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Bioinorganic Chemistry

What is bioinorganic chemistry?

  • Discovery of how inorganic elements work within biological systems
  • The introduction of inorganic components into biological systems to use as probes and drugs

Elements used in biochemistry

  • Primarily it is the organic elements used in biochemistry, however first row transitions metals are often used within protein complexes at metal cores.
  • The big six elements are:
    • C, H, N, O, P and S
  • But the chemistry that these elements alone, can create is not enough to produce life.
    • An additional seven or eight are required by all life on the planet

Metals in biology
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Iron

  • Primarily used for oxygen or electron transport
    • Haemoglobin
    • Myoglobin
    • Cytochromes
    • Ferredoxin

Cobalt

  • Used as a catalyst - acts within a larger molecule as a coenzyme
    • Vitamin B12

Copper

  • Used in oxygen transport where iron is scarce (blue blood)
    • Hemocyanin
  • Also used as catalysts within metalloenzymes

Zinc

  • Acts as a catalyst within an enzyme itself
    • Carboxypeptidase - protease that breaks down peptides from the carboxylic acid end
    • Carbonic anhydrase - interconverts \(\ce{CO2}\) to \(\ce{H2CO3}\) (carbonic acid) to regulate pH in the cells
  • Also has a structural element to it

Sodium/Potassium

  • Used as a regulating solute
    • Ion channels and action potentials

Calcium/Magnesium

  • Used as a structural element
    • \(\ce{Ca3(PO4)2}\)

Nickel, Molybdenum, Tungsten

  • Used as catalysts within metalloenzymes

Oxygen Carrying

  • The structures on the right are structures that exist within protein complexes
    • The protein itself provides conformational catalysis to the metal core
  • Haemoglobin consists of the porphyrin molecule heme bound within four subunits
  • Each is found within a different form of life
    • Haemoglobin is found in vertebrates
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    • Hemocyanin is found within molluscs
    • Hemerythrin is found within sea worms
  • CO/CN/NO have stronger binding affinities to the complexes than oxygen
    • This causes them to inhibit respiratory processes

Haemoglobin

  • Consists of four subunit peptides bound to four heme coenzymes
    • \(2\times\:\alpha\)-chains \(+2\times\:\beta\)-chains for adults
    • \(2\times\:\alpha\)-chains \(+2\times\:\delta\)-chains for foetuses
  • Three major types of Hb exist
    • Hb A which is present in adults
    • Hb F which is present in foetuses
      • Possibly to have a stronger oxygen affinity to the maternal Hb
      • All new cells after birth are produced with Hb A * Takes about 6 months to replace
    • Hs S which is present with the sickle cell mutation
      • Caused by a mutation in the $\beat}-chain, causing a build up of hydrophilic residues that aggregate (plaque) * Glutamic acid is replaced with valine
      • Helps to prevent malaria infections
      • Clogs blood vessels
      • Reduces oxygen carrying capacity

Myoglobin

  • Needs to be reversibly bound to oxygen, or it couldn’t release the oxygen where needed
    • Deoxymyoglobin
      • When not bound, the iron centre sits outside of the porphyrin ring, an is in high spin, causing it to be more paramagnetic
      • This is the “relaxed” state of Mb, which has a higher binding affinity to oxygen
    • Oxymyoglobin
      • When bound to oxygen, the iron enters a low spin state, is pulled into the porphyrin ring plane and pulls on the proximal histidine residue
      • This puts the Mb in a “tense” state which is more ready to release the oxygen
    • The states are also reinforced by pH
      • H+ is produced in metabolic cells but not in the lungs, making lungs have a lower pH.
      • The decrease in pH of the metabolic cells stabilises the tense state (oxymyoglobin), allowing the oxygen to be released more easily and vice versa in the lungs

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Synthetic Hb

  • The synthetic Hb, called the “picket fence” porphyrin was an attempt at making a synthetic haemoglobin
  • It failed, due to the lack of a protein structure around it, helping it to behave better in a biological environment

Photosynthesis

  • \(\ce{6CO2 + 6H2O -> C6H12O6 + 6O2}\) simple schematic reactions

    • Reduces \(\ce{CO2}\) to glucose while oxidising \(\ce{H2O}\) to \(\ce{O2}\)
    • This can be attempted by applying a reduction potential to the reactants, but there is no specificity in the products produced and requires a lot of energy to do so
    • Photosystem II was an attempt at atficial photosynthesis, but it had very low yields

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Stability constants

  • Going back to chem 1, stability constants describe where the equilibrium of a reaction lies:
\[ \ce{[M]^{x+} + nL -> [ML]^{x+}} \]
\[ \ce{K_{st}=\frac{[ML]}{[M][L]n}} \]
  • If K_st is really small, the equilibrium favours the products, it it’s really big, it favours the reactants

Denticity of ligands

Refer back to the Macrocycle effect.

  • The macrocycle effect shows that:
    1. The stability (\(K_st\)) of the ligand increases as its denticity does
    2. A cyclic ligand will have a massive increase in stability * This is very useful for stabilising radioisotopes for medical imaging

Enterobactin

  • Iron in water is particularly insoluble as it very quickly turns to rust.
  • Enterobactin, which is released as a bioligand for iron has a significantly stronger stability with iron, than it does with hydroxide. This allows it to convert insoluble rust into bioavailable iron
\[ \begin{gather} \ce{Fe^{3+} + enterobactin <=> [Fe(enterobactin)]^{3+}, K_{stab}=10^52}\\ \ce{[Fe(H2O)6]^{3+} + H2O <-> [Fe(H2O)5OH]^{2+} + H3O+, pK_{s1}=2.2}\\ \ce{[Fe(H2O)5(OH)]^{2+} + H2O <-> [Fe(H2O)4(OH)2]+ + H3O+, pK_{s2}=3.5}\\ \ce{[Fe(H2O)4(OH)2]+ + H2O <-> [Fe(H2O)3(OH)3](=Fe(OH)3.aq) + H3O+, pK_{s3}=6.0} \end{gather} \]
  • Each of these rust forming reactions significantly favours the products over the reactants to produce insoluble rust

Heavy metal poisoning

  • The vast majority of heavy metal poisoning happens as a result of heavy metals mimicking the behaviours of their biologically needed relatives
    • Cadmium likes to mimic zinc - is a big issue in battery manufacturing regions
    • Arsenic likes to mimic phosphorus - can be found in ground water
    • Beryllium likes to mimic magnesium and calcium
  • For a general trend, look up and down the period of the periodic table to see what biologically important element it might mimic

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Chelation therapy

  • Works by binding stable ligands to the heavy metal to stop it from being used by the biological system it’s contaminated
  • E.g. two Desferox (commercial) molecules binding to an iron atom

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Cisplatin

  • Is a common chemotherapy drug, which binds to rabidly dividing DNA, preventing transcription proteins from accessing that portion of the genetic material
  • The chlorine ligands bind to adjacent guanine residues on the DNA which causes a DNA repair which inevitably fails due to the strongly bound platinum
  • Discovered serendipitously when Rosenberg tested a hypothesis of magnetic cell division by putting platinum in a growth media with an electric field
  • When the electric current was turned on, the cells stopped growing, as the platinum was converted into cisplatin.

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The chloride ions are weakly bound to the platinum and will preferentially be exchanged with the amine groups on the guanine bases, causing the DNA to kink and be unreadable