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

Biomedicines

Saeid Malek Zadeh¹  Kuan-Hung Lin¹  Tsung-Lin Li¹  Zhe-Chong Wang¹  Yung-Lin Wang¹  R. Sidick Basha¹  Jin-Ping Lin¹  Rajesh Rattinam¹  Ning-Shian Hsu¹  Kamal Adhikari¹ 

[1] Genomics Research Center, Academia Sinica, Taipei 115, Taiwan;

关键词: kasugamycin;    kasugamine;    antibiotic biosynthesis;    epimerase and acetyltransferase;   

DOI  :  10.3390/biomedicines10020212

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown