The combined metabolic pathway for production of human neurotransmitters in the brain, adrenal gland, and sympathetic nervous system is outlined in Figure 1 below. The key starting material for both human and Clostridia pathways is the amino acid phenylalanine.
In humans, phenylalanine and/or tyrosine from dietary proteins or amino acid supplements are absorbed into blood from the intestinal tract where these amino acids cross the blood-brain barrier and enter the brain.
Phenylalanine in the brain is converted to tyrosine by phenylalanine hydroxylase. The ring of tyrosine is then hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. DOPA is then converted to dopamine by DOPA decarboxylase which requires a vitamin B6 cofactor. The fate of further dopamine metabolism depends on the neuron type. In dopamine-secreting neurons, dopamine is the final product. In these neurons, dopamine is metabolized into homovanillic acid which can be measured in the urine organic acid test. In norepinephrine-containing brain neurons, neurons in the peripheral central nervous system, and in the adrenal gland, dopamine is converted to norepinephrine by dopamine-beta-hydroxylase. Dopamine-beta-hydroxylase requires ascorbic acid and copper as cofactors. In the adrenal gland, norepinephrine is further converted to epinephrine. Both epinephrine and norepinephrine may then be metabolized into vanillylmandelic acid (VMA).
In the species of Clostridia bacteria mentioned at the beginning of the article, phenylalanine is converted to HPHPA by a pathway that requires both human and bacterial enzymes. If Clostridia difficile is present, tyrosine is largely converted to 4-cresol. These byproducts are then absorbed into the body through the intestinal tract where they have the ability to inhibit dopamine-beta-hydroxylase. These byproducts covalently bind to the enzyme active site, irreversibly inhibiting conversion of dopamine to norepinephrine.