Neocarzinostatin-based hybrid biocatalysts with a RNase like activity

Agathe Urvoas, Wadih Ghattas, Jean Didier Maréchal, Frédéric Avenier, Felix Bellande, Wei Mao, Rémy Ricoux, Jean Pierre Mahy

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

Abstract

© 2014 Elsevier Ltd. All rights reserved. A new zinc(II)-cofactor coupled to a testosterone anchor, zinc(II)-N,N-bis(2-pyridylmethyl)-1,3-diamino-propa-2-ol-N′(17′-succinimidyltestosterone) (Zn-Testo-BisPyPol) 1-Zn has been synthesized and fully characterized. It has been further associated with a neocarzinostatin variant, NCS-3.24, to generate a new artificial metalloenzyme following the so-called 'Trojan horse' strategy. This new 1-Zn-NCS-3.24 biocatalyst showed an interesting catalytic activity as it was found able to catalyze the hydrolysis of the RNA model HPNP with a good catalytic efficiency (kcat/KM = 13.6 M-1 s-1 at pH 7) that places it among the best artificial catalysts for this reaction. Molecular modeling studies showed that a synergy between the binding of the steroid moiety and that of the BisPyPol into the protein binding site can explain the experimental results, indicating a better affinity of 1-Zn for the NCS-3.24 variant than testosterone and testosterone-hemisuccinate themselves. They also show that the artificial cofactor entirely fills the cavity, the testosterone part of 1-Zn being bound to one the two subdomains of the protein providing with good complementarities whereas its metal ion remains widely exposed to the solvent which made it a valuable tool for the catalysis of hydrolysis reactions, such as that of HPNP. Some possible improvements in the 'Trojan horse' strategy for obtaining better catalysts of selective reactions will be further studied.
Original languageEnglish
Pages (from-to)5678-5686
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number20
DOIs
Publication statusPublished - 15 Oct 2014

Keywords

  • Artificial metalloenzyme
  • Molecular modeling
  • Phosphodiester hydrolysis
  • Trojan horse
  • Zinc complex

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