Editing Dopamine (section)

==Biochemistry==
{{Catecholamine and trace amine biosynthesis|align=right|caption=In humans, [[catecholamine]]s and phenethylaminergic [[trace amine]]s are derived from the amino acid [[phenylalanine]].  It is well established that dopamine is produced from <small>L</small>-tyrosine via <small>L</small>-DOPA; however, recent evidence has shown that CYP2D6 is expressed in the human brain and catalyzes the biosynthesis of dopamine from <small>L</small>-tyrosine via ''p''-tyramine.<ref name="CYP2D6 tyramine-dopamine metabolism" />}}

===Synthesis===
Dopamine is [[biosynthesis|synthesized]] in a restricted set of cell types, mainly neurons and cells in the [[adrenal medulla|medulla]] of the [[adrenal gland]]s.<ref name=Seeman/> The primary and minor [[metabolic pathway]]s respectively are:

:Primary: <small>L</small>-Phenylalanine → <small>L</small>-Tyrosine → <small>L</small>-DOPA → Dopamine<ref name="Trace amine template 1" /><ref name="Trace amine template 2" />
:Minor: <small>L</small>-Phenylalanine → <small>L</small>-Tyrosine → ''p''-Tyramine → Dopamine<ref name="Trace amine template 1" /><ref name="Trace amine template 2" /><ref name="CYP2D6 tyramine-dopamine metabolism" />
:Minor: <small>L</small>-Phenylalanine → [[L-m-tyrosine|''m''-Tyrosine]] → [[meta-tyramine|''m''-Tyramine]]  → Dopamine<ref name="CYP2D6 tyramine-dopamine metabolism" /><ref name="Tyrosine 3-hydroxylase m-tyrosine synthesis">{{cite encyclopedia|title=EC 1.14.16.2&nbsp;– Tyrosine 3-monooxygenase (Homo sapiens)|url=http://www.brenda-enzymes.org/enzyme.php?ecno=1.14.16.2&Suchword=&reference=&organism%5B%5D=Homo+sapiens&show_tm=0| encyclopedia =BRENDA|publisher=Technische Universität Braunschweig|access-date=7 October 2016|date=July 2016|quote = Substrate: L-phenylalanine + tetrahydrobiopterin + O2<br />Product: L-tyrosine + 3-hydroxyphenylalanine [(aka m-tyrosine)] + dihydropteridine + H2O<br />Organism: Homo sapiens}}<br />[http://www.brenda-enzymes.org/structure.php?show=reaction&id=428743&type=S&displayType=marvin Reaction diagram]</ref><ref name="AADC m-tyramine synthesis">{{cite encyclopedia|title=EC 4.1.1.28&nbsp;– Aromatic-L-amino-acid decarboxylase (Homo sapiens)|url=http://www.brenda-enzymes.org/enzyme.php?ecno=4.1.1.28&Suchword=&reference=&organism%5B%5D=Homo+sapiens&show_tm=0| encyclopedia =BRENDA|publisher=Technische Universität Braunschweig|access-date=7 October 2016|date=July 2016|quote = Substrate: m-tyrosine<br />Product: m-tyramine + CO2<br />Organism: Homo sapiens}}<br />[http://www.brenda-enzymes.org/structure.php?show=reaction&id=407269&type=S&displayType=marvin Reaction diagram]</ref>

The direct precursor of dopamine, [[L-DOPA|<small>L</small>-DOPA]], can be synthesized indirectly from the [[essential amino acid]] [[phenylalanine]] or directly from the non-essential amino acid [[tyrosine]].<ref name=Musacchio/> These [[amino acid]]s are found in nearly every protein and so are readily available in food, with tyrosine being the most common. Although dopamine is also found in many types of food, it is incapable of crossing the [[blood–brain barrier]] that surrounds and protects the brain.<ref name="Nice-pharma"/> It must therefore be synthesized inside the brain to perform its [[neurotransmission|neuronal activity]].<ref name="Nice-pharma"/>

<small>L</small>-Phenylalanine is converted into <small>L</small>-tyrosine by the [[enzyme]] [[phenylalanine hydroxylase]], with [[allotropes of oxygen#Dioxygen|molecular oxygen]] (O<sub>2</sub>) and [[tetrahydrobiopterin]] as [[cofactor (biochemistry)|cofactors]]. <small>L</small>-Tyrosine is converted into <small>L</small>-DOPA by the enzyme [[tyrosine hydroxylase]], with tetrahydrobiopterin, O<sub>2</sub>, and iron (Fe<sup>2+</sup>) as cofactors.<ref name=Musacchio>{{cite book |title=Biochemistry of Biogenic Amines |chapter=Chapter 1: Enzymes involved in the biosynthesis and degradation of catecholamines | vauthors= Musacchio JM | veditors = Iverson L |publisher=Springer | isbn = 978-1-4684-3171-1 |year=2013 |pages=1–35}}</ref> <small>L</small>-DOPA is converted into dopamine by the enzyme [[aromatic L-amino acid decarboxylase|aromatic <small>L</small>-amino acid decarboxylase]] (also known as DOPA decarboxylase), with [[pyridoxal phosphate]] as the cofactor.<ref name=Musacchio/>

Dopamine itself is used as precursor in the synthesis of the neurotransmitters norepinephrine and epinephrine.<ref name=Musacchio/> Dopamine is converted into norepinephrine by the enzyme [[dopamine beta hydroxylase|dopamine β-hydroxylase]], with O<sub>2</sub> and [[ascorbic acid|<small>L</small>-ascorbic acid]] as cofactors.<ref name=Musacchio/> Norepinephrine is converted into epinephrine by the enzyme [[phenylethanolamine N-methyltransferase|phenylethanolamine ''N''-methyltransferase]] with [[S-Adenosyl methionine|''S''-adenosyl-<small>L</small>-methionine]] as the cofactor.<ref name=Musacchio/>

Some of the cofactors also require their own synthesis.<ref name=Musacchio/> Deficiency in any required amino acid or cofactor can impair the synthesis of dopamine, norepinephrine, and epinephrine.<ref name=Musacchio/>

===Degradation===
Dopamine is broken down into inactive [[metabolite]]s by a set of enzymes—[[monoamine oxidase]] (MAO), [[catechol-O-methyl transferase|catechol-''O''-methyl transferase]] (COMT), and [[aldehyde dehydrogenase]] (ALDH), acting in sequence.<ref name=Eisenhofer>{{cite journal | vauthors = Eisenhofer G, Kopin IJ, Goldstein DS | s2cid = 12825309 | title = Catecholamine metabolism: a contemporary view with implications for physiology and medicine | journal = Pharmacological Reviews | volume = 56 | issue = 3 | pages = 331–49 | date = September 2004 | pmid = 15317907 | doi = 10.1124/pr.56.3.1 }}</ref> Both [[protein isoform|isoforms]] of monoamine oxidase, [[Monoamine oxidase A|MAO-A]] and [[Monoamine oxidase B|MAO-B]], effectively metabolize dopamine.<ref name=Musacchio/> Different breakdown pathways exist but the main end-product is [[homovanillic acid]] (HVA), which has no known biological activity.<ref name=Eisenhofer/> From the bloodstream, homovanillic acid is filtered out by the kidneys and then excreted in the urine.<ref name=Eisenhofer/> The two primary metabolic routes that convert dopamine into HVA are:<ref>{{Cite book | vauthors = Zahoor I, Shafi A, Haq E | chapter = Pharmacological Treatment of Parkinson’s Disease: Figure 1: [Metabolic pathway of dopamine synthesis...] | veditors = Stoker TB, Greenland JC | title = Parkinson's Disease: Pathogenesis and Clinical Aspects [Internet]. | location = Brisbane (AU) | publisher = Codon Publications | date = December 2018 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK536726/figure/Ch7-f0001/ }}</ref>
* Dopamine → [[DOPAL]] → [[DOPAC]] → HVA&nbsp;– catalyzed by MAO, ALDH, and COMT respectively
* Dopamine → [[3-Methoxytyramine]] → HVA&nbsp;– catalyzed by COMT and MAO+ALDH respectively

In clinical research on schizophrenia, measurements of homovanillic acid in [[blood plasma|plasma]] have been used to estimate levels of dopamine activity in the brain. A difficulty in this approach however, is separating the high level of plasma homovanillic acid contributed by the metabolism of norepinephrine.<ref>{{cite journal | vauthors = Amin F, Davidson M, Davis KL | title = Homovanillic acid measurement in clinical research: a review of methodology | journal = Schizophrenia Bulletin | volume = 18 | issue = 1 | pages = 123–48 | year = 1992 | pmid = 1553492 | doi = 10.1093/schbul/18.1.123 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Amin F, Davidson M, Kahn RS, Schmeidler J, Stern R, Knott PJ, Apter S | title = Assessment of the central dopaminergic index of plasma HVA in schizophrenia | journal = Schizophrenia Bulletin | volume = 21 | issue = 1 | pages = 53–66 | date = 1995 | pmid = 7770741 | doi = 10.1093/schbul/21.1.53 | doi-access = free }}<!--|access-date=13 November 2015--></ref>

Although dopamine is normally broken down by an [[oxidoreductase]] enzyme, it is also susceptible to oxidation by direct reaction with oxygen, yielding [[quinone]]s plus various [[radical (chemistry)|free radicals]] as products.<ref name=Sulzer>{{cite journal | vauthors = Sulzer D, Zecca L | s2cid = 21892355 | title = Intraneuronal dopamine-quinone synthesis: a review | journal = Neurotoxicity Research | volume = 1 | issue = 3 | pages = 181–95 | date = February 2000 | pmid = 12835101 | doi = 10.1007/BF03033289 }}</ref> The rate of oxidation can be increased by the presence of [[ferric]] iron or other factors. Quinones and free radicals produced by autoxidation of dopamine can [[neurotoxicity|poison cells]], and there is evidence that this mechanism may contribute to the cell loss that occurs in [[Parkinson's disease]] and other conditions.<ref>{{cite journal | vauthors = Miyazaki I, Asanuma M | title = Dopaminergic neuron-specific oxidative stress caused by dopamine itself | journal = Acta Medica Okayama | volume = 62 | issue = 3 | pages = 141–50 | date = June 2008 | pmid = 18596830 | doi = 10.18926/AMO/30942 | url = http://www.lib.okayama-u.ac.jp/www/acta/pdf/62_3_141.pdf }}</ref>