Phenylethanolamine N-methyltransferase
| phenylethanolamine N-methyltransferase | |
|---|---|
| Identifiers | |
| Symbol | PNMT |
| Alt. symbols | PENT |
| Entrez | 5409 |
| HUGO | 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). It is also expressed in small groups of neurons in the human brain.
PNMT is a protein whose encoding gene is found on chromosome 17 in humans. It consists of 4 exons and is a 30kDa 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.
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. 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 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.
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.
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