# 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 ¶

#### 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
• 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

## 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

## 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

## 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

## 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.

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