Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 16, Issue 18, Pages 8373-8378Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2008.08.043
Keywords
carbonic anhydrase; isozymes; activation; L-tryptophan; D-tryptophan; X-ray crystallography
Funding
- 6th Framework Programme of the European Union [EUROXY, DeZnIT]
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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 mu M for L-Trp and 0.37 mu M 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. ndings 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. (C) 2008 Elsevier Ltd. All rights reserved.
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