Catecholamines: Structure, Synthesis, and Function

Catecholamines Overview

• Catecholamines are types of hormones produced by the adrenal glands that sit atop the kidneys.
• These hormones are released into the bloodstream during physical or emotional stress.
• The main types of catecholamines include dopamine, norepinephrine, and epinephrine (previously known as adrenalin).

Structure

• Catecholamines have a distinct structure consisting of a benzene ring with two hydroxyl groups, an ethyl chain, and an amine group.
• Phenylethanolamines, such as norepinephrine, have a hydroxyl group attached to the ethyl chain.
• Catecholamines are named due to containing a catechol, or 3,4-dihydroxybenzene group.
• They are derived from the amino acid tyrosine.

Abundance and Synthesis

• Epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine are the most abundant catecholamines in the human body.
• These catecholamines are produced from the amino acids phenylalanine and tyrosine.
• Various stimulant drugs can act as catecholamine analogues.
• Being water-soluble, catecholamines are 50% bound to plasma proteins, allowing them to circulate in the bloodstream.
• Tyrosine is formed from phenylalanine via hydroxylation, catalyzed by the enzyme phenylalanine hydroxylase and is also ingested directly from dietary protein.
• Catecholamine-secreting neurons convert tyrosine to L-DOPA, then to dopamine, norepinephrine, and finally epinephrine, in a series of reactions.

Dopamine Receptors

• Dopamine receptors include the receptor subtypes D1, D2 , D3, D4 and D5.
• The agonists of the D1 receptor are SKF 38393 and Dihydrexidine; antagonists are Sch 23390, SKF83566 and SCH39166
• The second messenger of the D1 receptor is positive cAMP, which stimulates adenylyl cyclase, and can cause mouse knockout hyperactivity and Diastolic hypertension
• The agonists of the D2 receptor are (+)PHNO and Bromocriptine; antagonists are (s)-Sulpiride, Raclopride, Domperidone and Haloperidol
• The second messenger of the D2 receptor is positive gK+ G-protein, which inhibits adenylyl cyclase, and can cause Myoclonus-Dystonia and can be used in Anti-psychotic drugs
• The agonists of the D3 receptor are 7-OH-DPAT, PD128907 and BP897; the antagonists of the D3 receptor are Nafadotride
• The second messenger of the D3 receptor is a positive ion channel and can cause Mouse knockout hyperactivity
• The antagonists of the D4 receptor are L745870, L741742 and U101387; the second messenger of the D4 receptor is a positive ion channel, and can cause Autonomic dysfunction
• The second messenger of the D5 receptor is positive cAMP G-protein and it can cause Focal dystonia Blepharospasm

Metabolism-Synthesis

• Dopamine is the first catecholamine to be synthesized from DOPA.
• Norepinephrine and epinephrine are produced through metabolic modification of dopamine.
• Dopamine hydroxylase needs copper as a cofactor, and DOPA decarboxylase needs PLP.
• Hydroxylation of tyrosine is the rate-limiting step in the biosynthesis of catecholamines.
• Catecholamine synthesis is inhibited by alpha-methyl-p-tyrosine (AMPT), which inhibits tyrosine hydroxylase.

Breakdown

• Catecholamines have a short half-life, lasting only a few minutes in the blood.
• They are degraded either by methylation via catechol-O-methyltransferases (COMT) or by deamination via monoamine oxidases (MAO).
• Amphetamines and MAOIs inhibit MAO, preventing the breakdown of catecholamines.
• This action is why amphetamines have a longer lifespan compared to substances like cocaine.
• Amphetamines cause a release of dopamine, epinephrine, and norepinephrine into the bloodstream and suppress re-absorption.

Metabolizing Enzymes & Metabolites

• Tyrosine hydroxylase and L-aromatic amino acid decarboxylase are the synthesizing enzymes of dopamine.
• MAO and COMT are the metabolizing enzymes.
• 3,4-Dihydroxyphenylacetic acid (DOPAC) and Homovanillic acid (HVA) are the metabolites of dopamine.
• For adrenaline and Noradrenaline, Tyrosine hydroxylase, L-aromatic amino acid decarboxylase, Dopamine ß-hydroxylase, and phenylethanolamine-N-methyl transferase are the synthesizing enzymes.
• For adrenaline and Noradrenaline, MAO and COMT are the metabolizing enzymes.
• Vanillylmandelic acid (VMA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the metabolites of adrenaline and Noradrenaline.

Functions

• Norepinephrine and dopamine serve as neuromodulators in the central nervous system and function as circulating hormones.
• Norepinephrine acts as a neuromodulator in the peripheral sympathetic nervous system and can be found in the blood.
• High catecholamine levels relate to stress and can be triggered by psychological reactions or environmental factors like elevated sound levels, intense light, or low blood sugar levels.
• Extremely high catecholamine levels occur in central nervous system trauma and damage to nuclei in the brainstem.
• "Catecholamine dump" is a term used in emergency medicine to describe this occurrence.
• Neuroendocrine tumors in the adrenal medulla, known as pheochromocytoma, can also cause extremely high catecholamine levels; a condition that is treatable.
• Monoamine oxidase A (MAO-A) deficiency can also cause high levels of catecholamines.
• Deficiency in MAO-A, an enzyme responsible for neurotransmitter degradation, increases their bioavailability, which can lead to carcinoid syndrome.

Neurotransmitter Metabolic Intermediates

• Anabolism: tyrosine turns into epinephrine.
• Tyrosine is metabolized into levodopa, then dopamine, norepinephrine, and finally epinephrine.

Catabolism/Metabolites

• Dopamine metabolizes into DOPAL, DOPAC, MOPET, Hydroxytyrosol, 3-Methoxytyramine, and Homovanillic acid.
• Norepinephrine metabolizes into 3,4-Dihydroxymandelic acid, Normetanephrine, Vanillylmandelic acid, 3-Methoxy-4-hydroxyphenylglycol and Dihydroxyphenylethylene glycol.
• Epinephrine metabolizes into Metanephrine.