Unconventional Origin and Hybrid System for Construction of Pyrrolopyrrole Moiety in Kosinostatin Biosynthesis

Ma, Hongmin; Zhou, Qiang; Tang, Yanqiong; Zhang, Zhuan; Chen, Yongsheng; He, Haiyan; Pan, Hai‐Xue; Tang, Man-Cheng; Gao, Jufang; Zhao, Sheng‐Yin; Igarashi, Yasuhiro; Tang, Gong‐Li

doi:10.1016/j.chembiol.2013.04.013

Cited by 32 publications

(46 citation statements)

References 44 publications

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“…The high sequence identity between KST gene cluster and other anthracycline gene clusters indicates that KST may generate the C-4 hydroxyl anthracycline as primary anthracycline core; in addition, our labeled acetate feeding experiments further confirmed the prediction that KST has undergone similar assembly process to afford C-4 hydroxyl anthracycline (Fig. 1B) (12). If this is the case, an apparent hydroxyl regioisomerization of anthracycline must be involved in the KST biosynthesis, which is a chemically challenging transformation process.…”

supporting

confidence: 65%

“…During our previous studies, the anthracycline intermediate 4, bearing a C-1 hydroxyl group in D-ring, was identified from the kstB1-inactivation mutant strain (Fig. 1B) (12). The high sequence identity between KST gene cluster and other anthracycline gene clusters indicates that KST may generate the C-4 hydroxyl anthracycline as primary anthracycline core; in addition, our labeled acetate feeding experiments further confirmed the prediction that KST has undergone similar assembly process to afford C-4 hydroxyl anthracycline (Fig.…”

mentioning

confidence: 99%

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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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supporting

confidence: 65%

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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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“…In addition, the spirocyclic linkage between the tetracyclic aglycone and the pyrrolopyrrole is connected via an unusual N, O-spiro center, for which linkage an unknown C-C bond formation mechanism should be involved. Very recently, the biosynthetic origin of the pyrrolopyrrole was finally identified and a unique biosynthetic pathway was proposed for the quinocycline ( [19], Fig. 17.7).…”

Section: Kosinostatin a Dna-targeted Agent From Micromonospora Spmentioning

confidence: 99%

“…17.11). To date, four congeners, rakicidins A (17) and B (18) from Micromonospora and rakicidins C (19) and D (20) from Streptomyces, have been reported. All these compounds share the common amino acid components, 4-amino-2,4-pentadienoate, glycine and hydroxyaspargine (or glutamine in rakicidin C), and a 3-hydroxyfatty acid unit which varies in the chain length and the methylation pattern.…”

Section: Rakicidin a Hypoxia Selective Cytotoxic Agent From Micromonmentioning

confidence: 99%

Antitumor Compounds from Actinomycetes in Deep-sea Water of Toyama Bay

Igarashi

2014

Handbook of Anticancer Drugs From Marine Origin

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Actinomycetes are the richest source of bioactive small molecules with high structural complexity and diversity which have been an inspiration to drug development. After the intensive screening efforts from soil-derived actinomycetes over a half century, it became necessary to exploit new microbial resources for discovering new drug leads. The deep-sea water in Toyama Bay is known as the 'specific deep-sea water of Japan Sea' because Sea of Japan is almost enclosed from the Pacific Ocean and the water exchanges very slowly with the neighboring seas. Furthermore, high dissolved oxygen concentration in this sea water gives rise to high biological productivity. As a part of investigation on the deep-sea water in Toyama Bay, we undertook the isolation of actinomycetes from deep-sea water for evaluation of bioactive compound production. This chapter summarizes the chemistry and biology of antitumor compounds produced by actinomycetes collected from the deep-sea water in Toyama Bay.Keywords Actinomycetes · Micromonospora · Deep-sea water · Antitumor compounds IntroductionToyama Bay is located in the northern shores of Honshu, Japan, and faced to Sea of Japan. The sea water present deeper than 300 m is called 'deep-sea water', which occupies about 60 % of the total volume of Toyama Bay. The deep-sea water of Toyama Bay has a low temperature, annually stable around 2 °C. The salinity is also stable at 34.0-34.1 g/kg, higher than that of surface sea water (32-33 g/kg). Utilization of the deep-sea water is being studied for commercial/industrial purposes such as aquatic culture of cold-water shrimps. As a part of investigation on the deep-sea water in Toyama Bay, we undertook the isolation of actinomycetes from

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“…TP-A0468 is a producer of the antitumor polyketides KST and isoquinocycline B (Fig. 1B), and in our previous work the biosynthetic gene cluster was identified and characterized (21). Bioinformatic analysis of neighboring area of the kst cluster showed that a set of genes were homologues of the AHBA biosynthetic gene cassette (Fig.…”

Section: Resultsmentioning

confidence: 88%

Discovery of 16-Demethylrifamycins by Removing the Predominant Polyketide Biosynthesis Pathway in Micromonospora sp. Strain TP-A0468

Zhou

Luo

Zhang

et al. 2019

Appl Environ Microbiol

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A number of strategies have been developed to mine novel natural products based on biosynthetic gene clusters and there have been dozens of successful cases facilitated by the development of genomic sequencing. During our study on biosynthesis of the antitumor polyketide kosinostatin (KST), we found that the genome of Micromonospora sp. strain TP-A0468, the producer of KST, contains other potential polyketide gene clusters, with no encoded products detected. Deletion of kst cluster led to abolishment of KST and the enrichment of several new compounds, which were isolated and characterized as 16-demethylrifamycins (referred to here as compounds 3 to 6). Transcriptional analysis demonstrated that the expression of the essential genes related to the biosynthesis of compounds 3 to 6 was comparable to the level in the wild-type and in the kst cluster deletion strain. This indicates that the accumulation of these compounds was due to the redirection of metabolic flux rather than transcriptional activation. Genetic disruption, chemical complementation, and bioinformatic analysis revealed that the production of compounds 3 to 6 was accomplished by cross talk between the two distantly placed polyketide gene clusters pks3 and M-rif. This finding not only enriches the analogue pool and the biosynthetic diversity of rifamycins but also provides an auxiliary strategy for natural product discovery through genome mining in polyketide-producing microorganisms. IMPORTANCE Natural products are essential in the development of novel clinically used drugs. Discovering new natural products and modifying known compounds are still the two main ways to generate new candidates. Here, we have discovered several rifamycins with varied skeleton structures by redirecting the metabolic flux from the predominant polyketide biosynthetic pathway to the rifamycin pathway in the marine actinomycetes species Micromonospora sp. strain TP-A0468. Rifamycins are indispensable chemotherapeutics in the treatment of various diseases such as tuberculosis, leprosy, and AIDS-related mycobacterial infections. This study exemplifies a useful method for the discovery of cryptic natural products in genome-sequenced microbes. Moreover, the 16-demethylrifamycins and their genetically manipulable producer provide a new opportunity in the construction of novel rifamycin derivates to aid in the defense against the ever-growing drug resistance of Mycobacterium tuberculosis.

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Unconventional Origin and Hybrid System for Construction of Pyrrolopyrrole Moiety in Kosinostatin Biosynthesis

Cited by 32 publications

References 44 publications

Hydroxyl regioisomerization of anthracycline catalyzed by a four-enzyme cascade

Hydroxyl regioisomerization of anthracycline catalyzed by a four-enzyme cascade

Antitumor Compounds from Actinomycetes in Deep-sea Water of Toyama Bay

Discovery of 16-Demethylrifamycins by Removing the Predominant Polyketide Biosynthesis Pathway in Micromonospora sp. Strain TP-A0468

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