Phenylethanolamine N-methyltransferase: Difference between revisions

|image= 2opb.jpg

|width= 270

'''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 selected 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>

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"/>

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>

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>

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>

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>