Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors.

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Maresca A, Temperini C, Vu H, Pham NB, Poulsen SA, Scozzafava A, Quinn RJ, Supuran CT

Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors.

J Am Chem Soc. 2009 Mar 4;131(8):3057-62. doi: 10.1021/ja809683v.

PubMed ID
19206230 [ View in PubMed
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Abstract

The X-ray crystal structure of the adduct between the zinc metalloenzyme carbonic anhydrase II (CA, EC 4.2.1.1) with the recently discovered natural product coumarin derivative 6-(1S-hydroxy-3-methylbutyl)-7-methoxy-2H-chromen-2-one showed the coumarin hydrolysis product, a cis-2-hydroxy-cinnamic acid derivative, and not the parent coumarin, bound within the enzyme active site. The bound inhibitor exhibits an extended, two-arm conformation that effectively plugs the entrance to the enzyme active site with no interactions with the catalytically crucial zinc ion. The inhibitor is sandwiched between Phe131, with which it makes an edge-to-face stacking, and Asn67/Glu238sym, with which it makes several polar and hydrogen bonding interactions. This unusual binding mode, with no interactions between the inhibitor molecule and the active site metal ion is previously unobserved for this enzyme class and presents a new opportunity for future drug design campaigns to target a mode of inhibition that differs substantially from classical inhibitors such as the clinically used sulfonamides and sulfamates. Several structurally simple coumarin scaffolds were also shown to inhibit all 13 catalytically active mammalian CA isoforms, with inhibition constants ranging from nanomolar to millimolar. The inhibition is time dependent, with maximum inhibition being observed after 6 h.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Carbonic anhydrase 1P00915Details
Carbonic anhydrase 2P00918Details
Carbonic anhydrase 4P22748Details
Carbonic anhydrase 12O43570Details
Carbonic anhydrase 9Q16790Details
Carbonic anhydrase 3P07451Details
Carbonic anhydrase 5A, mitochondrialP35218Details
Carbonic anhydrase 5B, mitochondrialQ9Y2D0Details
Carbonic anhydrase 6P23280Details
Carbonic anhydrase 7P43166Details
Carbonic anhydrase 14Q9ULX7Details