SAM binding site

Substrates of COMT include xenobiotics catechols, catecholamines, and catechol estrogens. Three functional classes of chemicals are known to inhibit COMT. S-Adenosyl-I-homocysteine (SAH) is a potent inhibitor of COMT as well as the other SAM-dependent methyltransferases. Inhibition results from SAH binding to the SAM binding site on the enzyme. Certain divalent ions such as Ca+2 and trivalent metal ions such as the salts of lanthanides, neodymium, and europium are excellent inhibitors of COMT. A number of catechol-type substrates such as pyrogallol, fla-vonoids, pyrones, pyridenes, hydroxyquiolines, 3-mercaptotyramine, and tropolones are irreversible inhibitors of COMT. 

Residues 386-433 and 690-802 form a small, probably structural domain. The next two domains, residues 434-691 and 804-1022, are methyltransferase domains, and their folds are two different variations on the "universal" methyltransferase fold (Fig. 2D), a beta sheet with defined strand order and directionality sandwiched between alpha helices ". Soaking experiments with SAH confirm that for both domains the SAM binding site coincides with that in other methyltransferases. For the more N-terminal methyltransferase domain, SAH binding is accompanied by a conformational change, in which residues 519-524 and 579-587 rearrange in order to participate in binding. While each methyltransferase domain binds SAM independently, experiments indicate that 7N methyltransfer occurs only in X2 pentamers and not in monomers. (Equivalent experiments for 2 0 methyltransfer have not been reported.)... 

In collaboration with the Mainz group, Parma University workers synthesized CMPO-calix[6]arenes CP64 and CP65, bearing three CMPO binding sites onto the narrow and wide rim, respectively. CP65 and to a lesser extent CP64 display relatively low distribution ratios and a selectivity SAm/Eu lesser than 2.5.18... 

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