Download MendeleyStructural basis for stereoselective dehydration and hydrogen-bonding catalysis by the SAM-dependent pericyclase LepI.
Cai, Y., Hai, Y., Ohashi, M., Jamieson, C.S., Garcia-Borras, M., Houk, K.N., Zhou, J., Tang, Y.(2019) Nat Chem 11: 812-820
- PubMed: 31332284
- DOI: https://doi.org/10.1038/s41557-019-0294-x
- Primary Citation of Related Structures:
6IX3, 6IX5, 6IX7, 6IX8, 6IX9 - PubMed Abstract:
LepI is an S-adenosylmethionine (SAM)-dependent pericyclase that catalyses the formation of the 2-pyridone natural product leporin C. Biochemical characterization has shown that LepI can catalyse stereoselective dehydration to yield a reactive (E)-quinone methide that can undergo bifurcating intramolecular Diels-Alder (IMDA) and hetero-Diels-Alder (HDA) cyclizations from an ambimodal transition state, as well as a [3,3]-retro-Claisen rearrangement to recycle the IMDA product into leporin C. Here, we solve the X-ray crystal structures of SAM-bound LepI and in complex with a substrate analogue, the product leporin C, and a retro-Claisen reaction transition-state analogue to understand the structural basis for the multitude of reactions. Structural and mutational analysis reveals how nature evolves a classic methyltransferase active site into one that can serve as a dehydratase and a multifunctional pericyclase. Catalysis of both sets of reactions employs H133 and R295, two active-site residues that are not found in canonical methyltransferases. An alternative role of SAM, which is not found to be in direct contact with the substrate, is also proposed.
Organizational Affiliation:
State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, China.
