Diversity of Alkylproline Moieties in Pyrrolobenzodiazepines Arises from Postcondensation Modifications of a Unified Building Block

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F17%3A00477899" target="_blank" >RIV/61388971:_____/17:00477899 - isvavai.cz</a>
Result on the web
<a href="http://dx.doi.org/10.1021/acschembio.7b00335" target="_blank" >http://dx.doi.org/10.1021/acschembio.7b00335</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acschembio.7b00335" target="_blank" >10.1021/acschembio.7b00335</a>

Result language
angličtina
Original language name
Diversity of Alkylproline Moieties in Pyrrolobenzodiazepines Arises from Postcondensation Modifications of a Unified Building Block
Original language description
Anticancer pyrrolobenzocliazepiries (PBDs) are one of several groups of natural products that contain unusual 4-alkyl-L-proline derivatives (APDs) in their Structure. APD moieties of PBDs ate characterized by high structural diversity achieved through unknown biosynthetic machinery. Based on LC-MS analysis of culture broths, feeding experiments, and protein as says, we show that APDs are not incorporated into PBDs in their final form as was previously hypothesized. Instead, a uniform building block, 4-propylidene-L- proline or 4-ethylidene-L-proline, enters the condensation reaction. The subsequent postcondensation Steps are initiated by the introduction of an additional double bond catalyzed by a FAD-dependent oxidoreductase, which we demonstrated with Orf7 from anthramycin biosynthesis. The resulting double bond arrangement presumably represents a prerequisite for further modifications of the APD moieties. Our study gives general insight into the diversification of APD moieties of natural PBDs and provides proof-of-principle for precursor directed and combinatorial biosynthesis of new PBD-Based antitumor compounds.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10606 - Microbiology

Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2017
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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