Phenylethanolamine N-methyltransferase

Last updated
phenylethanolamine N-methyltransferase
2opb.jpg
Phenylethanolamine N-methyltransferase monomer, Human
Identifiers
SymbolPNMT
Alt. symbolsPENT
NCBI gene 5409
HGNC 9160
OMIM 171190
RefSeq NM_002686
UniProt P11086
Other data
EC number 2.1.1.28
Locus Chr. 17 q21-q22

Phenylethanolamine N-methyltransferase (PNMT) is an enzyme found primarily in the adrenal medulla that converts norepinephrine (noradrenaline) to epinephrine (adrenaline). [1] It is also expressed in small groups of neurons in the human brain [2] and in selected populations of cardiomyocytes. [3]

Contents

Structure

PNMT Cysteine Disulfide Bond.png
This is a representation of the disulfide bond made between monomers of PNMT. It was made using Chimera and 4MQ4. [4]
PNMT Active Site.png
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. [4]

PNMT is a protein whose encoding gene is found on chromosome 17 in humans. It consists of 4 exons and is a 30 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. [5]

S-adenosyl-L-methionine (SAM) is a required cofactor. [6] 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. [5]

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. [7]

In the absence of an inhibitor or ligand, a phosphate group is bound to the active site to stabilize this region. [8]

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. [9]

Mechanism

PNMT catalyzes the transfer of a methyl group from SAM to norepinephrine, converting it into epinephrine. It works by bringing the cofactor SAM and substrate together in close proximity, so that the reactive methyl group can be attacked by the primary amine of the norepinephrine molecule or another catecholamine substrate. The methyl group of SAM is very reactive, so the structure and placement of both norepinephrine and SAM is crucial for correct methylation pattern on the product.

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. [10]

PNMT is also involved in the biosynthesis of N-methylated trace amines: it metabolizes phenethylamine into N-methylphenethylamine (a positional isomer of amphetamine), p-octopamine into synephrine, and p-tyramine into N-methyltyramine. [11] [12]

Regulation

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. [14]

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. [15] Glucocorticoids have also been shown to increase the biological half life of the enzyme in vitro. [16] In animals who have had their pituitary gland removed, the addition of glucocorticoids significantly lengthens the half life of PNMT enzymes. [16]

Elevated PNMT levels can also be triggered by splanchnic nerve impulses. Nerve impulses increase the synthesis of PNMT mRNA by affecting certain promoter sequences. [16]

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. [17]

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. [16]

Localization

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. [1]

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, [18] and in both atria and ventricles in the hearts are now being elucidated as sites of PNMT expression. [19] Epinephrine is produced in small groups of neurons in the human brain which express PNMT; [2] 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. [2]

Disease

PNMT's normal function and defects are associated with multiple diseases and disorders.

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. [20]

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. [21]

Alzheimer's disease

Alzheimer's disease has also been associated with reduced human PNMT activity in the regions of the brain most associated with degeneration in the disease. There have also been significant associations with PNMT polymorphisms and early onset Alzheimer's disease. [22]

Inhibition

Classic PNMT inhibitors include benzimidazoles, quinolones, and purines. [8] Inhibition can also be produced by the addition of 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. [23] Another example is CGS19281A. [24]

Related Research Articles

<span class="mw-page-title-main">Adrenal gland</span> Endocrine gland

The adrenal glands are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which produces steroid hormones and an inner medulla. The adrenal cortex itself is divided into three main zones: the zona glomerulosa, the zona fasciculata and the zona reticularis.

<span class="mw-page-title-main">Catecholamine</span> Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

<span class="mw-page-title-main">Sympathetic nervous system</span> Division of the autonomic nervous system

The sympathetic nervous system is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of the autonomic nervous system, and sometimes considered an independent system.

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

<span class="mw-page-title-main">Adrenal medulla</span> Central part of the adrenal gland

The adrenal medulla is part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of chromaffin cells that secrete catecholamines, including epinephrine (adrenaline), norepinephrine (noradrenaline), and a small amount of dopamine, in response to stimulation by sympathetic preganglionic neurons.

A biogenic amine is a biogenic substance with one or more amine groups. They are basic nitrogenous compounds formed mainly by decarboxylation of amino acids or by amination and transamination of aldehydes and ketones. Biogenic amines are organic bases with low molecular weight and are synthesized by microbial, vegetable and animal metabolisms. In food and beverages they are formed by the enzymes of raw material or are generated by microbial decarboxylation of amino acids.

<span class="mw-page-title-main">Chromaffin cell</span> Neuroendocrine cells found in adrenal medulla in mammals

Chromaffin cells, also called pheochromocytes, are neuroendocrine cells found mostly in the medulla of the adrenal glands in mammals. These cells serve a variety of functions such as serving as a response to stress, monitoring carbon dioxide and oxygen concentrations in the body, maintenance of respiration and the regulation of blood pressure. They are in close proximity to pre-synaptic sympathetic ganglia of the sympathetic nervous system, with which they communicate, and structurally they are similar to post-synaptic sympathetic neurons. In order to activate chromaffin cells, the splanchnic nerve of the sympathetic nervous system releases acetylcholine, which then binds to nicotinic acetylcholine receptors on the adrenal medulla. This causes the release of catecholamines. The chromaffin cells release catecholamines: ~80% of adrenaline (epinephrine) and ~20% of noradrenaline (norepinephrine) into systemic circulation for systemic effects on multiple organs, and can also send paracrine signals. Hence they are called neuroendocrine cells.

Catechol-<i>O</i>-methyltransferase Class of enzymes

Catechol-O-methyltransferase is one of several enzymes that degrade catecholamines, catecholestrogens, and various drugs and substances having a catechol structure. In humans, catechol-O-methyltransferase protein is encoded by the COMT gene. Two isoforms of COMT are produced: the soluble short form (S-COMT) and the membrane bound long form (MB-COMT). As the regulation of catecholamines is impaired in a number of medical conditions, several pharmaceutical drugs target COMT to alter its activity and therefore the availability of catecholamines. COMT was first discovered by the biochemist Julius Axelrod in 1957.

The vesicular monoamine transporter (VMAT) is a transport protein integrated into the membranes of synaptic vesicles of presynaptic neurons. It transports monoamine neurotransmitters – such as dopamine, serotonin, norepinephrine, epinephrine, and histamine – into the vesicles, which release the neurotransmitters into synapses as chemical messages to postsynaptic neurons. VMATs utilize a proton gradient generated by V-ATPases in vesicle membranes to power monoamine import.

<span class="mw-page-title-main">Tyrosine hydroxylase</span> Enzime found in Homo sapiens that converts l-tyrosine to l-dopa, the precursor of cathecolamines

Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and tetrahydrobiopterin as cofactors. L-DOPA is a precursor for dopamine, which, in turn, is a precursor for the important neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Tyrosine hydroxylase catalyzes the rate limiting step in this synthesis of catecholamines. In humans, tyrosine hydroxylase is encoded by the TH gene, and the enzyme is present in the central nervous system (CNS), peripheral sympathetic neurons and the adrenal medulla. Tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase together make up the family of aromatic amino acid hydroxylases (AAAHs).

<span class="mw-page-title-main">Methyltransferase</span> Group of methylating enzymes

Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltransferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the leaving group and the methyl group attached to it acts as the electrophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA.

<span class="mw-page-title-main">Norepinephrine</span> Catecholamine hormone and neurotransmitter

Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" is more commonly used in the United Kingdom, whereas "norepinephrine" is usually preferred in the United States. "Norepinephrine" is also the international nonproprietary name given to the drug. Regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic.

<span class="mw-page-title-main">Adrenal tumor</span> Medical condition

An adrenal tumor or adrenal mass is any benign or malignant neoplasms of the adrenal gland, several of which are notable for their tendency to overproduce endocrine hormones. Adrenal cancer is the presence of malignant adrenal tumors, and includes neuroblastoma, adrenocortical carcinoma and some adrenal pheochromocytomas. Most adrenal pheochromocytomas and all adrenocortical adenomas are benign tumors, which do not metastasize or invade nearby tissues, but may cause significant health problems by unbalancing hormones.

<span class="mw-page-title-main">Adrenaline</span> Hormone and medication

Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions. Adrenaline is normally produced both by the adrenal glands and by a small number of neurons in the medulla oblongata. It plays an important role in the fight-or-flight response by increasing blood flow to muscles, output of the heart by acting on the SA node, pupil dilation response and blood sugar level. It does this by binding to alpha and beta receptors. It is found in many animals, including humans, and some single-celled organisms. In 1901, Japanese chemist Jōkichi Takamine developed a purified extract from the adrenal glands which was trademarked by Parke, Davis & Co in the US. The British Approved Name and European Pharmacopoeia term for this drug is hence adrenaline.

<span class="mw-page-title-main">Phenylethanolamine</span> Chemical compound

Phenylethanolamine, or β-hydroxyphenethylamine, is a trace amine with a structure similar to those of other trace phenethylamines as well as the catecholamine neurotransmitters dopamine, norepinephrine, and epinephrine. As an organic compound, phenylethanolamine is a β-hydroxylated phenethylamine that is also structurally related to a number of synthetic drugs in the substituted phenethylamine class. In common with these compounds, phenylethanolamine has strong cardiovascular activity and, under the name Apophedrin, has been used as a drug to produce topical vasoconstriction.

Adrenergic cell group C1 is a group of cells that show evidence of phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts norepinephrine to epinephrine (adrenalin); thus, they are regarded as 'putative adrenergic cells'. They are found in the ventrolateral medulla in conjunction with the noradrenergic cell group A1. The adrenergic group C1 is seen in vertebrates, including rodents and primates.

Adrenergic cell groups refers to collections of neurons in the central nervous system that stain for PNMT, the enzyme that converts norepinephrine to epinephrine (adrenaline). Thus, it is postulated that the neurotransmitter they produce may be epinephrine (adrenaline). Located in the medulla, they are named adrenergic cell group C1, adrenergic cell group C2, and adrenergic cell group C3.

<span class="mw-page-title-main">Sympathoadrenal system</span>

The sympathoadrenal system is a physiological connection between the sympathetic nervous system and the adrenal medulla and is crucial in an organism's physiological response to outside stimuli. When the body receives sensory information, the sympathetic nervous system sends a signal to preganglionic nerve fibers, which activate the adrenal medulla through acetylcholine. Once activated, norepinephrine and epinephrine are released directly into the blood by postganglionic nerve fibers where they act as the bodily mechanism for "fight-or-flight" responses. Because of this, the sympathoadrenal system plays a large role in maintaining glucose levels, sodium levels, blood pressure, and various other metabolic pathways that couple with bodily responses to the environment. During numerous diseased states, such as hypoglycemia or even stress, the body's metabolic processes are skewed. The sympathoadrenal system works to return the body to homeostasis through the activation or inactivation of the adrenal gland. However, more severe disorders of the sympathoadrenal system such as Pheochromocytoma can affect the body's ability to maintain a homeostatic state. In these cases, curative agents such as adrenergic agonists and antagonists are used to modify epinephrine and norepinephrine levels released by the adrenal medulla.

<span class="mw-page-title-main">History of catecholamine research</span>

The catecholamines comprise the endogenous substances dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine), as well as numerous artificially synthesized compounds such as isoprenaline, an anti-bradycardiac medication. Their investigation comprises a major chapter in the history of physiology, biochemistry, and pharmacology. Adrenaline was the first hormone extracted from an endocrine gland and obtained in pure form, before the word hormone was coined. Adrenaline was also the first hormone whose structure and biosynthesis were discovered. Second to acetylcholine, adrenaline and noradrenaline were some of the first neurotransmitters discovered, and the first intercellular biochemical signals to be found in intracellular vesicles. The β-adrenoceptor was the first G protein-coupled receptor whose gene was cloned.

<span class="mw-page-title-main">Epinephrine (medication)</span> Hormone used as a medicine

Epinephrine, also known as adrenaline, is a medication and hormone. As a medication, it is used to treat a number of conditions, including anaphylaxis, cardiac arrest, asthma, and superficial bleeding. Inhaled epinephrine may be used to improve the symptoms of croup. It may also be used for asthma when other treatments are not effective. It is given intravenously, by injection into a muscle, by inhalation, or by injection just under the skin.

References

  1. 1 2 Goldstein M, Fuxe K, Hökfelt T (June 1972). "Characterization and tissue localization of catecholamine synthesizing enzymes". Pharmacological Reviews. 24 (2): 293–309. PMID   4564603.
  2. 1 2 3 Kitahama K, Pearson J, Denoroy L, Kopp N, Ulrich J, Maeda T, Jouvet M (February 1985). "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". Neuroscience Letters. 53 (3): 303–8. doi:10.1016/0304-3940(85)90555-5. PMID   3885079. S2CID   2578817.
  3. ↑ Wang Y, Lin WK, Crawford W, Ni H, Bolton EL, Khan H, et al. (January 2017). "+ Cells in Murine Heart". Scientific Reports. 7 (1): 40687. doi:10.1038/srep40687. PMC   5234027 . PMID   28084430.
  4. 1 2 PDB: 4MQ4 ​; Bart AG, Scott EE. Crystal Structure of hPNMT in Complex with bisubstrate inhibitor N-(3-((((2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)thio)propyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (Report). RCSB Protein Data Bank.
  5. 1 2 Martin JL, Begun J, McLeish MJ, Caine JM, Grunewald GL (October 2001). "Getting the adrenaline going: crystal structure of the adrenaline-synthesizing enzyme PNMT". Structure. 9 (10): 977–85. doi: 10.1016/s0969-2126(01)00662-1 . PMID   11591352.
  6. ↑ Wong DL, Lesage A, Siddall B, Funder JW (November 1992). "Glucocorticoid regulation of phenylethanolamine N-methyltransferase in vivo". FASEB Journal. 6 (14): 3310–5. doi:10.1096/fasebj.6.14.1426768. PMID   1426768. S2CID   23761885.
  7. ↑ Drinkwater N, Gee CL, Puri M, Criscione KR, McLeish MJ, Grunewald GL, Martin JL (August 2009). "Molecular recognition of physiological substrate noradrenaline by the adrenaline-synthesizing enzyme PNMT and factors influencing its methyltransferase activity". The Biochemical Journal. 422 (3): 463–71. doi:10.1042/bj20090702. hdl:1808/26489. PMC   5940352 . PMID   19570037.
  8. 1 2 Drinkwater N, Vu H, Lovell KM, Criscione KR, Collins BM, Prisinzano TE, et al. (October 2010). "Fragment-based screening by X-ray crystallography, MS and isothermal titration calorimetry to identify PNMT (phenylethanolamine N-methyltransferase) inhibitors". The Biochemical Journal. 431 (1): 51–61. doi:10.1042/bj20100651. PMID   20642456.
  9. ↑ Gee CL, Nourse A, Hsin AY, Wu Q, Tyndall JD, Grunewald GL, et al. (June 2005). "Disulfide-linked dimers of human adrenaline synthesizing enzyme PNMT are catalytically active". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1750 (1): 82–92. doi:10.1016/j.bbapap.2005.03.006. PMID   15893506.
  10. ↑ Brandt. "The Adrenal Medulla" (PDF).
  11. 1 2 Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacology & Therapeutics. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID   19948186.
  12. 1 2 Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends in Pharmacological Sciences. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID   15860375.
  13. ↑ Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". European Journal of Pharmacology. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025. PMID   24374199.
  14. ↑ Wurtman RJ (June 2002). "Stress and the adrenocortical control of epinephrine synthesis". Metabolism. 51 (6 Suppl 1): 11–4. doi:10.1053/meta.2002.33185. PMID   12040535.
  15. ↑ Jiang W, Uht R, Bohn MC (1989). "Regulation of phenylethanolamine N-methyltransferase (PNMT) mRNA in the rat adrenal medulla by corticosterone". International Journal of Developmental Neuroscience. 7 (5): 513–20. doi:10.1016/0736-5748(89)90010-5. PMID   2816488. S2CID   24803398.
  16. 1 2 3 4 Ciaranello RD (1978). "Regulation of phenylethanolamine N-methyltransferase". Biochemical Pharmacology. 27 (15): 1895–7. doi:10.1016/0006-2952(78)90002-3. PMID   708473.
  17. ↑ Cahill AL, Eertmoed AL, Mangoura D, Perlman RL (September 1996). "Differential regulation of phenylethanolamine N-methyltransferase expression in two distinct subpopulations of bovine chromaffin cells". Journal of Neurochemistry. 67 (3): 1217–24. doi:10.1046/j.1471-4159.1996.67031217.x. PMID   8752129. S2CID   26602827.
  18. ↑ Park DH, Teitelman G, Evinger MJ, Woo JI, Ruggiero DA, Albert VR, et al. (April 1986). "Phenylethanolamine N-methyltransferase-containing neurons in rat retina: immunohistochemistry, immunochemistry, and molecular biology". The Journal of Neuroscience. 6 (4): 1108–13. doi:10.1523/JNEUROSCI.06-04-01108.1986. PMC   6568425 . PMID   2871139.
  19. ↑ Krizanová O, Micutková L, Jeloková J, Filipenko M, Sabban E, Kvetnanský R (September 2001). "Existence of cardiac PNMT mRNA in adult rats: elevation by stress in a glucocorticoid-dependent manner". American Journal of Physiology. Heart and Circulatory Physiology. 281 (3): H1372-9. doi:10.1152/ajpheart.2001.281.3.H1372. PMID   11514309.
  20. ↑ Schallreuter KU, Wood JM, Pittelkow MR, Buttner G, Swanson N, Korner C, Ehrke C (1996). "Increased monoamine oxidase A activity in the epidermis of patients with vitiligo". Archives of Dermatological Research. 288 (1): 14–8. doi:10.1007/bf02505037. PMID   8750929. S2CID   31646987.
  21. ↑ Mefford IN, Lister RG, Ota M, Linnoila M (February 1990). "Antagonism of ethanol intoxication in rats by inhibitors of phenylethanolamine N-methyltransferase". Alcoholism: Clinical and Experimental Research. 14 (1): 53–7. doi:10.1111/j.1530-0277.1990.tb00446.x. PMID   2178473.
  22. ↑ Mann MB, Wu S, Rostamkhani M, Tourtellotte W, MacMurray J, Comings DE (May 2001). "Phenylethanolamine N-methyltransferase (PNMT) gene and early-onset Alzheimer disease". American Journal of Medical Genetics. 105 (4): 312–6. doi:10.1002/ajmg.1363. PMID   11378842.
  23. ↑ Borchardt RT, Wu YS (March 1975). "Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 3. Modifications of the sugar portion of S-adenosylhomocysteine". Journal of Medicinal Chemistry. 18 (3): 300–4. doi:10.1021/jm00237a018. PMID   1133821.
  24. ↑ Atobe M, Kubota M, Nakagawara M, Kariya T (1996). "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". Neuropsychobiology. 34 (2): 82–89. doi:10.1159/000119297. PMID   8904737.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.