An Unexpected Oxidosqualene Cyclase Active Site Architecture in the Iris tectorum Multifunctional α-Amyrin Synthase

  • ACS Catal. 2020 Aug 21;10(16):9515-9520. doi: 10.1021/acscatal.0c03231.
Shidan Wu  1 ,  Fan Zhang  2 ,  Wenbo Xiong  1 ,  István Molnár  3 ,  Jincai Liang  1 ,  Aijia Ji  1 ,  Caixia Wang  4 ,  Shengliang Wang  1 ,  Zhongqiu Liu  1  5 ,  Ruibo Wu  2 ,  Lixin Duan  1
Affiliations
  • 1. Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the Peo-ple's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, P.R. China.
  • 2. Guangdong Provincial Key Laboratory of New Drug De-sign and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China.
  • 3. Southwest Center for Natural Products Research, The University of Arizona, Tucson, AZ 85706, USA.
  • 4. Institute of Chinese Material Medica, China Academy of Chinese Medical Sciences, Beijing 100700, P.R. China.
  • 5. State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (SAR) 999078, China.
PMID: 34306805 DOI: 10.1021/acscatal.0c03231
Abstract

Ordered polycyclization catalyzed by oxidosqualene synthases (OSCs) morph a common linear precursor into structurally complex and diverse triterpene scaffolds with varied bioactivities. We identified three OSCs from Iris tectorum. ItOSC2 is a rare multifunctional α-amyrin synthase. Sequence comparisons, site-directed mutagenesis and multiscale simulations revealed that three spatially clustered residues, Y531/L256/L258 form an unusual Y-LL triad at the active site, replacing the highly conserved W-xY triad occurring in other amyrin synthases. The discovery of this unprecedented active site architecture in ItOSC2 underscores the plasticity of terpene cyclase catalytic mechanisms and opens new avenues for protein engineering towards custom designed OSCs.

Keywords
Enzyme Catalysis; Enzyme Promiscuity; Oxidosqualene Cyclase; QM/MM; Triterpene.
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