One way that it can regulate PNMT expression is by corticosterone's positive influence on the maintenance of PNMT mRNA. PNMT is known to be regulated by glucocorticoids made in the adrenal gland. This increases the potency of the catecholamine response system, increasing the sympathetic output and making the stress response more profound. An increase in stress hormones or nerve impulses due to stress can cause PNMT to convert more norepinephrine into epinephrine. Įlevated PNMT expression is one of the ways that the stress response positively feeds back on itself. 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. Methyltransferases are very common in the catecholamine synthesis and deactivation pathways. 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. 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. 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. PNMT catalyzes the transfer of a methyl group from SAM to norepinephrine, converting it into epinephrine. This dimerization has no effect on the catalytic activity of the enzyme. When PNMT crystals are grown in non-reducing solutions, two disulfide bonds form between cysteines 48 and 139 on opposite chains. In the absence of an inhibitor or ligand, a phosphate group is bound to the active site to stabilize this region. The replacement of this residue another reduces the catalytic efficiency of PNMT by tenfold up to three hundredfold. The residue Glutamine 185 is necessary in binding the catecholamine substrate. Among all known PNMT variants in nature there are 7 crucial aromatic residues conserved in the active site. 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. S-adenosyl- L-methionine (SAM) is a required cofactor. 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. 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. It is closest in sequence to glycine- N-methyl transferase ( GNMT).
It shares many properties found among the other methyltransferases. It consists of 4 exons and is a 30 kDa protein. PNMT is a protein whose encoding gene is found on chromosome 17 in humans. 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.
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