Genomes and Genes
phenylethanolamine n methyltransferase
Summary: A methyltransferase that catalyzes the reaction of S-adenosyl-L-methionine and phenylethanolamine to yield S-adenosyl-L-homocysteine and N-methylphenylethanolamine. It can act on various phenylethanolamines and converts norepinephrine into epinephrine. (From Enzyme Nomenclature, 1992) EC 22.214.171.124.
- Kvetnansky R, Micutkova L, Kubovcakova L, Sabban E, Palkovits M, Krizanova O. Localization and regulation of phenylethanolamine N-methyltransferase gene expression in the heart of rats and mice during stress. Ann N Y Acad Sci. 2004;1018:405-17 pubmed..Mechanism responsible for the regulation of stress-induced increase of PNMT gene expression in cardiac atria is clearly dependent on the presence of glucocorticoids. ..
- Ji Y, Salavaggione O, Wang L, Adjei A, Eckloff B, Wieben E, et al. Human phenylethanolamine N-methyltransferase pharmacogenomics: gene re-sequencing and functional genomics. J Neurochem. 2005;95:1766-76 pubmed..These observations raise the possibility of inherited variation in the ability to form epinephrine from norepinephrine as a result of variant PNMT polymorphisms and haplotypes. ..
- Tai T, Wong D. Protein kinase A and protein kinase C signaling pathway interaction in phenylethanolamine N-methyltransferase gene regulation. J Neurochem. 2003;85:816-29 pubmed..PNMT promoter analysis further showed that synergistic stimulation by PKA and PKC involves DNA sequences between - 442 and - 392 bp, and potentially a GCM binding element lying within this region. ..
- Wong D, Tank A. Stress-induced catecholaminergic function: transcriptional and post-transcriptional control. Stress. 2007;10:121-30 pubmed..Post-transcriptional and/or post-translational regulatory influences that may contribute to the complex effects of stress on TH, PNMT and the stress hormone epinephrine are explored. ..
- Ziegler M, Bao X, Kennedy B, Joyner A, Enns R. Location, development, control, and function of extraadrenal phenylethanolamine N-methyltransferase. Ann N Y Acad Sci. 2002;971:76-82 pubmed..PNMT may also play a role in the regulation of fetal heart rate prior to development of the adrenal medulla. ..
- Wong D, Anderson L, Tai T. Cholinergic and peptidergic regulation of phenylethanolamine N-methyltransferase gene expression. Ann N Y Acad Sci. 2002;971:19-26 pubmed..However, the magnitude of stimulation and antagonist blockade with H-89 or the polypeptide inhibitor PKI suggests that the extent of activation is much less than that with PACAP. ..
- Ji Y, Snyder E, Fridley B, Salavaggione O, Moon I, Batzler A, et al. Human phenylethanolamine N-methyltransferase genetic polymorphisms and exercise-induced epinephrine release. Physiol Genomics. 2008;33:323-32 pubmed publisher..Our studies suggest that functionally significant variant sequence in the human PNMT gene might contribute to individual variation in levels of circulating epinephrine during exercise. ..
- Martin J, Begun J, McLeish M, Caine J, Grunewald G. Getting the adrenaline going: crystal structure of the adrenaline-synthesizing enzyme PNMT. Structure. 2001;9:977-85 pubmed..The PNMT structure reported here enables the design of potent and selective inhibitors with which to characterize the role of adrenaline in the CNS. Such chemical probes could potentially be useful as novel therapeutics. ..
- Mann M, Wu S, Rostamkhani M, Tourtellotte W, MacMurray J, Comings D. Phenylethanolamine N-methyltransferase (PNMT) gene and early-onset Alzheimer disease. Am J Med Genet. 2001;105:312-6 pubmed..007), but not in late-onset AD (LOAD). These data suggest that genetic variation in the promoter of the PNMT gene is associated with increased susceptibility to the sporadic form of EOAD. ..
- Kaneda N, Ichinose H, Kobayashi K, Oka K, Kishi F, Nakazawa A, et al. Molecular cloning of cDNA and chromosomal assignment of the gene for human phenylethanolamine N-methyltransferase, the enzyme for epinephrine biosynthesis. J Biol Chem. 1988;263:7672-7 pubmed..Chromosomal assignment of the gene for human PNMT was carried out using mouse-human somatic cell hybrids. The PNMT gene was assigned to chromosome 17. ..
- Koike G, Jacob H, Krieger J, Szpirer C, Hoehe M, Horiuchi M, et al. Investigation of the phenylethanolamine N-methyltransferase gene as a candidate gene for hypertension. Hypertension. 1995;26:595-601 pubmed
- Wong D, Siddall B, Ebert S, Bell R, Her S. Phenylethanolamine N-methyltransferase gene expression: synergistic activation by Egr-1, AP-2 and the glucocorticoid receptor. Brain Res Mol Brain Res. 1998;61:154-61 pubmed
- Mann M, Wu S, Rostamkhani M, Tourtellotte W, MacMurray J, Comings D. Association between the phenylethanolamine N-methyltransferase gene and multiple sclerosis. J Neuroimmunol. 2002;124:101-5 pubmed..The data suggest that these promoter polymorphisms of the PNMT gene, both independently and cumulatively, show association with MS. ..
- Zeman M, Petrak J, Stebelova K, Nagy G, Krizanova O, Herichova I, et al. Endocrine rhythms and expression of selected genes in the brain, stellate ganglia, and adrenals of hypertensive TGR rats. Ann N Y Acad Sci. 2008;1148:308-16 pubmed publisher..We hypothesize that upregulated adrenal medulla functioning in the morning and disturbed communication between circadian oscillators and mechanisms involved in BP control can explain the reversed BP profile in TGR rats. ..
- Hoehe M, Plaetke R, Otterud B, Stauffer D, Holik J, Byerley W, et al. Genetic linkage of the human gene for phenylethanolamine N-methyltransferase (PNMT), the adrenaline-synthesizing enzyme, to DNA markers on chromosome 17q21-q22. Hum Mol Genet. 1992;1:175-8 pubmed..As an increase of PNMT activity has been associated with the development of hypertension in SHR-SP, it will be of interest to perform comparative mapping of the PNMT gene. ..
- Li Q, Goodchild A, Pilowsky P. Effect of haemorrhage on the expression of neurotransmitter-related genes in rat ventrolateral medulla: a quantitative real-time RT-PCR study. Brain Res Mol Brain Res. 2003;114:46-54 pubmed..Our results also demonstrate that real-time RT-PCR is a sensitive and accurate method for quantitative studies on neurotransmitter gene expressions in restricted brain regions. ..
- Grunewald G, Caldwell T, Li Q, Criscione K. 1,3-Dimethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines as probes for the binding orientation of tetrahydroisoquinoline at the active site of phenylethanolamine N-methyltransferase. Bioorg Med Chem. 1999;7:869-80 pubmed..However, no significant increases in selectivity versus the alpha2-adrenoceptor were observed for these compounds. ..
- Grunewald G, Caldwell T, Li Q, Dahanukar V, McNeil B, Criscione K. Enantiospecific synthesis of 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-1,2,3,4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the alpha(2)-adrenoceptor. J Med Chem. 1999;42:4351-61 pubmed..These compounds give important insight into the steric and stereochemical preferences of both PNMT and the alpha(2)-adrenoceptor, which should assist in the development of new PNMT inhibitors. ..
- Gearhart D, Neafsey E, Collins M. Phenylethanolamine N-methyltransferase has beta-carboline 2N-methyltransferase activity: hypothetical relevance to Parkinson's disease. Neurochem Int. 2002;40:611-20 pubmed
- Mantione K, Kream R, Stefano G. Variations in critical morphine biosynthesis genes and their potential to influence human health. Neuro Endocrinol Lett. 2010;31:11-8 pubmed..The presence of morphine signaling in almost all organ systems suggests that it is most likely playing a role in maintaining the health and promoting the normal functioning of these physiological systems. ..
- Grunewald G, Dahanukar V, Criscione K. Effects of a 3-alkyl-, 4-hydroxy- and/or 8-aromatic-substituent on the phenylethanolamine N-methyltransferase inhibitor potency and alpha2-adrenoceptor affinity of 2,3,4,5-tetrahydro-1H-2-benzazepines. Bioorg Med Chem. 2001;9:1957-65 pubmed..Compound 3 is the most selective (PNMT/alpha2) and one of the more potent at PNMT compounds yet reported in the benzazepine series, and should have sufficient lipophilicity to penetrate the blood-brain barrier (CLogP = 1.8). ..
- Grunewald G, Dahanukar V, Teoh B, Criscione K. 3,7-Disubstituted-1,2,3,4-tetrahydroisoquinolines display remarkable potency and selectivity as inhibitors of phenylethanolamine N-methyltransferase versus the alpha2-adrenoceptor. J Med Chem. 1999;42:1982-90 pubmed..55 microM, alpha2 Ki = 100 microM, selectivity = 180) and 4 (selectivity = 6.0) and is thus the most selective PNMT inhibitor yet reported. ..
- Ehrhart Bornstein M, Bornstein S. Cross-talk between adrenal medulla and adrenal cortex in stress. Ann N Y Acad Sci. 2008;1148:112-7 pubmed publisher..The data summarized here indicate an involvement of intra-adrenal interactions in this coordination of the body's response to stress...
- Kvetnansky R, Krizanova O, Tillinger A, Sabban E, Thomas S, Kubovcakova L. Regulation of gene expression of catecholamine biosynthetic enzymes in dopamine-beta-hydroxylase- and CRH-knockout mice exposed to stress. Ann N Y Acad Sci. 2008;1148:257-68 pubmed publisher..They also confirm that the HPA system plays a crucial role in the stress-induced regulation of PNMT gene expression. ..
- Adams J, Legan S, Ott C, Jackson B. Modulation of hypoglycemia-induced increases in plasma epinephrine by estrogen in the female rat. J Neurosci Res. 2005;79:360-7 pubmed..In contrast, acute exposure to high levels of E2 can also suppress hypoglycemia-induced increases in plasma epinephrine, due at least in part to inhibition of stimulus-secretion coupling. ..
- Reinecke M, Maake C. A phylogenetic survey of pancreastatin and chromogranin immunoreactivity in chromaffin (TH-, DBH-, and PNMT-immunoreactive) cells of the adrenal organ of vertebrates. Gen Comp Endocrinol. 1993;90:251-65 pubmed..Since no immunoreactions were obtained with antiserum CgA, nonmammalian Pst may be derived from a precursor different from mammalian CgA. ..
- Grunewald G, Seim M, Regier R, Criscione K. Exploring the active site of phenylethanolamine N-methyltransferase with 1,2,3,4-tetrahydrobenz[h]isoquinoline inhibitors. Bioorg Med Chem. 2007;15:1298-310 pubmed..22mM), which has a lipophilic 7-substituent that cannot hydrogen bond to the enzyme, is twice as potent at PNMT than 11. This once again illustrates the limitations of docking studies for lead optimization. ..
- Gallo V, Civinini A. The development of adrenal homolog of rainbow trout Oncorhynchus mykiss: an immunohistochemical and ultrastructural study. Anat Embryol (Berl). 2005;209:233-42 pubmed..The immunohistochemical and ultrastructural results are compared with those obtained by other authors in the same and other vertebrate species...
- Foley C, Stanton J, Price E, Cunningham J, Hasser E, Heesch C. GABA(A) alpha1 and alpha2 receptor subunit expression in rostral ventrolateral medulla in nonpregnant and pregnant rats. Brain Res. 2003;975:196-206 pubmed
- Bao X, Kennedy B, Enns R, Mahata M, Mahata S, O CONNOR D, et al. A truncated mouse phenylethanolamine N-methyltransferase splice variant with dominant-negative activity. Ann N Y Acad Sci. 2002;971:89-91 pubmed
- Micutkova L, Kiss A, Filipenko M, Rychkova N, Krizanova O, Palkovits M, et al. Gene expression of catecholamine synthesizing enzymes in A5 cell group and modulation of tyrosine hydroxylase mRNA by immobilization stress. Endocr Regul. 2001;35:195-200 pubmed..We also showed how the gene expression of tyrosine hydroxylase changed with the function of time after the single immobilization exposure. Thus, TH mRNA in A5 cell group is modulated by immobilization stress in a time-dependent manner. ..
- Tai T, Morita K, Wong D. Role of Egr-1 in cAMP-dependent protein kinase regulation of the phenylethanolamine N-methyltransferase gene. J Neurochem. 2001;76:1851-9 pubmed..These findings demonstrate that the rat PNMT gene promoter can be activated via the cAMP-PKA signal transduction pathway, mediated by the immediate early gene transcription factor, Egr-1. ..
- Makeham J, Goodchild A, Pilowsky P. NK1 receptor and the ventral medulla of the rat: bulbospinal and catecholaminergic neurons. Neuroreport. 2001;12:3663-7 pubmed..We also demonstrate the NK1 receptor on bulbospinal neurons of the ventral respiratory group, in a region overlapping the pre-Bötzinger Complex. ..
- Cleary S, Brouwers F, Eisenhofer G, Pacak K, Christie D, Lipski J, et al. Expression of the noradrenaline transporter and phenylethanolamine N-methyltransferase in normal human adrenal gland and phaeochromocytoma. Cell Tissue Res. 2005;322:443-53 pubmed..The altered pattern of expression for both NAT and PNMT in phaeochromocytoma indicates a significant disruption in the regulation and possibly in the function of these proteins in adrenal medullary tumours. ..
- Sartor D, Verberne A. Phenotypic identification of rat rostroventrolateral medullary presympathetic vasomotor neurons inhibited by exogenous cholecystokinin. J Comp Neurol. 2003;465:467-79 pubmed..CCK-induced inhibition of a subpopulation of RVLM presympathetic neurons may be implicated in postprandial hyperemia and postprandial hypotension. ..
- Ebert S, Rong Q, Boe S, Pfeifer K. Catecholamine-synthesizing cells in the embryonic mouse heart. Ann N Y Acad Sci. 2008;1148:317-24 pubmed publisher..Thus, our results suggest that catecholamine-synthesizing cells serve as cardiomyocyte progenitors in the embryonic heart. ..
- Nishimura F, Kimura Y, Abe S, Fukunaga T, Minami J, Tanii H, et al. Effects of functional polymorphisms related to catecholaminergic systems on changes in blood catecholamine and cardiovascular measures after alcohol ingestion in the Japanese population. Alcohol Clin Exp Res. 2008;32:1937-46 pubmed publisher
- Grunewald G, Seim M, Regier R, Martin J, Gee C, Drinkwater N, et al. Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase. J Med Chem. 2006;49:5424-33 pubmed..The interaction of this residue with the sulfonamide -NH- is likely responsible for much of the enhanced inhibitory potency of the sulfonamides versus the sulfones. ..
- Kennedy B, Ziegler M. Ontogeny of epinephrine metabolic pathways in the rat: role of glucocorticoids. Int J Dev Neurosci. 2000;18:53-9 pubmed..We conclude that expression of PNMT in all three tissues is glucocorticoid independent until the latter part of gestation when it is readily enhanced by glucocorticoids. ..
- Burke W, Hanson D, Chung H. A highly sensitive assay for phenylethanolamine N-methyltransferase in human brain. Proc Soc Exp Biol Med. 1986;181:66-70 pubmed..The sensitivity is enhanced by homogenizing tissue in small volumes and removing potential inhibitors by dialysis. We report for the first time PNMT activity in specific regions of the human cerebral and cerebellar cortex. ..
- D Mello S, Weisberg E, Stachowiak M, Turzai L, Gioio A, Kaplan B. Isolation and nucleotide sequence of a cDNA clone encoding bovine adrenal tyrosine hydroxylase: comparative analysis of tyrosine hydroxylase gene products. J Neurosci Res. 1988;19:440-9 pubmed..Comparison of the size of bovine and rat TH mRNA and protein by northern blot and immunoblot analyses yielded differences consistent with those predicted from the nucleotide sequence data. ..
- Saha S, Drinkhill M, Moore J, Batten T. Central nucleus of amygdala projections to rostral ventrolateral medulla neurones activated by decreased blood pressure. Eur J Neurosci. 2005;21:1921-30 pubmed
- Grunewald G, Romero F, Seim M, Criscione K, Deupree J, Spackman C, et al. Exploring the active site of phenylethanolamine N-methyltransferase with 3-hydroxyethyl- and 3-hydroxypropyl-7-substituted-1,2,3,4-tetrahydroisoquinolines. Bioorg Med Chem Lett. 2005;15:1143-7 pubmed..Although alpha(2)-adrenoceptor affinity decreased for these compounds, selectivity was not gained over the parent 3-hydroxymethyl compounds (1, 2) due to a loss in PNMT inhibitory potency. ..
- Adams M, Meijer O, Wang J, Bhargava A, Pearce D. Homodimerization of the glucocorticoid receptor is not essential for response element binding: activation of the phenylethanolamine N-methyltransferase gene by dimerization-defective mutants. Mol Endocrinol. 2003;17:2583-92 pubmed..We further suggest that protein-DNA and protein-protein interactions that support such complexes are essential for activation of this type of gene, and that DNA binding of GR might be essential to survival. ..
- Sakai K, Kanamori N. Are there non-monoaminergic paradoxical sleep-off neurons in the brainstem?. Sleep Res Online. 1999;2:57-63 pubmed..These findings indicate the existence, in the medulla, of non-monoaminergic PS-off neurons that would play an important role in PS generation. ..
- Powers J, Evinger M, Tsokas P, Bedri S, Alroy J, Shahsavari M, et al. Pheochromocytoma cell lines from heterozygous neurofibromatosis knockout mice. Cell Tissue Res. 2000;302:309-20 pubmed..Mouse pheochromocytomas are a new tool for studying genes and signaling pathways that regulate cell growth and differentiation in adrenal medullary neoplasms and are a unique model for studying the regulation of PNMT expression. ..
- Zelena D, Barna I, Csabai K, Orlando G, Makara G, Engelmann M. Response of the adrenomedullary system to early postnatal stress in the Brattleboro rat. Ann N Y Acad Sci. 2008;1148:456-61 pubmed publisher..Furthermore, our results imply that the congenital absence of AVP affects the synthesis of PNMT in response to defined stressor exposure...
- Wan D, Livett B. Induction of phenylethanolamine N-methyltransferase mRNA expression by glucocorticoids in cultured bovine adrenal chromaffin cells. Eur J Pharmacol. 1989;172:107-15 pubmed
- Silveira D, Schachter S, Schomer D, Holmes G. Flurothyl-induced seizures in rats activate Fos in brainstem catecholaminergic neurons. Epilepsy Res. 2000;39:1-12 pubmed..Further studies are necessary to determine whether activation of brainstem catecholaminergic neurons contribute to the autonomic manifestations that frequently accompany epileptic seizures. ..