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

18 Scopus citations


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
Issue number11
StatePublished - 11 Nov 2020
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported in part (in the DAH laboratory) by the NIH New Innovator Award (DP2-HD075698), NCI (R01-CA215719), NIDDK (R01-DK114321), NINDS (R01-NS116353), the Cancer Center Support Grant (P30 CA008748), the National Science Foundation CAREER Award (1752506), the American Cancer Society Research Scholar Grant (GC230452), the Honorable Tina Brozman Foundation for Ovarian Cancer Research, the Ara Parseghian Medical Research Fund, the Expect Miracles Foundation - Financial Services Against Cancer, the Pershing Square Sohn Cancer Research Alliance, the Cycle for Survival’s Equinox Innovation Award in Rare Cancers, Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center, and the Center for Molecular Imaging and Nanotechnology of Memorial Sloan Kettering Cancer Center. Work in the ML laboratory was supported by NIGMS (R35GM134878), Functional Genomic Initiative, the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center. H.A.B. was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH under award number T32GM007739 to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program. R.S.F. was supported by the Alfred Benzon Foundation. Work in the Scheuring laboratory was supported by an NIH Director’s Pioneer Award (DP1AT010874 from NCCIH) and an NIH Research Project Grant (RO1NS110790 from NINDS). The authors would like to thank the Molecular Cytology Core Facility at Memorial Sloan Kettering Cancer Center. We would like to thank Yangang Pan for acquiring the DNA–CNT wet AFM images, Biran Wang for acquiring the DNA–CNT and TYR–CNT dry AFM images, and Emma Portnoy for helpful discussions.

Publisher Copyright:


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


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