Phenylethanolamine N-methyltransferase
phenylethanolamine N-methyltransferase | |||||||
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Chr. 17 q21-q22 | |||||||
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Phenylethanolamine N-methyltransferase (PNMT) is an
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
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
PNMT is also involved in the biosynthesis of N-methylated
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
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
Disease
PNMT's normal function and defects are associated with multiple diseases and disorders.
Vitiligo
Decreased levels of PNMT activity measured by
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
References
- ^ PMID 4564603.
- ^ S2CID 2578817.
- PMID 28084430.
- ^ a b 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.
- ^ PMID 11591352.
- S2CID 23761885.
- PMID 19570037.
- ^ PMID 20642456.
- PMID 15893506.
- ^ Brandt. "The Adrenal Medulla" (PDF).
- ^ PMID 19948186.
- ^ PMID 15860375.
- PMID 24374199.
- PMID 12040535.
- S2CID 24803398.
- ^ PMID 708473.
- S2CID 26602827.
- PMID 2871139.
- PMID 11514309.
- S2CID 31646987.
- PMID 2178473.
- PMID 11378842.
- PMID 1133821.
- PMID 8904737.
External links
- Phenylethanolamine+N-Methyltransferase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)