Synthesis

Dopamine is synthesized in a restricted set of cell types, mainly neurons, and cells in the medulla of the adrenal glands. The primary and minor metabolic pathways respectively are:

Primary: L-Phenylalanine → L-Tyrosine → L-DOPA → Dopamine
Minor: L-Phenylalanine → L-Tyrosine → p-Tyramine → Dopamine
Minor: L-Phenylalanine → m-Tyrosine → m-Tyramine → Dopamine
The direct precursor of dopamine, L-DOPA, can be synthesized indirectly from the essential amino acid phenylalanine or directly from the non-essential amino acid tyrosine. These amino acids are found in nearly every protein and so are readily available in food, with tyrosine being the most common. Although dopamine is also found in many types of food, it is incapable of crossing the blood-brain barrier that surrounds and protects the brain. It must, therefore, be synthesized inside the brain to perform its neuronal activity.

L-Phenylalanine is converted into L-tyrosine by the enzyme phenylalanine hydroxylase, with molecular oxygen (O2) and tetrahydrobiopterin as cofactors. L-Tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase, with tetrahydrobiopterin, O2, and iron (Fe2+) as cofactors. L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (also known as DOPA decarboxylase), with pyridoxal phosphate as the cofactor.

Dopamine itself is used as a precursor in the synthesis of the neurotransmitters norepinephrine and epinephrine. Dopamine is converted into norepinephrine by the enzyme dopamine β-hydroxylase, with O2 and L-ascorbic acid as cofactors. Norepinephrine is converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase with S-adenosyl-L-methionine as the cofactor.

Some of the cofactors also require their own synthesis. Deficiency in any required amino acid or cofactor can impair the synthesis of dopamine, norepinephrine, and epinephrine.

Degradation

Dopamine is broken down into inactive metabolites by a set of enzymes—monoamine oxidase (MAO), catechol-O-methyl transferase (COMT), and aldehyde dehydrogenase (ALDH), acting in sequence. Both isoforms of monoamine oxidase, MAO-A and MAO-B, effectively metabolize dopamine. Different breakdown pathways exist but the main end-product is homovanillic acid (HVA), which has no known biological activity. From the bloodstream, homovanillic acid is filtered out by the kidneys and then excreted in the urine. The two primary metabolic routes that convert dopamine into HVA are:

Dopamine → DOPAL → DOPAC → HVA – catalyzed by MAO, ALDH, and COMT respectively
Dopamine → 3-Methoxytyramine → HVA – catalyzed by COMT and MAO+ALDH respectively
In clinical research on schizophrenia, measurements of homovanillic acid in plasma have been used to estimate levels of dopamine activity in the brain. A difficulty in this approach, however, is separating the high level of plasma homovanillic acid contributed by the metabolism of norepinephrine.

Although dopamine is normally broken down by an oxidoreductase enzyme, it is also susceptible to oxidation by direct reaction with oxygen, yielding quinones plus various free radicals as products. The rate of oxidation can be increased by the presence of ferric iron or other factors. Quinones and free radicals produced by autoxidation of dopamine can poison cells, and there is evidence that this mechanism may contribute to the cell loss that occurs in Parkinson’s disease and other