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

Autor: Alferova VA; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Zotova PA; Department of Chemistry, Lomonosov Moscow State University, 119992 Moscow, Russia., Baranova AA; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Guglya EB; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Belozerova OA; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Pipiya SO; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Kudzhaev AM; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Logunov SE; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Prokopenko YA; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Marenkova EA; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Marina VI; Department of Chemistry, Lomonosov Moscow State University, 119992 Moscow, Russia., Novikova EA; Department of Chemistry, Lomonosov Moscow State University, 119992 Moscow, Russia., Komarova ES; A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia., Starodumova IP; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia.; All-Russian Collection of Microorganisms (VKM), Pushchino Scientific Center for Biological Research, Russian Academy of Sciences, 142290 Pushchino, Russia., Bueva OV; All-Russian Collection of Microorganisms (VKM), Pushchino Scientific Center for Biological Research, Russian Academy of Sciences, 142290 Pushchino, Russia., Evtushenko LI; All-Russian Collection of Microorganisms (VKM), Pushchino Scientific Center for Biological Research, Russian Academy of Sciences, 142290 Pushchino, Russia., Ariskina EV; All-Russian Collection of Microorganisms (VKM), Pushchino Scientific Center for Biological Research, Russian Academy of Sciences, 142290 Pushchino, Russia., Kovalchuk SI; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Mineev KS; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Babenko VV; Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Malaya Pirogovskaya Str. 1a, 119435 Moscow, Russia., Sergiev PV; Department of Chemistry, Lomonosov Moscow State University, 119992 Moscow, Russia.; A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia.; Center for Molecular and Cellular Biology, 121205 Moscow, Russia., Lukianov DA; Department of Chemistry, Lomonosov Moscow State University, 119992 Moscow, Russia.; Center for Molecular and Cellular Biology, 121205 Moscow, Russia., Terekhov SS; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2024 Nov 30; Vol. 25 (23). Date of Electronic Publication: 2024 Nov 30.
DOI: 10.3390/ijms252312901
Abstrakt: Puromycin (Puro) is a natural aminonucleoside antibiotic that inhibits protein synthesis by its incorporation into elongating peptide chains. The unique mechanism of Puro finds diverse applications in molecular biology, including the selection of genetically engineered cell lines, in situ protein synthesis monitoring, and studying ribosome functions. However, the key step of Puro biosynthesis remains enigmatic. In this work, pur6-guided genome mining is carried out to explore the natural diversity of Puro-like antibiotics. The diversity of biosynthetic gene cluster (BGC) architectures suggests the existence of distinct structural analogs of puromycin encoded by pur-like clusters. Moreover, the presence of tRNA Cys in some BGCs, i.e., cst -like clusters, leads us to the hypothesis that Pur6 utilizes aminoacylated tRNA as an activated peptidyl precursor, resulting in cysteine-based analogs. Detailed metabolomic analysis of Streptomyces sp. VKM Ac-502 containing cst -like BGC revealed 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. Aminonucleoside N-acetyltransferase CstC inactivated Cst, mediating antibiotic resistance in genetically modified bacteria and human cells. The substrate specificity of CstC originated from the steric hindrance of its active site. We believe that novel aminonucleosides and their inactivating enzymes can be developed through the directed evolution of the discovered biosynthetic machinery.
Databáze: MEDLINE
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