Elucidation of salicylate attachment in celesticetin biosynthesis opens the door to create a library of more efficient hybrid lincosamide antibiotics

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F17%3A00476004" target="_blank" >RIV/61388971:_____/17:00476004 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1039/c6sc04235j" target="_blank" >http://dx.doi.org/10.1039/c6sc04235j</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/c6sc04235j" target="_blank" >10.1039/c6sc04235j</a>

Result language

angličtina

Original language name

Elucidation of salicylate attachment in celesticetin biosynthesis opens the door to create a library of more efficient hybrid lincosamide antibiotics

Original language description

Lincosamides, which are produced by streptomycetes, compose a small but clinically important class of antibiotics. The recent elucidation of the condensation and post-condensation biosynthetic steps of the lincosamides lincomycin and celesticetin revealed several unexpected reaction mechanisms. Here, we prepared recombinant proteins involved in the celesticetin biosynthetic pathway and used them for in vitro assays that were monitored by LC-MS. Our results elucidate the last biosynthetic step of celesticetin: the attachment of salicylic acid is catalyzed by the Ccb2 acyl-CoA ligase and the Ccb1 acyltransferase. Ccb1 belongs to the WS/DGAT protein family and, in contrast to the characterized members of the family, has unusual substrate specificity. To the best of our knowledge, Ccb1 is the first protein in this family that transfers a benzoyl derivative-CoA conjugate and is the first WS/DGAT protein involved in the biosynthesis of secondary metabolites. Furthermore, we exploited the relaxed substrate specificities of Ccb1 and Ccb2, as well as three additional upstream post-condensation biosynthetic proteins in the celesticetin pathway, and combined the lincomycin and the celesticetin biosynthetic pathways in vitro. In this way, we prepared a library of 150 novel hybrid lincosamides, including two unnatural chimeras of lincomycin and celesticetin, which were shown to have antibacterial properties more pronounced than clinically used lincomycin. These achievements may be considered a case study in applying knowledge about biosynthetic machinery to assemble a large number of compounds from originally a small group of natural products without the need for chemical synthesis.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10606 - Microbiology

Project

<a href="/en/project/LQ1604" target="_blank" >LQ1604: BIOCEV: from Fundamental to Applied Research</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2017

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Chemical Science

ISSN

2041-6520

e-ISSN

—

Volume of the periodical

8

Issue of the periodical within the volume

5

Country of publishing house

GB - UNITED KINGDOM

Number of pages

7

Pages from-to

3349-3355

UT code for WoS article

000400553000004

EID of the result in the Scopus database

2-s2.0-85021623740