Mining Translation Inhibitors by a Unique Peptidyl-Aminonucleoside Synthetase Reveals Cystocin Biosynthesis and Self-Resistance

Alferova, V.A.; Zotova, P.A.; Baranova, A.A.; Guglya, E.B.; Belozerova, O.A.; Pipiya, S.O.; Kudzhaev, A.M.; Logunov, S.E.; Prokopenko, Y.A.; Marenkova, E.A.; Marina, V.I.; Novikova, E.A.; Komarova, E.S.; Starodumova, I.P.; Bueva, O.V.; Evtushenko, L.I.; Ariskina, E.V.; Kovalchuk, S.I.; Mineev, K.S.; Babenko, V.V.; Sergiev, P.V.; Lukianov, D.A.; Terekhov, S.S.

Авторы: Alferova Vera A., Zotova Polina A., Baranova Anna A., Guglya Elena B., Belozerova Olga A., Pipiya Sofiya O., Kudzhaev Arsen M., Logunov Stepan E., Prokopenko Yuri A., Marenkova Elisaveta A., Marina Valeriya I., Novikova Evgenia A., Komarova Ekaterina S., Starodumova Irina P., Bueva Olga V., Evtushenko Lyudmila I., Ariskina Elena V., Kovalchuk Sergey I., Mineev Konstantin S., Babenko Vladislav V., Sergiev Petr V., Lukianov Dmitrii A., Terekhov Stanislav S.
Журнал: International Journal of Molecular Sciences
Том: 25
Номер: 23
Год издания: 2024
Издательство: MDPI
Местоположение издательства: Basel, Switzerland
Номер статьи: 12901
DOI: 10.3390/ijms252312901
Аннотация: Puromycin (Puro) is a natural aminonucleoside antibiotic that inhibits protein synthesisby its incorporation into elongating peptide chains. The unique mechanism of Puro finds diverseapplications in molecular biology, including the selection of genetically engineered cell lines, in situprotein synthesis monitoring, and studying ribosome functions. However, the key step of Purobiosynthesis remains enigmatic. In this work, pur6-guided genome mining is carried out to explorethe natural diversity of Puro-like antibiotics. The diversity of biosynthetic gene cluster (BGC) architec-tures suggests the existence of distinct structural analogs of puromycin encoded by pur-like clusters.Moreover, the presence of tRNACys in some BGCs, i.e., cst-like clusters, leads us to the hypothesisthat Pur6 utilizes aminoacylated tRNA as an activated peptidyl precursor, resulting in cysteine-basedanalogs. Detailed metabolomic analysis of Streptomyces sp. VKM Ac-502 containing cst-like BGCrevealed the production of a cysteinyl-based analog of Puro—cystocin (Cst). Similar to puromycin,cystocin inhibits both prokaryotic and eukaryotic translation by the same mechanism. Aminonucleo-side N-acetyltransferase CstC inactivated Cst, mediating antibiotic resistance in genetically modifiedbacteria and human cells. The substrate specificity of CstC originated from the steric hindrance of itsactive site. We believe that novel aminonucleosides and their inactivating enzymes can be developedthrough the directed evolution of the discovered biosynthetic machinery.
Добавил в систему: Алферова Вера Александровна

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Mining Translation Inhibitors by a Unique Peptidyl-Aminonucleoside Synthetase Reveals Cystocin Biosynthesis and Self-Resistanceстатья

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