2.3 Some proteins require small-molecule cofactors
Cofactors are non-protein substances that complex with particular proteins and are essential for their activity. They include prosthetic groups and coenzymes.
Coenzymes are organic molecules that bind only temporarily to an enzyme. They are often derivatives of a mono- or dinucleotide, e.g. nicotinamide adenine dinucleotide (NAD), and may serve as a vehicle for a chemical group generated or required in an enzyme-catalysed reaction. In contrast to coenzymes, prosthetic groups are permanently associated with a protein to give a functional complex.
The activity of up to a third of all enzymes depends on the presence of a metal ion. In some cases, the ion associates loosely with the protein and in others it remains tightly bound for the lifetime of the enzyme (i.e. as prosthetic groups). The latter group of enzymes are referred to as metalloenzymes and in these the prosthetic group is typically a transition metal ion such as Cu2+, Fe2+, Fe3+, Zn2+ or Mn2+. Other enzymes are activated on binding metal ions. Such interactions are usually weaker than those in metalloenzymes and generally involve ionic forms of the alkali and alkaline earth metals such as Na+, K+, Mg2+ and Ca2+.
Many respiratory pigments contain more complex prosthetic groups. An example is the haem porphyrin ring in haemoglobin, which contains eight heterocyclic rings (i.e. rings comprising one or more atoms other than carbon) (Figure 24). The haem ring structure is a derivative of porphyrin and has four N atoms arranged around an iron atom in the Fe(II) oxidation state. Together with a fifth N from a histidine side-chain of the protein, these N atoms serve to coordinate the Fe2+ ion. O2 binds to the Fe2+ on the opposite side of the porphyrin ring from the histidine residue. Each of the four subunits of haemoglobin has an associated haem group, and it is this group that gives haemoglobin its red colour.
There are a number of different types of haem groups (Figure 24 shows one example) and several genetic defects affect their biosynthesis, resulting in diseases known as porphyrias. Famously, King George III of England (1738–1820) is believed to have suffered from such a disease. Porphyrias are characterised by the accumulation of porphyrin and/or its biosynthetic precursors. Excretion of these compounds in individuals suffering from a porphyria gives their urine a characteristic red colour. Other symptoms include psychiatric disturbance caused by neurological dysfunction.