Editing Catecholamine (section)

==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.
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[[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>