How to understand the structure of serotonin
By: Shamal Gunawardhana
Tags: Serotonin, Psychedelics, Biochemistry, Neuroscience, Pharmacology

Serotonin or commonly known as the happy chemical is many things, it functions as a neurotransmitter in the central nervous system and a hormone in the periphery. The scientific name for serotonin is the 5-Hydroxytryptamine or its much easier abbreviated form of 5-HT.

Building blocks

Serotonin is biologically derived from the amino acid L-tryptophan. Tryptophan is an essential amino acid; therefore must be included in our dietary intake.

Much of the complexity of the structure of the serotonin molecule arises from the structure of tryptophan. It follows the basic blueprint of amino acid.

The basic structure of an amino acid consists of a central alpha carbon atom joined by an amino group, carboxylic acid group, hydrogen atom and an ‘R’ side chain, a variable.

In the amino acid tryptophan R group consist of a methyl group (-CH2-) joined by an indole ring. Indole ring is a bicyclic structure formed by the fusion of a benzene ring to a pyrrole ring.

Pyrrole ring is essentially a pentameric aromatic ring containing 4 carbon atoms and a single nitrogen atom.

Benzene is a hexameric aromatic ring containing 6 carbon atoms, adding one of these to the side of the pyrrole ring gives us the indole ring.

Structure of serotonin is easily understood studying its biosynthesis pathway. Since we got ourselves some tryptophan now…

5-HT here we come…

Serotonin is produced in a multi-step pathway. When producing 5-HT from tryptophan 2 key changes occur in the structure tryptophan molecule, hydroxylation which is then followed by decarboxylation.

Hydroxylation

Essentially we’ll be adding an alcohol(OH) group to the 5th position of the tryptophan structure, just one catch where the heck exactly is the 5th position? This is where numbering the carbon atoms of this structure becomes essential.

We’ve already gotten one atom named, the alpha carbon of the amino acid. The carbon atom of the methyl group attached to this alpha carbon is named Beta.

So where do we start next, the only other interesting atom in this whole structure is the nitrogen atom. So we’ll start our naming ceremony here. let’s label it as the 1st position of the indole ring and continue the numbering from here onwards away from the benzene ring. When we are met with C atoms at the junction between the pyrrole ring and the benzene ring it’s numbered as an ‘a’ of the previous numeral. Two such positions are found in this structure 3a and 7a.

Since we found the 5th position the tryptophan structure, let’s add the OH(alcohol) group to this position and voilà we have 5-Hydroxytryptophan.

This reaction is catalyzed by the appropriately named enzyme Tryptophan 5 hydroxylase(Tph). This is the rate-limiting step of serotonin biosynthesis.

Decarboxylation

This step is fairly simple we just have to remove the CO2 group bound to the alpha carbon of the amino acid and what remains is a hydrogen atom, simple enough. This step is catalyzed by the enzyme aromatic L-amino acid decarboxylase.

One more thing…

There are 2 genes coding for the Tph(Tryptophan 5 hydroxylase) enzyme: Tph1 and Tph2. Tph1 is expressed mostly in enterochromaffin cells of the gut and is responsible for most of the serotonin present in the blood. On the other hand, the gene Tph2 is expressed exclusively in serotonergic neurons of the brainstem(Raphe nuclei) and is responsible for the production of serotonin in the brain.

These two pools of serotonin, one in the blood and the other in the brain, never cross over; therefore these should be viewed from a functional point of view as two distinct molecules. Brain-derived serotonin (BDS) acts as a neurotransmitter, while gut-derived serotonin (GDS) acts as a hormone and regulates a wide variety of processes.

References

https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/serotonin

https://pubchem.ncbi.nlm.nih.gov/compound/Indole

https://pubchem.ncbi.nlm.nih.gov/compound/Pyrrole#section=2D-Structure

https://pubchem.ncbi.nlm.nih.gov/compound/Tryptophan#section=2D-Structure

https://en.wikipedia.org/wiki/Amino_acid

https://en.m.wikipedia.org/wiki/Indole

https://pubchem.ncbi.nlm.nih.gov/compound/Serotonin#section=2D-Structure