Nanoreporter of an enzymatic suicide inactivation pathway

Zvi Yaari, Justin M. Cheung, Hanan A. Baker, Rune S. Frederiksen, Prakrit V. Jena, Christopher P. Horoszko, Fang Jiao, Simon Scheuring, Minkui Luo, Daniel A. Heller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Enzymatic suicide inactivation, a route of permanent enzyme inhibition, is the mechanism of action for a wide array of pharmaceuticals. Here, we developed the first nanosensor that selectively reports the suicide inactivation pathway of an enzyme. The sensor is based on modulation of the near-infrared fluorescence of an enzyme-bound carbon nanotube. The nanosensor responded selectively to substrate-mediated suicide inactivation of the tyrosinase enzyme via bathochromic shifting of the nanotube emission wavelength. Mechanistic investigations revealed that singlet oxygen generated by the suicide inactivation pathway induced the response. We used the nanosensor to quantify the degree of enzymatic inactivation by measuring response rates to small molecule tyrosinase modulators. This work resulted in a new capability of interrogating a specific route of enzymatic death. Potential applications include drug screening and hit-validation for compounds that elicit or inhibit enzymatic inactivation and single-molecule measurements to assess population heterogeneity in enzyme activity.

Original languageAmerican English
Pages (from-to)7819-7827
Number of pages9
JournalNano Letters
Volume20
Issue number11
DOIs
StatePublished - 11 Nov 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
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Keywords

  • Drug development
  • Drug screening
  • Enzymology
  • High throughput assay
  • Reactive oxygen species

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