Phenylethanolamine ''N''-methyltransferase (PNMT) is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
found primarily in the
adrenal medulla
The adrenal medulla ( la, medulla glandulae suprarenalis) 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 cel ...
that converts
norepinephrine
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" (from Latin '' ad'', ...
(noradrenaline) to
epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
(adrenaline).
It is also expressed in small groups of
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s in the human brain
and in selected populations of
cardiomyocytes
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...
.
Structure
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
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 Rossm ...
. 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
Catechol-''O''-methyltransferase (COMT; ) is one of several enzymes that degrade catecholamines (neurotransmitters such as dopamine, epinephrine, and norepinephrine), catecholestrogens, and various drugs and substances having a catechol structu ...
(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.
''S''-adenosyl-L-methionine (SAM) is a required cofactor.
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
In chemistry, pi stacking (also called π–π stacking) refers to the presumptive attractive, noncovalent pi interactions ( orbital overlap) between the pi bonds of aromatic rings. However this is a misleading description of the phenomena sinc ...
. Among all known PNMT variants in nature there are 7 crucial aromatic residues conserved in the active site.
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.
In the absence of an inhibitor or ligand, a
phosphate
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid .
The phosphate or orthophosphate ion is derived from phospho ...
group is bound to the active site to stabilize this region.
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.
Mechanism
PNMT catalyzes the transfer of a
methyl group
In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...
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
A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine.
Catechol can be either a free molecule or a subst ...
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
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
, norepinephrine can also be methylated by
catechol-O-methyl transferase
Catechol-''O''-methyltransferase (COMT; ) is one of several enzymes that degrade catecholamines (neurotransmitters such as dopamine, epinephrine, and norepinephrine), catecholestrogens, and various drugs and substances having a catechol structu ...
(COMT), another
methyltransferase
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 Rossm ...
which adds a methyl group in a different location, in turn producing the inactive compound
metanephrine
Metanephrine (metadrenaline) is a metabolite of epinephrine (adrenaline) created by action of catechol-O-methyl transferase on epinephrine. An article in the ''Journal of the American Medical Association'', 2002, indicated that the measurement of ...
.
Methyltransferases
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 Rossm ...
are very common in the catecholamine synthesis and deactivation pathways.
PNMT is also involved in the biosynthesis of ''N''-methylated
trace amine
Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the ...
s: it metabolizes
phenethylamine
Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amin ...
into
''N''-methylphenethylamine (a
positional isomer
In chemistry, a structural isomer (or constitutional isomer in the IUPAC nomenclature) of a compound is another compound whose molecule has the same number of atoms of each element, but with logically distinct bonds between them. The term meta ...
of
amphetamine
Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
), ''p''-
octopamine
Octopamine (molecular formula C8H11NO2; also known as OA, and also norsynephrine, ''para''-octopamine and others) is an organic chemical closely related to norepinephrine, and synthesized biologically by a homologous pathway. Octopamine is ofte ...
into
synephrine
Synephrine, or, more specifically, ''p''-synephrine, is an alkaloid, occurring naturally in some plants and animals, and also in approved drugs products as its ''m''-substituted analog known as neo-synephrine. ''p''-Synephrine (or formerly Sympat ...
, and ''p''-
tyramine
Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-b ...
into
''N''-methyltyramine.
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.
PNMT is known to be regulated by
glucocorticoids
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...
made in the
adrenal gland
The adrenal glands (also known as suprarenal 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 ...
. One way that it can regulate PNMT expression is by
corticosterone
Corticosterone, also known as 17-deoxycortisol and 11β,21-dihydroxyprogesterone, is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands. It is of minor importance in humans, except in the very rare ...
's positive influence on the maintenance of PNMT mRNA.
Glucocorticoids
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...
have also been shown to increase the
biological half life
Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...
of the enzyme in vitro.
In animals who have had their pituitary gland removed, the addition of
glucocorticoids
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...
significantly lengthens the half life of PNMT enzymes.
Elevated PNMT levels can also be triggered by
splanchnic Splanchnic is usually used to describe organs in the abdominal cavity.
It is used when describing:
* Splanchnic tissue
* Splanchnic organs - including the stomach, small intestine, large intestine, pancreas, spleen, liver, and may also include the ...
nerve impulses. Nerve impulses increase the synthesis of PNMT mRNA by affecting certain promoter sequences.
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.
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
Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting these long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the dig ...
protease.
Localization
Epinephrine synthesis and therefore PNMT location has been largely found to be contained in the
adrenal medulla
The adrenal medulla ( la, medulla glandulae suprarenalis) 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 cel ...
or
adrenal gland
The adrenal glands (also known as suprarenal 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 ...
of most species. PNMT has been localized in most adult mammals to the cytoplasm of these medullary cells.
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
The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
, and in both
atria and
ventricles in the hearts are now being elucidated as sites of PNMT expression.
Epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
is produced in small groups of neurons in the human brain which express PNMT;
these neurons project from a nucleus that is adjacent (ventrolateral) to the
area postrema
The area postrema, a paired structure in the medulla oblongata of the brainstem, is a circumventricular organ having permeable capillaries and sensory neurons that enable its dual role to detect circulating chemical messengers in the blood and ...
and from a nucleus in the dorsal region of the
solitary tract
The solitary tract (tractus solitarius, or fasciculus solitarius), is a compact fiber bundle that extends longitudinally through the posterolateral region of the medulla oblongata. The solitary tract is surrounded by the solitary nucleus, and des ...
.
Disease
PNMT's normal function and defects are associated with multiple diseases and disorders.
Vitiligo
Decreased levels of PNMT activity measured by
epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
and
norepinephrine
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" (from Latin '' ad'', ...
is seen in the skin of patients with
vitiligo
Vitiligo is a disorder that causes the skin to lose its color. Specific causes are unknown but studies suggest a link to immune system changes.
Signs and symptoms
The only sign of vitiligo is the presence of pale patchy areas of depigmen ...
in the
keratinocytes
Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells.
Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referred ...
, which normally have higher PNMT activity.
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
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...
and
pentobarbital
Pentobarbital (previously known as pentobarbitone in Britain and Australia) is a short-acting barbiturate typically used as a sedative, a preanesthetic, and to control convulsions in emergencies. It can also be used for short-term treatment of ...
induced sedation and intoxication.
Alzheimer's disease
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
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.
Inhibition
Classic PNMT inhibitors include
benzimidazoles
Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound may be viewed as fused rings of the aromatic compounds benzene and imidazole. It is a colorless solid.
Preparation
Benzimidazole is produced by condensation of o- ...
,
quinolones
Quinolone may refer to:
* 2-Quinolone
* 4-Quinolone
* Quinolone antibiotic
A quinolone antibiotic is a member of a large group of broad-spectrum bacteriocidals that share a bicyclic core structure related to the substance 4-quinolone. They ar ...
, and
purines
Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines ...
.
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. Another example is CGS19281A.
References
External links
*
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