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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10606 - Microbiology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2017

Kód důvěrnosti údajů

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

Název periodika

ACS Chemical Biology

ISSN

1554-8929

e-ISSN

—

Svazek periodika

12

Číslo periodika v rámci svazku

8

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

6

Strana od-do

1993-1998

Kód UT WoS článku

000408285900004

EID výsledku v databázi Scopus

2-s2.0-85027585373