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Article

Understand the Specific Regio- and Enantioselectivity of Fluostatin Conjugation in the Post-Biosynthesis

1
State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
2
Key Laboratory of Tropical Marine Bio-resource and Ecology, Guangdong Key Laboratory of Marine Materia, RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, 164 West Xingang Road, Guangzhou 510301, China
3
Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(6), 815; https://doi.org/10.3390/biom10060815
Received: 30 March 2020 / Revised: 7 May 2020 / Accepted: 8 May 2020 / Published: 26 May 2020
(This article belongs to the Special Issue Recent Advance of Actinomycetes)
Fluostatins, benzofluorene-containing aromatic polyketides in the atypical angucycline family, conjugate into dimeric and even trimeric compounds in the post-biosynthesis. The formation of the C–C bond involves a non-enzymatic stereospecific coupling reaction. In this work, the unusual regio- and enantioselectivities were rationalized by density functional theory calculations with the M06-2X (SMD, water)/6–311 + G(d,p)//6–31G(d) method. These DFT calculations reproduce the lowest energy C1-(R)-C10′-(S) coupling pathway observed in a nonenzymatic reaction. Bonding of the reactive carbon atoms (C1 and C10′) of the two reactant molecules maximizes the HOMO–LUMO interactions and Fukui function involving the highest occupied molecular orbital (HOMO) of nucleophile p-QM and lowest unoccupied molecular orbital (LUMO) of electrophile FST2 anion. In particular, the significant π–π stacking interactions of the low-energy pre-reaction state are retained in the lowest energy pathway for C–C coupling. The distortion/interaction–activation strain analysis indicates that the transition state (TScp-I) of the lowest energy pathway involves the highest stabilizing interactions and small distortion among all possible C–C coupling reactions. One of the two chiral centers generated in this step is lost upon aromatization of the phenol ring in the final difluostatin products. Thus, the π–π stacking interactions between the fluostatin 6-5-6 aromatic ring system play a critical role in the stereoselectivity of the nonenzymatic fluostatin conjugation. View Full-Text
Keywords: fluostatin; conjugation, regioselectivity; stereoselectivity; π–π stacking interaction fluostatin; conjugation, regioselectivity; stereoselectivity; π–π stacking interaction
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MDPI and ACS Style

Wang, Y.; Zhang, C.; Zhao, Y.-L.; Zhao, R.; Houk, K.N. Understand the Specific Regio- and Enantioselectivity of Fluostatin Conjugation in the Post-Biosynthesis. Biomolecules 2020, 10, 815. https://doi.org/10.3390/biom10060815

AMA Style

Wang Y, Zhang C, Zhao Y-L, Zhao R, Houk KN. Understand the Specific Regio- and Enantioselectivity of Fluostatin Conjugation in the Post-Biosynthesis. Biomolecules. 2020; 10(6):815. https://doi.org/10.3390/biom10060815

Chicago/Turabian Style

Wang, Yuanqi, Changsheng Zhang, Yi-Lei Zhao, Rosalinda Zhao, and Kendall N. Houk 2020. "Understand the Specific Regio- and Enantioselectivity of Fluostatin Conjugation in the Post-Biosynthesis" Biomolecules 10, no. 6: 815. https://doi.org/10.3390/biom10060815

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