Herboxidiene biosynthesis, production, and structural modifications: prospect for hybrids with related polyketide

Pokhrel, Anaya Raj; Dhakal, Dipesh; Jha, Amit Kumar; Sohng, Jae Kyung

doi:10.1007/s00253-015-6860-2

Cited by 20 publications

(14 citation statements)

References 98 publications

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“…Elucidating and engineering the bottlenecks of post‐PKS pathway is a feasible approach for the production improvement of desired polyketides . In previous work, the post‐PKS modifications in AP‐3 biosynthesis were fully elucidated by us and coworkers through gene inactivation and characterization of corresponding metabolites.…”

Section: Discussionmentioning

confidence: 99%

Identification and Engineering of Post‐PKS Modification Bottlenecks for Ansamitocin P‐3 Titer Improvement in Actinosynnema pretiosum subsp. pretiosum ATCC 31280

Ning

Wang

et al. 2017

Biotechnology Journal

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The type-I polyketide ansamitocin P-3 (AP-3) is a potent antitumor agent. Its production is most likely hampered by the required multiple substrate supplies and complicated post-PKS modifications in Actinosynnema pretiosum subsp. pretiosum ATCC 31280. For titer improvement, gene ansa30, encoding for a glycosyltransferase competing for the N-demethyl-AP-3 (PND-3) intermediate for AP-3 biosynthesis, was initially inactivated. In the mutant NXJ-22, the AP-3 titer was increased by 66% along with an obvious accumulation of PND-3, indicating that the N-methylation is a rate-limiting step. Alternatively, when abundant upstream intermediate 19-chloroproansamitocin was fed into a PKS mutant, 3-O-acylation was further identified along with the N-methylation as the rate-limiting steps. Subsequent overexpression of N-methyltransferase gene asm10 in NXJ-22 resulted in a 93% increase of AP-3 and a corresponding 92% decrease of PND-3. Additional supplementation of L-methionine, the precursor for SAM biosynthesis, substantially decreased the accumulation of PND-3. In parallel, the 3-O-acylation bottleneck was relieved by feeding with L-valine to NXJ-22, resulting in a 126% increase of AP-3. Eventually, a combined asm10 overexpression and supplementation of L-methionine and L-valine resulted in a 5-fold increase of AP-3, from 42 ± 2 mg L to 246 ± 6 mg L , without any noticeable accumulation of PND-3.

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Section: Discussionmentioning

confidence: 99%

Identification and Engineering of Post‐PKS Modification Bottlenecks for Ansamitocin P‐3 Titer Improvement in Actinosynnema pretiosum subsp. pretiosum ATCC 31280

Ning

Wang

et al. 2017

Biotechnology Journal

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“…7) and 18-O-β-d-glucopyranoside-25-demethyl herboxidiene (18 shown in Fig. 7) [55]. Such examples can also be found in spinosad [56], narbomycin [57], and other polyketides with sugar moieties attached to the aglycone core structures [58].…”

Section: Glycosylationmentioning

confidence: 90%

The Combinatorial Biosynthesis of “Unnatural” Products with Polyketides

Zhang

Duan

et al. 2018

Trans. Tianjin Univ.

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Polyketides have been widely used clinically due to their significant biological activities, but the needed structural and functional diversity cannot be achieved by common chemical synthetic methods. The tool of combinatorial biosynthesis provides the possibility to produce "unnatural" natural drugs, which has achieved initial success. This paper provides an overview for the strategies of combinatorial biosynthesis in producing the structural and functional diversity of polyketides, including the redesign of metabolic flow, polyketide synthase (PKS) engineering, and PKS post-translational modification. Although encouraging progress has been made in the last decade, challenges still exist regarding the rational combinatorial biosynthesis of polyketides. In this review, the perspectives of polyketide combinatorial biosynthesis are also discussed.

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“…These structural characteristics and its biological properties contributed to its name [63]. This compound was initially identified as a secondary metabolite from Streptomyces chromofuscus A7841.…”

Section: Microbial Metabolites That Regulate Splicingmentioning

confidence: 99%

Microbial and Natural Metabolites That Inhibit Splicing: A Powerful Alternative for Cancer Treatment

Martínez-Montiel

Rosas-Murrieta

Martínez-Montiel

et al. 2016

BioMed Research International

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In eukaryotes, genes are frequently interrupted with noncoding sequences named introns. Alternative splicing is a nuclear mechanism by which these introns are removed and flanking coding regions named exons are joined together to generate a message that will be translated in the cytoplasm. This mechanism is catalyzed by a complex machinery known as the spliceosome, which is conformed by more than 300 proteins and ribonucleoproteins that activate and regulate the precision of gene expression when assembled. It has been proposed that several genetic diseases are related to defects in the splicing process, including cancer. For this reason, natural products that show the ability to regulate splicing have attracted enormous attention due to its potential use for cancer treatment. Some microbial metabolites have shown the ability to inhibit gene splicing and the molecular mechanism responsible for this inhibition is being studied for future applications. Here, we summarize the main types of natural products that have been characterized as splicing inhibitors, the recent advances regarding molecular and cellular effects related to these molecules, and the applications reported so far in cancer therapeutics.

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Herboxidiene biosynthesis, production, and structural modifications: prospect for hybrids with related polyketide

Cited by 20 publications

References 98 publications

Identification and Engineering of Post‐PKS Modification Bottlenecks for Ansamitocin P‐3 Titer Improvement in Actinosynnema pretiosum subsp. pretiosum ATCC 31280

Identification and Engineering of Post‐PKS Modification Bottlenecks for Ansamitocin P‐3 Titer Improvement in Actinosynnema pretiosum subsp. pretiosum ATCC 31280

The Combinatorial Biosynthesis of “Unnatural” Products with Polyketides

Microbial and Natural Metabolites That Inhibit Splicing: A Powerful Alternative for Cancer Treatment

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