Biosynthetic pathways for 

catecholamines and trace amines in the human brain[5][6][7]

L-Phenylalanine
L-Tyrosine
L-DOPA
Epinephrine
Phenethylamine
p-Tyramine
Dopamine
Norepinephrine
N-Methylphenethylamine
N-Methyltyramine
p-Octopamine
Synephrine
3-Methoxytyramine
AADC
AADC
AADC
primary
pathway
PNMT
PNMT
PNMT
PNMT
AAAH
AAAH
brain
CYP2D6
minor
pathway
COMT
DBH
DBH

In humans, catecholamines (shown in yellow) are derived from the amino acid L-phenylalanine.

L-Phenylalanine is converted into L-tyrosine by an aromatic amino acid hydroxylase (AAAH) enzyme (phenylalanine 4-hydroxylase), with molecular oxygen (O2)

and tetrahydrobiopterin as cofactors. L-Tyrosine is converted into L-DOPA by another AAAH enzyme (tyrosine 3-hydroxylase) with tetrahydrobiopterin, O2, and ferrous iron (Fe2+) as cofactors. L-
DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC), with pyridoxal phosphate as the cofactor. Dopamine itself is also used as precursor in the

synthesis of the neurotransmitters norepinephrine and epinephrine. Dopamine is converted into norepinephrine by the enzyme dopamine β-hydroxylase (DBH), with O2 and L-ascorbic acid as

cofactors. Norepinephrine is converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT) with S-adenosyl-L-methionine as the cofactor.

Location[edit]
Catecholamines are produced mainly by the chromaffin cells of the adrenal medulla and the postganglionic fibers of the sympathetic nervous system. Dopamine, which acts as
a neurotransmitter in the central nervous system, is largely produced in neuronal cell bodies in two areas of the brainstem: the ventral tegmental area and the substantia nigra,
the latter of which contains neuromelanin-pigmented neurons. The similarly neuromelanin-pigmented cell bodies of the locus coeruleus produce norepinephrine. Epinephrine is
produced in small groups of neurons in the human brain which express its synthesizing enzyme, phenylethanolamine  N-methyltransferase;[8] these neurons project from a
nucleus that is adjacent (ventrolateral) to the area postrema and from a nucleus in the dorsal region of the solitary tract.[8]

Biosynthesis[edit]
Dopamine is the first catecholamine synthesized from DOPA. In turn, norepinephrine and epinephrine are derived from further metabolic modification of dopamine. The enzyme
dopamine hydroxylase requires copper as a cofactor (not shown in the diagram) and DOPA decarboxylase requires PLP (not shown in the diagram). The rate limiting step in
catecholamine biosynthesis through the predominant metabolic pathway is the hydroxylation of L-tyrosine to L-DOPA.[citation needed]

Catecholamine synthesis is inhibited by alpha-methyl-p-tyrosine (AMPT), which inhibits tyrosine hydroxylase.[citation needed]

The amino acids phenylalanine and tyrosine are precursors for catecholamines. Both amino acids are found in high concentrations in blood plasma and the brain. In mammals,
tyrosine can be formed from dietary phenylalanine by the enzyme phenylalanine hydroxylase, found in large amounts in the liver. Insufficient amounts of phenylalanine
hydroxylase result in phenylketonuria, a metabolic disorder that leads to intellectual deficits unless treated by dietary manipulation. [citation needed] Catecholamine synthesis is usually
considered to begin with tyrosine. The enzyme tyrosine hydroxylase (TH) converts the amino acid L-tyrosine into 3,4-dihydroxyphenylalanine (L-DOPA). The hydroxylation of L-
tyrosine by TH results in the formation of the DA precursor L-DOPA, which is metabolized by aromatic L-amino acid decarboxylase (AADC; see Cooper et al., 2002[citation needed]) to
the transmitter dopamine. This step occurs so rapidly that it is difficult to measure L-DOPA in the brain without first inhibiting AADC.[citation needed] In neurons that use DA as the
transmitter, the decarboxylation of L-DOPA to dopamine is the final step in formation of the transmitter; however, in those neurons using norepinephrine (noradrenaline)
or epinephrine (adrenaline) as transmitters, the enzyme dopamine β-hydroxylase (DBH), which converts dopamine to yield norepinephrine, is also present. In still other neurons
in which epinephrine is the transmitter, a third enzyme phenylethanolamine  N-methyltransferase (PNMT) converts norepinephrine into epinephrine. Thus, a cell that uses
epinephrine as its transmitter contains four enzymes (TH, AADC, DBH, and PNMT), whereas norepinephrine neurons contain only three enzymes (lacking PNMT) and
dopamine cells only two (TH and AADC).[citation needed]

Degradation[edit]
Catecholamines have a half-life of a few minutes when circulating in the blood. They can be degraded either by methylation by catechol- O-methyltransferases (COMT) or by
deamination by monoamine oxidases (MAO).

MAOIs bind to MAO, thereby preventing it from breaking down catecholamines and other monoamines.

Catabolism of catecholamines is mediated by two main enzymes: catechol-O-methyltransferase (COMT) which is present in the synaptic cleft and cytosol of the cell and
monoamine oxidase (MAO) which is located in the mitochondrial membrane. Both enzymes require cofactors: COMT uses Mg2+ as a cofactor while MAO uses FAD. The first step
of the catabolic process is mediated by either MAO or COMT which depends on the tissue and location of catecholamines (for example degradation of catecholamines in the
synaptic cleft is mediated by COMT because MAO is a mitochondrial enzyme). The next catabolic steps in the pathway involve alcohol dehydrogenase, aldehyde
dehydrogenase and aldehyde reductase. The end product of epinephrine and norepinephrine is vanillylmandelic acid (VMA) which is excreted in the urine. Dopamine catabolism
leads to the production of homovanillic acid (HVA).[9]

Function[edit]
Modality[edit]
Two catecholamines, norepinephrine and dopamine, act as neuromodulators in the central nervous system and as hormones in the blood circulation. The
catecholamine norepinephrine is a neuromodulator of the peripheral sympathetic nervous system but is also present in the blood (mostly through "spillover" from
the synapses of the sympathetic system).[citation needed]

High catecholamine levels in blood are associated with stress, which can be induced from psychological reactions or environmental stressors such as elevated sound
levels, intense light, or low blood sugar levels.[citation needed]

Extremely high levels of catecholamines (also known as catecholamine toxicity) can occur in central nervous system trauma due to stimulation or damage of nuclei in
the brainstem, in particular, those nuclei affecting the sympathetic nervous system. In emergency medicine, this occurrence is widely known as a "catecholamine dump".

Extremely high levels of catecholamine can also be caused by neuroendocrine tumors in the adrenal medulla, a treatable condition known as pheochromocytoma.

High levels of catecholamines can also be caused by monoamine oxidase A (MAO-A) deficiency, known as Brunner syndrome. As MAO-A is one of the enzymes responsible for
degradation of these neurotransmitters, its deficiency increases the bioavailability of these neurotransmitters considerably. It occurs in the absence
of pheochromocytoma, neuroendocrine tumors, and carcinoid syndrome, but it looks similar to carcinoid syndrome with symptoms such as facial flushing and aggression. [10][11]

Acute porphyria can cause elevated catecholamines. [12]

Effects[edit]
Catecholamines cause general physiological changes that prepare the body for physical activity (the fight-or-flight response). Some typical effects are increases in heart
rate, blood pressure, blood glucose levels, and a general reaction of the sympathetic nervous system.[citation needed] Some drugs, like tolcapone (a central COMT-inhibitor), raise the
levels of all the catecholamines. Increased catecholamines may also cause an increased respiratory rate (tackypnoea) in patients.[13]

Catecholamine is secreted into urine after being broken down, and its secretion level can be measured for the diagnosis of illnesses associated with catecholamine levels in the
body.[14] Urine testing for catecholamine is used to detect pheochromocytoma.

Function in plants[edit]
"They have been found in 44 plant families, but no essential metabolic function has been established for them. They are precursors of benzo[c]phenanthridine alkaloids, which
are the active principal ingredients of many medicinal plant extracts. CAs have been implicated to have a possible protective role against insect predators, injuries, and nitrogen
detoxification. They have been shown to promote plant tissue growth, somatic embryogenesis from in vitro cultures, and flowering. CAs inhibit indole-3-acetic acid oxidation and
enhance ethylene biosynthesis. They have also been shown to enhance synergistically various effects of gibberellins."[15]

Testing for catecholamines[edit]

Catecholamines are secreted by cells in tissues of different systems of the human body, mostly by the nervous and the endocrine systems. The adrenal glands secrete certain
catecholamines into the blood when the person is physically or mentally stressed and this is usually a healthy physiological response. [16] However, acute or chronic excess of
circulating catecholamines can potentially increase blood pressure and heart rate to very high levels and eventually provoke dangerous effects. Tests for fractionated plasma
free metanephrines or the urine metanephrines are used to confirm or exclude certain diseases when the doctor identifies signs of hypertension and tachycardia that don't
adequately respond to treatment.[17][18] Each of the tests measure the amount of adrenaline and noradrenaline metabolites, respectively
called metanephrine and normetanephrine.

Blood tests are also done to analyze the amount of catecholamines present in the body.

Catecholamine tests are done to identify rare tumors at the adrenal gland or in the nervous system. Catecholamine tests provide information relative to tumors such as:
pheocromocytoma, paraganglioma, and neuroblastoma. [19][20]