Phenylethanolamine N-methyltransferase: Difference between revisions

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{{short description|Mammalian protein found in Homo sapiens}}
{{infobox protein
|Name=phenylethanolamine N-methyltransferase
|caption= Phenylethanolamine ''N''-methyltransferase monomer, Human
|caption=
|image= 2opb.jpg
|width= 270
|HGNCid=9160
|Symbol=PNMT
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|LocusSupplementaryData=-q22
}}
'''Phenylethanolamine ''N''-methyltransferase''' ('''PNMT''') is an [[enzyme]] found primarily in the [[adrenal medulla]] that converts [[norepinephrine]] (noradrenaline) to [[epinephrine]] (adrenaline).<ref name="Medulla PNMT" /> It is also expressed in small groups of [[neuron]]s in the human brain<ref name="Human PNMT neurons" /> and in selectselected populations of [[Cardiac muscle cell|cardiomyocytes]].<ref>{{cite journal | vauthors = Wang Y, Lin WK, Crawford W, Ni H, Bolton EL, Khan H, Shanks J, Bub G, Wang X, Paterson DJ, Zhang H, Galione A, Ebert SN, Terrar DA, Lei M | display-authors = 6 | title = + Cells in Murine Heart | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 40687 | date = January 2017 | pmid = 28084430 | pmc = 5234027 | doi = 10.1038/srep40687 }}</ref>
 
== Structure ==
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| caption2 = This is a model of the active site of PNMT showing both the distance between amino and sulfur groups, and a proposed area for methyl transfer. It was made using Chimera and 4MQ4.<ref name="4MQ4"/>
}}
PNMT is a protein whose encoding gene is found on chromosome 17 in humans. It consists of 4 exons and is a 30kDa30&nbsp;kDa protein. It shares many properties found among the other [[methyltransferases]]. It is closest in sequence to glycine-''N''-methyl transferase ([[GNMT]]). It also shares many structural properties like the shape of the folding lip with [[catechol-O-methyl transferase]] (COMT), though it shares less sequence identity. Several features of the structure like this folding lip suggest that PNMT is a recent adaptation to the catecholamine synthesizing enzyme family, evolving later than COMT, but before other methyltransferases like GNMT.<ref name="PNMT 1993">{{cite journal | vauthors = Martin JL, Begun J, McLeish MJ, Caine JM, Grunewald GL | title = Getting the adrenaline going: crystal structure of the adrenaline-synthesizing enzyme PNMT | journal = Structure | volume = 9 | issue = 10 | pages = 977–85 | date = October 2001 | pmid = 11591352 | doi = 10.1016/s0969-2126(01)00662-1 | doi-access = free }}</ref>
 
[[S-Adenosyl methionine|''S''-adenosyl-<small>L</small>-methionine]] (SAM) is a required cofactor.<ref name="pmid1426768">{{cite journal | vauthors = Wong DL, Lesage A, Siddall B, Funder JW | title = Glucocorticoid regulation of phenylethanolamine N-methyltransferase in vivo | journal = FASEB Journal | volume = 6 | issue = 14 | pages = 3310–5 | date = November 1992 | pmid = 1426768 | doi = 10.1096/fasebj.6.14.1426768 | doi-access = free | s2cid = 23761885 }}</ref> The active site binding region for the cofactor SAM contains a rich number of pi bonds from phenylalanine and tyrosine residues in the active site help to keep it in its binding pocket through [[pi stacking]]. Among all known PNMT variants in nature there are 7 crucial aromatic residues conserved in the active site.<ref name="PNMT 1993"/>
 
The residue Glutamine 185 is necessary in binding the catecholamine substrate. The replacement of this residue another reduces the catalytic efficiency of PNMT by tenfold up to three hundredfold.<ref>{{cite journal | vauthors = Drinkwater N, Gee CL, Puri M, Criscione KR, McLeish MJ, Grunewald GL, Martin JL | title = Molecular recognition of physiological substrate noradrenaline by the adrenaline-synthesizing enzyme PNMT and factors influencing its methyltransferase activity | journal = The Biochemical Journal | volume = 422 | issue = 3 | pages = 463–71 | date = August 2009 | pmid = 19570037 | pmc = 5940352 | doi = 10.1042/bj20090702 | hdl = 1808/26489 }}</ref>
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In the absence of an inhibitor or ligand, a [[phosphate]] group is bound to the active site to stabilize this region.<ref name="ReferenceA">{{cite journal | vauthors = Drinkwater N, Vu H, Lovell KM, Criscione KR, Collins BM, Prisinzano TE, Poulsen SA, McLeish MJ, Grunewald GL, Martin JL | display-authors = 6 | title = Fragment-based screening by X-ray crystallography, MS and isothermal titration calorimetry to identify PNMT (phenylethanolamine N-methyltransferase) inhibitors | journal = The Biochemical Journal | volume = 431 | issue = 1 | pages = 51–61 | date = October 2010 | pmid = 20642456 | doi = 10.1042/bj20100651 }}</ref>
 
Human PNMT forms dimers in solution. When PNMT crystals are grown in non-reducing solutions, two disulfide bonds form between cysteines 48 and 139 on opposite chains. This dimerization has no effect on the catalytic activity of the enzyme.<ref>{{cite journal | vauthors = Gee CL, Nourse A, Hsin AY, Wu Q, Tyndall JD, Grunewald GL, McLeish MJ, Martin JL | display-authors = 6 | title = Disulfide-linked dimers of human adrenaline synthesizing enzyme PNMT are catalytically active | journal = Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics | volume = 1750 | issue = 1 | pages = 82–92 | date = June 2005 | pmid = 15893506 | doi = 10.1016/j.bbapap.2005.03.006 }}</ref>
 
==Mechanism==
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While PNMT methylates norepinephrine into the active compound [[epinephrine]], norepinephrine can also be methylated by [[catechol-O-methyl transferase]] (COMT), another [[methyltransferase]] which adds a methyl group in a different location, in turn producing the inactive compound [[metanephrine]]. [[Methyltransferases]] are very common in the catecholamine synthesis and deactivation pathways.<ref>{{cite web|last1=Brandt|title=The Adrenal Medulla|url=https://www.rose-hulman.edu/~brandt/Chem330/EndocrineNotes/Chapter_4_Adrenal_Medulla.pdf }}</ref>
 
PNMT is also involved in the biosynthesis of ''N''-methylated [[trace amine]]s: it metabolizes [[phenethylamine]] into [[N-methylphenethylamine|''N''-methylphenethylamine]] (a [[positional isomer]] of [[amphetamine]]), ''p''-[[octopamine (neurotransmitter)|octopamine]] into [[synephrine]], and ''p''-[[tyramine]] into [[N-methyltyramine|''N''-methyltyramine]].<ref name="Trace amine template 1" /><ref name="Trace amine template 2" />
{{Phenylalanine biosynthesis|align=left|caption=PNMT plays an important role in trace amine and catecholamine biosynthesis.}}
{{Clear}}
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Elevated PNMT expression is one of the ways that the stress response positively feeds back on itself. An increase in stress hormones or nerve impulses due to stress can cause PNMT to convert more norepinephrine into epinephrine. This increases the potency of the catecholamine response system, increasing the sympathetic output and making the stress response more profound.<ref>{{cite journal | vauthors = Wurtman RJ | title = Stress and the adrenocortical control of epinephrine synthesis | journal = Metabolism | volume = 51 | issue = 6 Suppl 1 | pages = 11–4 | date = June 2002 | pmid = 12040535 | doi = 10.1053/meta.2002.33185 }}</ref>
 
PNMT is known to be regulated by [[glucocorticoids]] made in the [[adrenal gland]]. One way that it can regulate PNMT expression is by [[corticosterone]]'s positive influence on the maintenance of PNMT mRNA.<ref>{{cite journal | vauthors = Jiang W, Uht R, Bohn MC | title = Regulation of phenylethanolamine N-methyltransferase (PNMT) mRNA in the rat adrenal medulla by corticosterone | journal = International Journal of Developmental Neuroscience | volume = 7 | issue = 5 | pages = 513–20 | date = 1989 | pmid = 2816488 | doi = 10.1016/0736-5748(89)90010-5 | s2cid = 24803398 }}</ref> [[Glucocorticoids]] have also been shown to increase the [[biological half life]] of the enzyme in vitro.<ref name="ReferenceB">{{cite journal | vauthors = Ciaranello RD | title = Regulation of phenylethanolamine N-methyltransferase | journal = Biochemical Pharmacology | volume = 27 | issue = 15 | pages = 1895–7 | date = 1978 | pmid = 708473 | doi = 10.1016/0006-2952(78)90002-3 }}</ref> In animals who have had their pituitary gland removed, the addition of [[glucocorticoids]] significantly lengthens the half life of PNMT enzymes.<ref name="ReferenceB"/>
 
Elevated PNMT levels can also be triggered by [[splanchnic]] nerve impulses. Nerve impulses increase the synthesis of PNMT mRNA by affecting certain promoter sequences.<ref name="ReferenceB"/>
 
Stress immobilization for a few hours has also been shown to increase PNMT activity in rats. This treatment takes about one week to manifest a difference in PNMT levels.<ref>{{cite journal | vauthors = Cahill AL, Eertmoed AL, Mangoura D, Perlman RL | title = Differential regulation of phenylethanolamine N-methyltransferase expression in two distinct subpopulations of bovine chromaffin cells | journal = Journal of Neurochemistry | volume = 67 | issue = 3 | pages = 1217–24 | date = September 1996 | pmid = 8752129 | doi = 10.1046/j.1471-4159.1996.67031217.x | s2cid = 26602827 }}</ref>
 
SAM not only acts as a cofactor for PNMT, but also helps to stabilize the enzyme and increase the half life by making it more resistant to being cut by [[trypsin]] protease.<ref name="ReferenceB"/>
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Epinephrine synthesis and therefore PNMT location has been largely found to be contained in the [[adrenal medulla]] or [[adrenal gland]] of most species. PNMT has been localized in most adult mammals to the cytoplasm of these medullary cells.<ref name="Medulla PNMT">{{cite journal | vauthors = Goldstein M, Fuxe K, Hökfelt T | title = Characterization and tissue localization of catecholamine synthesizing enzymes | journal = Pharmacological Reviews | volume = 24 | issue = 2 | pages = 293–309 | date = June 1972 | pmid = 4564603 }}</ref>
 
Newer studies are also showing PNMT mRNA and protein to be expressed in other regions of the body as well. Certain neural tracts, the [[retina]],<ref>{{cite journal | vauthors = Park DH, Teitelman G, Evinger MJ, Woo JI, Ruggiero DA, Albert VR, Baetge EE, Pickel VM, Reis DJ, Joh TH | display-authors = 6 | title = Phenylethanolamine N-methyltransferase-containing neurons in rat retina: immunohistochemistry, immunochemistry, and molecular biology | journal = The Journal of Neuroscience | volume = 6 | issue = 4 | pages = 1108–13 | date = April 1986 | pmid = 2871139 | pmc = 6568425 | doi = 10.1523/JNEUROSCI.06-04-01108.1986 }}</ref> and in both [[atrium (heart)|atria]] and [[ventricle (heart)|ventricles]] in the hearts are now being elucidated as sites of PNMT expression.<ref>{{cite journal | vauthors = Krizanová O, Micutková L, Jeloková J, Filipenko M, Sabban E, Kvetnanský R | title = Existence of cardiac PNMT mRNA in adult rats: elevation by stress in a glucocorticoid-dependent manner | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 281 | issue = 3 | pages = H1372-9 | date = September 2001 | pmid = 11514309 | doi = 10.1152/ajpheart.2001.281.3.H1372 }}</ref> [[Epinephrine]] is produced in small groups of neurons in the human brain which express PNMT;<ref name="Human PNMT neurons">{{cite journal | vauthors = Kitahama K, Pearson J, Denoroy L, Kopp N, Ulrich J, Maeda T, Jouvet 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 = 303–8 | date = February 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" />
 
==Disease==
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===Vitiligo===
Decreased levels of PNMT activity measured by [[epinephrine]] and [[norepinephrine]] is seen in the skin of patients with [[vitiligo]] in the [[keratinocytes]], which normally have higher PNMT activity.<ref>{{cite journal | vauthors = [[Karin Schallreuter|Schallreuter KU]], Wood JM, Pittelkow MR, Buttner G, Swanson N, Korner C, Ehrke C | title = Increased monoamine oxidase A activity in the epidermis of patients with vitiligo | journal = Archives of Dermatological Research | volume = 288 | issue = 1 | pages = 14–8 | date = 1996 | pmid = 8750929 | doi = 10.1007/bf02505037 | s2cid = 31646987 }}</ref>
 
===Ethanol intoxication===
Two potent PNMT inhibitors (LY134046 and LY78335) were long lasting antagonists of both ethanol intoxication and sedation. This suggests a central role that PNMT and epinephrine play in the synthesis of [[ethanol]] and [[pentobarbital]] induced sedation and intoxication.<ref>{{cite journal | vauthors = Mefford IN, Lister RG, Ota M, Linnoila M | title = Antagonism of ethanol intoxication in rats by inhibitors of phenylethanolamine N-methyltransferase | journal = Alcoholism,: Clinical and Experimental Research | volume = 14 | issue = 1 | pages = 53–7 | date = February 1990 | pmid = 2178473 | doi = 10.1111/j.1530-0277.1990.tb00446.x | url = https://zenodo.org/record/1230661 }}</ref>
 
===Alzheimer's disease===
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==Inhibition==
Classic PNMT inhibitors include [[benzimidazoles]], [[quinolones]], and [[purines]].<ref name="ReferenceA"/> Inhibition can also be produced by the addition of [[S deoxyadenosyl L homocysteine|S-deoxyadenosyl L-homocysteine]], a replacement for the cofactor SAM, which resembles it, but is missing the methyl group, so no methyl transfer is possible.<ref>{{cite journal | vauthors = Borchardt RT, Wu YS | title = Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 3. Modifications of the sugar portion of S-adenosylhomocysteine | journal = Journal of Medicinal Chemistry | volume = 18 | issue = 3 | pages = 300–4 | date = March 1975 | pmid = 1133821 | doi = 10.1021/jm00237a018 }}</ref> Another example is CGS19281A.<ref>{{cite journal | vauthors = Atobe M, Kubota M, Nakagawara M, Kariya T | title = Effect of Phenylethanolamine N-methyltransferase Inhibitor, CGS19281A, on the Alpha-2-Adrenoceptor Function in the Hypothalamus of Rats in Comparison with SKF29661, SKF64139 and Yohimbine | journal = Neuropsychobiology | volume = 34 | issue = 2 | pages = 82–89 | date = 1996 | pmid = 8904737 | doi = 10.1159/000119297 }}</ref>
 
== References ==