Decoding Molecular Mechanism Underlying Human Olfactory Receptor OR8D1 Activation by Sotolone Enantiomers

  • J Agric Food Chem. 2024 Mar 13;72(10):5403-5415. doi: 10.1021/acs.jafc.3c09142.
Juan Wang  1  2  3 ,  Danqing Wang  1  2 ,  Mingquan Huang  1  2 ,  Baoguo Sun  1  2  3 ,  Fazheng Ren  3 ,  Jihong Wu  1  2 ,  Jinglin Zhang  1  2 ,  Hehe Li  1  2 ,  Xiaotao Sun  1  2
Affiliations
  • 1. Key Laboratory of Brewing Molecular Engineering of China Light Industry, Beijing Technology & Business University (BTBU), Beijing 100048, China.
  • 2. Key Laboratory of Geriatric Nutrition and Health, Beijing Technology and Business University, Ministry of Education, Beijing 100048, China.
  • 3. Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China.
PMID: 38386648 DOI: 10.1021/acs.jafc.3c09142
Abstract

Sotolone, a chiral compound, plays an important role in the food industry. Herein, (R)-/(S)-sotolone were separated to determine their odor characteristics and thresholds in air (R-form: smoky, burned, herb, and green aroma, 0.0514 μg/m3; S-form: sweet, milk, acid, and nutty aroma, 0.0048 μg/m3). OR8D1 responses to (R)-/(S)-sotolone were detected in a HEK293 cell-based luminescence assay. (S)-Sotolone was a more potent agonist than (R)-sotolone (EC50 values of 84.98 ± 1.05 and 167.20 ± 0.25 μmol/L, respectively). Molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area analyses confirmed that the combination of (S)-sotolone and OR8D1 was more stable than that of (R)-sotolone. Odorant docking, multiple sequence alignments, site-directed mutagenesis, and functional studies with recombinant odorant receptors (ORs) in a cell-based luminescence assay identified 11 amino-acid residues that influence the enantioselectivity of OR8D1 toward sotolone significantly and that N2065.46 was indispensable to the activation of OR8D1 by (S)-sotolone.

Keywords
molecular docking; molecular dynamics simulations; olfactory receptor (OR8D1); site-directed mutagenesis; sotolone.
Products