Snapshots from the Catalytic Landscape of Chalcone Isomerase

Abstract

Chalcone isomerase (CHI) catalyzes the cyclization of 3-ring scaffolds of flavonoids, a class of plant-based natural products important for nutrition and disease prevention. A persistent question has been whether the enzyme uses dynamics to facilitate conformational rearrangements of substrates within the active site. To help resolve this question, CHI was crystallized with phloretin, a flexible substrate analogue that cannot undergo cyclization. The crystal structure possesses eight protein molecules per asymmetric unit, revealing different active site conformations that accommodate different bound conformers of phloretin. Together, the structural snapshots depict a series of coordinated, dynamic chemical interactions that lower barriers to substrate rearrangements approaching bond formation. Differential scanning fluorimetry combined with mutational analysis and enzyme kinetics further confirm that phloretin binds to the enzyme active site and that it acts as a competitive inhibitor of CHI. Together these findings answer outstanding questions about the flexibility and dynamics of CHI catalysis, information that may be useful for future biosynthetic design and enzyme engineering goals. Overall, this work supports a catalytic model in which the CHI enzyme operates as a dynamic ensemble of structures necessary to facilitate catalytic substrate rearrangements.

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BibTeX RIS

BibTeX

@misc{burke2026snapshots,
  title = {{Snapshots from the Catalytic Landscape of Chalcone Isomerase}},
  author = {J. R. Burke and M. A. Rangel and V. I. Vasquez Meza and H. N. Mims and T. O. Darko and K. M. Ixcoy and A. Ruiz Rivera and J. Zhang and E. R. Wolf-Saxon and C. C. Moorman},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.01.748576},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748576v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Snapshots from the Catalytic Landscape of Chalcone Isomerase
AU  - J. R. Burke
AU  - M. A. Rangel
AU  - V. I. Vasquez Meza
AU  - H. N. Mims
AU  - T. O. Darko
AU  - K. M. Ixcoy
AU  - A. Ruiz Rivera
AU  - J. Zhang
AU  - E. R. Wolf-Saxon
AU  - C. C. Moorman
PY  - 2026
DA  - 2026/09/01
PB  - bioRxiv
DO  - 10.64898/2026.09.01.748576
UR  - https://www.biorxiv.org/content/10.64898/2026.09.01.748576v1
AB  - Chalcone isomerase (CHI) catalyzes the cyclization of 3-ring scaffolds of flavonoids, a class of plant-based natural products important for nutrition and disease prevention. A persistent question has been whether the enzyme uses dynamics to facilitate conformational rearrangements of substrates within the active site. To help resolve this question, CHI was crystallized with phloretin, a flexible substrate analogue that cannot undergo cyclization. The crystal structure possesses eight protein molecules per asymmetric unit, revealing different active site conformations that accommodate different bound conformers of phloretin. Together, the structural snapshots depict a series of coordinated, dynamic chemical interactions that lower barriers to substrate rearrangements approaching bond formation. Differential scanning fluorimetry combined with mutational analysis and enzyme kinetics further confirm that phloretin binds to the enzyme active site and that it acts as a competitive inhibitor of CHI. Together these findings answer outstanding questions about the flexibility and dynamics of CHI catalysis, information that may be useful for future biosynthetic design and enzyme engineering goals. Overall, this work supports a catalytic model in which the CHI enzyme operates as a dynamic ensemble of structures necessary to facilitate catalytic substrate rearrangements.
ER  -

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