Heterocyclic Chemistry at a Glance, Second Edition. John A. Joule and Keith Mills.
© 2013 John Wiley & Sons, Ltd. Published 2013 by John Wiley & Sons, Ltd.
17. Heterocycles in Nature
Heterocyclic -amino acids and related substances
There are four -amino acids, amongst the 22 that make up proteins, that have an aromatic side-chain and, of these,
two have a heteroaromatic side-chain – histidine with an imidazole and tryptophan with an indole. Both of these
are amongst the ‘essential amino acids’, that is they need to be part of the diet as they cannot be biosynthesised by
human beings (cf. proline below). Decarboxylation of histidine produces the hormone histamine, a vasodilator
and a major factor in allergic reactions such as hay fever. Decarboxylated tryptophan is called tryptamine. The
phenol 5-hydroxytryptamine (5-HT or serotonin) is a very important neurotransmitter substance in the central
nervous system and also in the cardiovascular and gastrointestinal systems.
The acetamide of 5-methoxytryptamine, known as melatonin, is produced by the pineal gland, a pea-sized gland
at the base of the brain. It is involved in controlling the natural daily cycle of hormone release in the body – the
circadian rhythm. The secretion of melatonin is triggered by the dark and is suppressed by natural daylight, there-
fore controlling periods of sleepiness and wakefulness. It is used as a supplement to treat disruption of circadian
rhythm, including jet lag.
The ability of imidazole to act both as an acid (N-hydrogen) and as a base (the imine nitrogen) is put to good use in the
active sites of several enzymes. The imidazole rings of appropriately placed histidines effectively ‘shuffl e’ protons from
one place to another. One example is the digestive enzyme chymotrypsin, which brings about the hydrolysis of protein
amide groups (‘peptide bonds’) in the small intestine: the enzyme provides a proton at one site, while it accepts a proton at
another, making use of the ambivalent character of the imidazole ring to achieve this. Effectively, the imidazole activates the
serine alcoholic hydroxyl by removing the proton as the oxygen attacks the amide bond. Subsequently, that same proton is
delivered to the cleaving amide nitrogen as the tetrahedral intermediate breaks down.