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Article

KasQ an Epimerase Primes the Biosynthesis of Aminoglycoside Antibiotic Kasugamycin and KasF/H Acetyltransferases Inactivate Its Activity

1
Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
2
Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan
3
Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan
4
Biotechnology Center, National Chung Hsing University, Taichung City 402, Taiwan
*
Author to whom correspondence should be addressed.
Academic Editors: Leonardo Caputo, Laura Quintieri and Orazio Nicolotti
Biomedicines 2022, 10(2), 212; https://doi.org/10.3390/biomedicines10020212
Received: 19 November 2021 / Revised: 17 January 2022 / Accepted: 17 January 2022 / Published: 19 January 2022
(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)
Kasugamycin (KSM), an aminoglycoside antibiotic, is composed of three chemical moieties: D-chiro-inositol, kasugamine and glycine imine. Despite being discovered more than 50 years ago, the biosynthetic pathway of KSM remains an unresolved puzzle. Here we report a structural and functional analysis for an epimerase, KasQ, that primes KSM biosynthesis rather than the previously proposed KasF/H, which instead acts as an acetyltransferase, inactivating KSM. Our biochemical and biophysical analysis determined that KasQ converts UDP-GlcNAc to UDP-ManNAc as the initial step in the biosynthetic pathway. The isotope-feeding study further confirmed that 13C, 15N-glucosamine/UDP-GlcNH2 rather than glucose/UDP-Glc serves as the direct precursor for the formation of KSM. Both KasF and KasH were proposed, respectively, converting UDP-GlcNH2 and KSM to UDP-GlcNAc and 2-N’-acetyl KSM. Experimentally, KasF is unable to do so; both KasF and KasH are instead KSM-modifying enzymes, while the latter is more specific and reactive than the former in terms of the extent of resistance. The information gained here lays the foundation for mapping out the complete KSM biosynthetic pathway. View Full-Text
Keywords: kasugamycin; kasugamine; antibiotic biosynthesis; epimerase and acetyltransferase kasugamycin; kasugamine; antibiotic biosynthesis; epimerase and acetyltransferase
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MDPI and ACS Style

Rattinam, R.; Basha, R.S.; Wang, Y.-L.; Wang, Z.-C.; Hsu, N.-S.; Lin, K.-H.; Zadeh, S.M.; Adhikari, K.; Lin, J.-P.; Li, T.-L. KasQ an Epimerase Primes the Biosynthesis of Aminoglycoside Antibiotic Kasugamycin and KasF/H Acetyltransferases Inactivate Its Activity. Biomedicines 2022, 10, 212. https://doi.org/10.3390/biomedicines10020212

AMA Style

Rattinam R, Basha RS, Wang Y-L, Wang Z-C, Hsu N-S, Lin K-H, Zadeh SM, Adhikari K, Lin J-P, Li T-L. KasQ an Epimerase Primes the Biosynthesis of Aminoglycoside Antibiotic Kasugamycin and KasF/H Acetyltransferases Inactivate Its Activity. Biomedicines. 2022; 10(2):212. https://doi.org/10.3390/biomedicines10020212

Chicago/Turabian Style

Rattinam, Rajesh, R. S. Basha, Yung-Lin Wang, Zhe-Chong Wang, Ning-Shian Hsu, Kuan-Hung Lin, Saeid M. Zadeh, Kamal Adhikari, Jin-Ping Lin, and Tsung-Lin Li. 2022. "KasQ an Epimerase Primes the Biosynthesis of Aminoglycoside Antibiotic Kasugamycin and KasF/H Acetyltransferases Inactivate Its Activity" Biomedicines 10, no. 2: 212. https://doi.org/10.3390/biomedicines10020212

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