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Carbonic anhydrase activators: kinetic and X-ray crystallographic study for the interaction of D- and L-tryptophan with the mammalian isoforms I-XIV.

Abstract：

:An activation study of mammalian carbonic anhydrase (CA, EC 4.2.1.1) isoforms I-XIV with D- and L-tryptophan has been performed both by means of kinetic and X-ray crystallographic techniques. These compounds show a time dependent activity against isozyme CA II, with activation constants of 1.13 microM for L-Trp and 0.37 microM for D-Trp, respectively, after 24 h of incubation between enzyme and activator. The high resolution X-ray crystal structure of the hCA II-D-Trp adduct revealed the activator to bind in a totally unprecedented way to the enzyme active site as compared to histamine, L-/D-Phe, L-/D-His or L-adrenaline. D-Trp is anchored at the edge of the CA II active site entrance, strongly interacting with amino acid residues Asp130, Phe131 and Gly132 as well as with a loop of a second symmetry related protein molecule from the asymmetric unit, by means of hydrogen bonds and several weak van der Waals interactions involving Glu234, Gly235, Glu236 and Glu238. Thus, a second activator binding site (B) within the CA II cavity has been detected, where only D-Trp was shown so far to bind, in addition to the activator binding site A, in which histamine, L-/D-Phe, and L-/D-His are bound. These findings explain the strong affinity of D-Trp for CA II and may be useful for designing novel classes of CA activators by using this compound as lead molecule.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Temperini C,Innocenti A,Scozzafava A,Supuran CT

doi

10.1016/j.bmc.2008.08.043

subject

Has Abstract

pub_date

2008-09-15 00:00:00

pages

8373-8

issue

18

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(08)00773-6

journal_volume

16

pub_type

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