMR Spectrum from Evans’ Method Inside capillary: sample in CHCl3, produces broad singlet for paramagnetically shifted CHCl3 below 7.3 ppm Outside capillary: 99.5 %D CDCl3 produces usual sharp singlet for 0.5% CHCl3 at 7.3 ppm 

  12. Why is H resonance in CHCl3 shifted downfield and broadened? • pseudocontact and contact terms • addition of new small magnetic field to local magnetic fields • of neighboring nuclei • is used in NMR Shift Reagents to “de-tangle” complicated spectra

  13. Shift of signal, in Hz mass susceptibility of solvent -a diamagnetic contribution, a (-) value Mass susceptibility (+) Magnetic field (400 MHz, or 400 x 106 Hz) Concentration of sample, in g/mL How does shift, , relate to a magnetization of paramagnetic sample? g = 3  0 c

  14. Magnetic field lines of flux Magnetic field lines affected by a paramagnetic substance: attracts Susceptibility, X > 0 Magnetic field lines affected by a diamagnetic substance: repels Susceptibility, X < 0

  15. How does mass susceptibility, g , relate to unpaired electrons in a paramagnetic sample? Mass susceptibility g x (Mol. Wt.) = M Molar susceptibility corr= M - diamagnetic corrections where diamagnetic corrections for Fe, porphyrin, Cl, imidazole, a negative number! eff = 3 R T corr1/2 = 2.828 (T corr) 1/2 N 2 eff = (n(n+2))1/2

  16. Diamagnetic Corrections (cgs units) Xo (CHCl3) = - 4.97 x 10-7 cgs Porphyrin: TPP= -700 x 10-6 cgs TTP= -753 x 10-6 cgs TClPP= -760 x 10-6 cgs Fe = -13 x 10-6 cgs Cl = -20 x 10-6 cgs Imidazole = -38 x 10-6 cgs

  17. Characterization by Cyclic Voltammetry 1. How will the Ered of Fe(porphyrin) complexes vary with the porphyrin? 2. How will the Ered of Fe(porphyrin) complexes change on binding imidazole? 3. Will the Ered potentials also reflect a change in spin state? High Spin S = 5/2 n = 5 Low Spin S = 1/2 n = 1 Intermediate Spin S = 3/2 n = 3

  18. The Role of Axial Ligation and the Allosteric Effect in Hemoglobin O2 Binding

  19. 3d orbitals on Fe Spin State of Fe affects size of ion

  20. Large, high spin Fe(2+): In T state, transmitted by His on protein helix Small, low spin Fe(2+): In R state, transmitted to His on protein helix

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