Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 26, Issue 17, Pages 4184-4190Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.07.060
Keywords
Malaria; Carbonic anhydrase; Metalloenzymes; Inhibitors; Sulfonamide; Protozoa; Hydratase activity
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Funding
- Distinguished Scientists Fellowship Program (DSFP) from King Saud University, Saudi Arabia
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We report the cloning, purification and characterization of the full domain of carbonic anhydrase (CA, EC 4.2.1.1) from Plasmodium falciparum, which incorporates 358 amino acid residues (from 181 to 538, in the sequence of this 600 amino acid long protein), called PfCAdom. The enzyme, which belongs to the eta-CA class showed the following kinetic parameters: k(cat) of 3.8 x 10(5) s(-1) and k(cat)/K-m of 7.2 x 10(7) M-1 x s(-1) being 13.3 times more effective as a catalyst compared to the truncated form PfCA. PfCAdom is more effective than the human (h) isoform hCA I, being around 50% less effective compared to hCA II, one of the most catalytically efficient enzymes known so far. Intriguingly, the sulfonamides CA inhibitors generally showed much weaker inhibitory activity against PfCAdom compared to PfCA, prompting us to hypothesize that the 69 amino acid residues insertion present in the active site of this eta-CA is crucial for the active site architecture. The best sulfonamide inhibitors for PfCAdom were acetazolamide, methazolamide, metanilamide and sulfanilamide, with /Cis in the range of 366-808 nM. (C) 2016 Elsevier Ltd. All rights reserved.
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