View source for Catecholamine

{{Short description|Class of chemical compounds}}
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|image1=Adrenalin - Adrenaline.svg
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|caption1=[[Epinephrine]] (adrenaline)
|image2=Noradrenalin - Noradrenaline.svg
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|caption2=[[Norepinephrine]] (noradrenaline)
|image3=Dopamin - Dopamine.svg
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|caption3=[[Dopamine]]
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[[Image:Pyrocatechol.svg|class=skin-invert-image|thumb|80px|[[Catechol]]]]

A '''catecholamine''' ({{IPAc-en|ˌ|k|æ|t|ə|ˈ|k|oʊ|l|ə|m|iː|n}}; abbreviated '''CA'''), most typically a '''3,4-dihydroxyphenethylamine''', is a [[monoamine neurotransmitter]], an [[organic compound]] that has a [[catechol]] ([[benzene]] with two [[hydroxyl]] side groups next to each other) and a [[Side chain|side-chain]] [[amine]].<ref>{{cite book | last = Fitzgerald | first = P. A. | chapter = Chapter 11. Adrenal Medulla and Paraganglia | editor1-last = Gardner | editor1-first = D. G. | editor2-last = Shoback | editor2-first= D. | title = Greenspan's Basic & Clinical Endocrinology | edition = 9th | location = New York | publisher = McGraw-Hill | year = 2011 | chapter-url = http://www.accessmedicine.com/content.aspx?aID=8404198 | access-date = October 26, 2011 }}</ref>

[[Catechol]] can be either a free molecule or a [[substituent]] of a larger molecule, where it represents a 1,2-dihydroxybenzene group.

Catecholamines are derived from the [[amino acid]] [[tyrosine]], which is derived from dietary sources as well as synthesis from [[phenylalanine]].<ref name="Purves">{{cite book |editor1-last=Purves |editor1-first=D. |editor2-last=Augustine |editor2-first=G. J. |editor3-last=Fitzpatrick |editor3-first=D. |editor4-last=Hall |editor4-first=W. C. |editor5-last=LaMantia |editor5-first=A. S. |editor6-last=McNamara |editor6-first=J. O. |editor7-last=White |editor7-first=L. E. | title = Neuroscience | edition = 4th | publisher = Sinauer Associates | pages = 137–138 | year = 2008 | isbn = 978-0-87893-697-7 }}</ref> Catecholamines are water-soluble and are 50% bound to plasma proteins in circulation.

Included among catecholamines are [[epinephrine]] (adrenaline), [[norepinephrine]] (noradrenaline), and [[dopamine]]. Release of the [[hormone]]s epinephrine and norepinephrine from the [[adrenal medulla]] of the [[adrenal gland]]s is part of the [[fight-or-flight response]].<ref>{{cite web | url = http://myhealth.ucsd.edu/library/healthguide/en-us/support/topic.asp?hwid=te7424 | publisher = University of California | location = San Diego, CA | work = Health Library | title = Catecholamines | url-status = dead | archive-url = https://web.archive.org/web/20110716025522/http://myhealth.ucsd.edu/library/healthguide/en-us/support/topic.asp?hwid=te7424 | archive-date = July 16, 2011 }}</ref>

Tyrosine is created from phenylalanine by [[hydroxylation]] by the enzyme [[phenylalanine hydroxylase]]. Tyrosine is also ingested directly from dietary protein. Catecholamine-secreting cells use several reactions to convert tyrosine serially to [[L-DOPA|<small>L</small>-DOPA]] and then to dopamine. Depending on the cell type, dopamine may be further converted to norepinephrine or even further converted to epinephrine.<ref>{{cite journal |last1=Joh |first1=T. H. |last2=Hwang |first2=O. | title = Dopamine Beta-Hydroxylase: Biochemistry and Molecular Biology | journal = Annals of the New York Academy of Sciences | volume = 493 | pages = 342–350 | year = 1987 | pmid = 3473965 | doi = 10.1111/j.1749-6632.1987.tb27217.x |s2cid=86229251 }}</ref>

Various [[stimulant]] drugs (such as a number of [[substituted amphetamine]]s) are catecholamine analogues.

==Structure==
Catecholamines have the distinct structure of a [[benzene ring]] with two [[hydroxyl]] groups, an intermediate [[ethyl group|ethyl]] chain, and a terminal [[amine]] group. Phenylethanolamines such as norepinephrine have a hydroxyl group on the ethyl chain.{{citation needed|date=January 2021}}

==Production and degradation==
{{Catecholamine and trace amine biosynthesis|align=right|caption=In humans, catecholamines (shown in yellow) are derived from the [[amino acid]] <small>L</small>-phenylalanine.<br /><small>L</small>-Phenylalanine is converted into <small>L</small>-tyrosine by an [[aromatic amino acid hydroxylase|aromatic amino acid hydroxylase (AAAH)]] enzyme ([[phenylalanine 4-hydroxylase]]), with molecular [[oxygen]] (O<sub>2</sub>) and [[tetrahydrobiopterin]] as [[cofactor (biochemistry)|cofactor]]s. <small>L</small>-Tyrosine is converted into <small>L</small>-DOPA by another AAAH enzyme ([[tyrosine 3-hydroxylase]]) with [[tetrahydrobiopterin]], O<sub>2</sub>, and [[ferrous]] [[iron]] (Fe<sup>2+</sup>) as cofactors. <small>L</small>-DOPA is converted into dopamine by the enzyme [[aromatic L-amino acid decarboxylase|aromatic <small>L</small>-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 beta hydroxylase|dopamine β-hydroxylase (DBH)]], with O<sub>2</sub> and [[ascorbic acid|<small>L</small>-ascorbic acid]] as cofactors. Norepinephrine is converted into epinephrine by the enzyme [[phenylethanolamine N-methyltransferase|phenylethanolamine ''N''-methyltransferase]] (PNMT) with [[S-Adenosyl methionine|''S''-adenosyl-<small>L</small>-methionine]] as the cofactor.}}

===Location===

Catecholamines are produced mainly by the [[chromaffin cells]] of the [[adrenal medulla]] and the [[postganglionic fiber]]s 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|phenylethanolamine ''N''-methyltransferase]];<ref name="Human PNMT neurons">{{cite journal | last1= Kitahama |first1=K. |last2=Pearson |first2=J. |last3=Denoroy |first3=L. |last4=Kopp |first4=N. |last5=Ulrich |first5=J. |last6=Maeda |first6=T. |last7=Jouvet |first7=M. | title = Adrenergic neurons in human brain demonstrated by immunohistochemistry with antibodies to phenylethanolamine-''N''-methyltransferase (PNMT): discovery of a new group in the nucleus tractus solitarius | journal = Neuroscience Letters | volume = 53 | issue = 3 | pages = 303–308 | year = 1985 | pmid = 3885079 | doi = 10.1016/0304-3940(85)90555-5|s2cid=2578817 }}</ref> 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]].<ref name="Human PNMT neurons" />

===Biosynthesis===

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 (biochemistry)|cofactor]] (not shown in the diagram) and DOPA decarboxylase requires [[Pyridoxal phosphate|PLP]] (not shown in the diagram). The rate limiting step in catecholamine biosynthesis through the predominant metabolic pathway is the hydroxylation of <small>L</small>-tyrosine to <small>L</small>-DOPA.<ref>{{cite journal |url=https://link.springer.com/article/10.1007/s00702-014-1238-7 |doi=10.1007/s00702-014-1238-7 |title=Complex molecular regulation of tyrosine hydroxylase |date=2014 |last1=Tekin |first1=Izel |last2=Roskoski |first2=Robert |last3=Carkaci-Salli |first3=Nurgul |last4=Vrana |first4=Kent E. |journal=Journal of Neural Transmission |volume=121 |issue=12 |pages=1451–1481 |url-access=subscription }}</ref>

Catecholamine synthesis is inhibited by alpha-methyl-''p''-tyrosine ([[AMPT]]), which inhibits [[tyrosine hydroxylase]].{{Citation needed|date=February 2012}}

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|date=April 2019}} Catecholamine synthesis is usually considered to begin with tyrosine. The enzyme [[tyrosine hydroxylase]] (TH) converts the amino acid <small>L</small>-tyrosine into 3,4-dihydroxyphenylalanine (<small>L</small>-DOPA). The hydroxylation of <small>L</small>-tyrosine by TH results in the formation of the DA precursor <small>L</small>-DOPA, which is metabolized by [[Aromatic L-amino acid decarboxylase|aromatic <small>L</small>-amino acid decarboxylase]] (AADC; see Cooper et al., 2002{{citation needed|date=April 2019}}) to the transmitter dopamine. This step occurs so rapidly that it is difficult to measure <small>L</small>-DOPA in the brain without first inhibiting AADC.{{citation needed|date=April 2019}} In [[neuron]]s that use DA as the transmitter, the decarboxylation of <small>L</small>-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 beta-hydroxylase|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|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|date=April 2019}}

===Degradation===

Catecholamines have a half-life of a few minutes when circulating in the blood. They can be degraded either by methylation by [[Catechol-O-methyl transferase|catechol-''O''-methyltransferases (COMT)]] or by deamination by [[Monoamine oxidase|monoamine oxidases (MAO)]].

[[MAOI]]s bind to MAO, thereby preventing it from breaking down catecholamines and other monoamines.
{{clear right}}

[[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 [[Magnesium in biology|Mg<sup>2+</sup>]] as a cofactor while MAO uses [[Flavin adenine dinucleotide|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|vanillylmandelic acid (VMA)]] which is excreted in the [[urine]]. Dopamine catabolism leads to the production of [[homovanillic acid|homovanillic acid (HVA)]].<ref>{{cite journal|last1=Eisenhofer|first1=G.|last2=Kopin|first2=I. J.|last3=Goldstein|first3=D. S.|s2cid=12825309|title=Catecholamine metabolism: a contemporary view with implications for physiology and medicine|journal= Pharmacological Reviews|date=2004|volume=3|issue=56|pages=331–349|pmid=15317907|doi=10.1124/pr.56.3.1}}</ref>

==Function==

===Modality===
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 [[synapse]]s of the sympathetic system).{{citation needed|date=January 2021}}

High catecholamine levels in blood are associated with [[Stress (medicine)|stress]], which can be induced from psychological reactions or environmental stressors such as [[noise health effects|elevated sound levels]], [[light pollution|intense light]], or [[Hypoglycemia|low blood sugar levels]].<ref>{{Citation |last1=Chu |first1=Brianna |title=Physiology, Stress Reaction |date=2024 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK541120/ |access-date=2024-06-28 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31082164 |last2=Marwaha |first2=Komal |last3=Sanvictores |first3=Terrence |last4=Awosika |first4=Ayoola O. |last5=Ayers |first5=Derek}}</ref>

Extremely high levels of catecholamines (also known as catecholamine toxicity) can occur in [[central nervous system]] trauma due to stimulation or damage of [[nucleus (neuroanatomy)|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 tumor]]s in the [[adrenal medulla]], a treatable condition known as [[pheochromocytoma]].

High levels of catecholamines can also be caused by [[monoamine oxidase A|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 tumor]]s, and [[carcinoid syndrome]], but it looks similar to carcinoid syndrome with symptoms such as facial flushing and aggression.<ref>{{ cite journal | last1 = Manor | first1 = I. | last2 = Tyano | first2 = S. | last3 = Mel | first3 = E. | last4 = Eisenberg | first4 = J. | last5 = Bachner-Melman | first5 = R. | last6 = Kotler | first6 = M. | last7 = Ebstein | first7 = R. P. | title = Family-Based and Association Studies of Monoamine Oxidase A and Attention Deficit Hyperactivity Disorder (ADHD): Preferential Transmission of the Long Promoter-Region Repeat and its Association with Impaired Performance on a Continuous Performance Test (TOVA) | journal = Molecular Psychiatry | volume = 7 | issue = 6 | pages = 626–632 | year = 2002 | pmid = 12140786 | doi = 10.1038/sj.mp.4001037 | doi-access = free }}</ref><ref>{{ Cite book | author = Brunner, H. G. | chapter = MAOA Deficiency and Abnormal Behaviour: Perspectives on an Association | title = Genetics of Criminal and Antisocial Behaviour | series = Ciba Foundation Symposium | volume = 194 | pages = 155–167 | year = 1996 | pmid = 8862875 | doi = 10.1002/9780470514825.ch9 | publisher = Wiley| isbn = 978-0-470-51482-5 }}</ref>

Acute [[porphyria]] can cause elevated catecholamines.<ref>{{cite journal| last1=Stewart |first1=M. F. |last2=Croft |first2=J. |last3=Reed |first3=P. |last4=New |first4=J. P. | pmc= 1994495 | pmid=17660335 | doi=10.1136/jcp.2005.032722 | volume=60 |issue=8 | title=Acute intermittent porphyria and phaeochromocytoma: shared features | journal=Journal of Clinical Pathology | pages=935–936 | year=2006}}</ref>

==Aging==
Degeneration of the [[locus coeruleus]] and reduced production of norepinephrine during aging are under preliminary research as possible factors in the pathogenesis of [[Alzheimer's disease]].<ref name="heneka">{{cite journal |vauthors=Heneka MT, Carson MJ, El Khoury J, et al. |title=Neuroinflammation in Alzheimer's disease |journal=The Lancet. Neurology |volume=14 |issue=4 |pages=388–405 |date=April 2015 |pmid=25792098 |pmc=5909703 |doi=10.1016/S1474-4422(15)70016-5}}</ref>

== Physiological effects ==
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|date=April 2019}} Some drugs, like [[tolcapone]] (a central [[COMT]]-inhibitor), raise the levels of all the catecholamines. Increased catecholamines may also cause an increased respiratory rate ([[Tachypnea|tachypnoea]]) in patients.<ref>{{Cite book|last=Estes|first=Mary|title=Health assessment and physical examination|publisher=[[Cengage]]|year=2016|isbn=978-0-17-035484-4|edition=2nd|location=[[Melbourne]]|pages=143}}</ref>

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.<ref>{{cite web|title=Catecholamines in Urine|url=http://www.webmd.com/heart-disease/catecholamines-14697#1|website=webmd.com|access-date=4 May 2017}}</ref> [[Clinical urine tests|Urine testing]] for catecholamine is used to detect [[pheochromocytoma]].

===Function in plants===
{{over-quotation|section|date=December 2024}}
{{blockquote|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 [[alkaloid]]s, 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 [[gibberellin]]s.<ref>{{ cite journal |last1=Kuklin |first1=A. I. |last2=Conger |first2=B. V. | title = Catecholamines in Plants | journal = Journal of Plant Growth Regulation | volume = 14 | issue = 2 | year = 1995 | doi = 10.1007/BF00203119 | pages = 91–97 |bibcode=1995JPGR...14...91K |s2cid=41493767 }}</ref>}}

== Testing for catecholamines ==
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.{{Citation needed|date=January 2023}} 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.<ref>{{Cite web|url=https://labtestsonline.org/tests/plasma-free-metanephrines|title=Plasma Free Metanephrines {{!}} Lab Tests Online|website=labtestsonline.org|access-date=2019-12-24}}</ref><ref>{{Cite web|url=https://labtestsonline.org/tests/urine-metanephrines|title=Urine Metanephrines {{!}} Lab Tests Online|website=labtestsonline.org|date=6 December 2019|access-date=2019-12-24}}</ref> 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: pheochromocytoma, paraganglioma, and neuroblastoma.<ref>{{Cite web|url=https://www.webmd.com/heart-disease/catecholamines-test-facts|title=Catecholamine Urine & Blood Tests|website=WebMD|language=en|access-date=2019-10-09}}</ref><ref>{{Cite web|url=https://labtestsonline.org/tests/catecholamines|title=Catecholamines|website=labtestsonline.org|language=en|access-date=2019-10-09}}</ref>

==See also==
{{colbegin|colwidth=25em}}
*[[Catechol-O-methyltransferase|Catechol-''O''-methyltransferase]]
*[[Catecholaminergic polymorphic ventricular tachycardia]]
*[[History of catecholamine research]]
*[[Hormone]]
*[[Julius Axelrod]]
*[[Peptide hormone]]
*[[Phenethylamine]]
*[[Steroid hormone]]
*[[Sympathomimetic drug]]
*[[Vanillylmandelic acid]]
{{colend}}

==References==
{{reflist}}

==External links==
* {{MeshName|Catecholamines}}

{{Neurotransmitters}}
{{Neurotransmitter metabolism intermediates}}
{{TAAR ligands}}
{{Chemical classes of psychoactive drugs}}

{{Authority control}}

[[Category:Catecholamines| ]]
[[Category:Neurotransmitters]]
[[Category:TAAR1 agonists]]
[[Category:Stress hormones]]