Post-PKS tailoring steps in natural product-producing actinomycetes from the perspective of combinatorial biosynthesis

Olano, Carlos; Méndez, Cármen; Salas, José A.

doi:10.1039/b911956f

Cited by 154 publications

(132 citation statements)

References 303 publications

(259 reference statements)

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“…[1][2][3][4] Here we deal with jadomycin derivatives, which form a series of angucycline-derived molecules with a unique pentacyclic benz [b]oxazolophenanthridine skeleton, 5,6 produced by Streptomyces venezuelae ISP5230 under stress conditions, such as phage infection, heat and ethanol shock. 7 Jadomycin provides a model system to study secondary metabolism in streptomycetes, with unique biosynthetic and regulatory features.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the cytotoxic activity of new jadomycin derivatives reveals the potential to improve its selectivity against tumor cells

et al. 2012

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The jadomycins are a unique family of angucycline-derived antibiotics with interesting cytotoxic activities. In this work, six new jadomycin derivatives were produced in vivo by providing non-natural amino acids in fermentation media. They were further purified and identified by MS and NMR analyses. The cytotoxicities of these derivatives were evaluated against tumor cell lines MCF-7 and HCT116, as well as the normal human microvascular epithelial cells. The derivatives with alkyl side chains showed similar levels of cytotoxicity as jadomycin B and other known derivatives with nonpolar side chains, with IC 50 ranging from 1.3 to 10 lM; but the activities are not selective as these compounds also showed similar levels of cytotoxicity toward the normal human microvascular epithelial cells in the same concentration range. For the first time, derivatives with amino side chains (jadomycin Orn and K) were prepared and evaluated. Significantly, jadomycin Orn showed differential activity against normal and tumor cell lines. This result points to a new direction to modify jadomycin structure. The insights on the structure-activity relationship of jadomycins will guide further efforts to generate new and improved jadomycin derivatives against tumor cells.

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Section: Introductionmentioning

confidence: 99%

Evaluation of the cytotoxic activity of new jadomycin derivatives reveals the potential to improve its selectivity against tumor cells

et al. 2012

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“…1A) (3,7). The anthracycline core is then decorated with various tailoring enzymes to generate types of anthracycline antibiotics (8)(9)(10). Therefore, most of the anthracyclines possess a C-4 hydroxyl group, and a very few C-4 deoxyanthracyclines have been isolated in nature.…”

mentioning

confidence: 99%

Hydroxyl regioisomerization of anthracycline catalyzed by a four-enzyme cascade

Zhang

Gong

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Ranking among the most effective anticancer drugs, anthracyclines represent an important family of aromatic polyketides generated by type II polyketide synthases (PKSs). After formation of polyketide cores, the post-PKS tailoring modifications endow the scaffold with various structural diversities and biological activities. Here we demonstrate an unprecedented four-enzyme-participated hydroxyl regioisomerization process involved in the biosynthesis of kosinostatin. First, KstA15 and KstA16 function together to catalyze a cryptic hydroxylation of the 4-hydroxyl-anthraquinone core, yielding a 1,4-dihydroxyl product, which undergoes a chemically challenging asymmetric reduction-dearomatization subsequently acted by KstA11; then, KstA10 catalyzes a region-specific reduction concomitant with dehydration to afford the 1-hydroxyl anthraquinone. Remarkably, the shunt product identifications of both hydroxylation and reduction-dehydration reactions, the crystal structure of KstA11 with bound substrate and cofactor, and isotope incorporation experiments reveal mechanistic insights into the redox dearomatization and rearomatization steps. These findings provide a distinguished tailoring paradigm for type II PKS engineering.biosynthesis | C-4 deoxyanthracycline | two-component hydroxylase | NmrA-like short-chain dehydrogenase | dehydroxylation

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“…Although genetic manipulation of PKS genes is indeed an attractive methodology to create novel polyketide molecules, [8,9] the genes for the tailoring enzymes can be more easily inactivated to create biosynthetic intermediates that were not accumulated in the wildtype producer strains. [10] Furthermore, such enzymes can be utilized for the in vitro transformation to create diverse structures of analogous compounds. Glycosyltransferase is one of the most applicable enzymes for the purpose, and thus glycorandomization methodology are widely accepted to create biologically relevant glycosides.…”

Section: Introductionmentioning

confidence: 99%

Cloning and Characterization of the Biosynthetic Gene Cluster of 16‐Membered Macrolide Antibiotic FD‐891: Involvement of a Dual Functional Cytochrome P450 Monooxygenase Catalyzing Epoxidation and Hydroxylation

et al. 2010

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FD‐891 is a 16‐membered cytotoxic antibiotic macrolide that is especially active against human leukemia such as HL‐60 and Jurkat cells. We identified the FD‐891 biosynthetic (gfs) gene cluster from the producer Streptomyces graminofaciens A‐8890 by using typical modular type I polyketide synthase (PKS) genes as probes. The gfs gene cluster contained five typical modular type I PKS genes (gfsA, B, C, D, and E), a cytochrome P450 gene (gfsF), a methyltransferase gene (gfsG), and a regulator gene (gfsR). The gene organization of PKSs agreed well with the basic polyketide skeleton of FD‐891 including the oxidation states and α‐alkyl substituent determined by the substrate specificities of the acyltransferase (AT) domains. To clarify the involvement of the gfs genes in the FD‐891 biosynthesis, the P450 gfsF gene was inactivated; this resulted in the loss of FD‐891 production. Instead, the gfsF gene‐disrupted mutant accumulated a novel FD‐891 analogue 25‐O‐methyl‐FD‐892, which lacked the epoxide and the hydroxyl group of FD‐891. Furthermore, the recombinant GfsF enzyme coexpressed with putidaredoxin and putidaredoxin reductase converted 25‐O‐methyl‐FD‐892 into FD‐891. In the course of the GfsF reaction, 10‐deoxy‐FD‐891 was isolated as an enzymatic reaction intermediate, which was also converted into FD‐891 by GfsF. Therefore, it was clearly found that the cytochrome P450 GfsF catalyzes epoxidation and hydroxylation in a stepwise manner in the FD‐891 biosynthesis. These results clearly confirmed that the identified gfs genes are responsible for the biosynthesis of FD‐891 in S. graminofaciens.

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Post-PKS tailoring steps in natural product-producing actinomycetes from the perspective of combinatorial biosynthesis

Cited by 154 publications

References 303 publications

Evaluation of the cytotoxic activity of new jadomycin derivatives reveals the potential to improve its selectivity against tumor cells

Evaluation of the cytotoxic activity of new jadomycin derivatives reveals the potential to improve its selectivity against tumor cells

Hydroxyl regioisomerization of anthracycline catalyzed by a four-enzyme cascade

Cloning and Characterization of the Biosynthetic Gene Cluster of 16‐Membered Macrolide Antibiotic FD‐891: Involvement of a Dual Functional Cytochrome P450 Monooxygenase Catalyzing Epoxidation and Hydroxylation

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