Activation and characterization of a cryptic gene cluster reveals a cyclization cascade for polycyclic tetramate macrolactams

Saha, Subhasish; Zhang, Wenjun; Zhang, Guangtao; Zhu, Yiguang; Chen, Yuchan; Liu, Wei; Yuan, Chengqian; Zhang, Qingbo; Zhang, Haibo; Zhang, Liping; Zhang, Weimin; Zhang, Changsheng

doi:10.1039/c6sc03875a

Cited by 85 publications

(99 citation statements)

References 33 publications

(65 reference statements)

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“…There is a large number of reported PoTeM gene clusters that contain four OX genes as seen in HSAF gene cluster (Figure S14). So far, several PoTeM clusters have been linked to their products (HSAF, ikarugamycin, frontalamides, compound d, and pactamides, capsimycins, and clifednamides) . In this work, we successful identified two new HSAF biosynthetic intermediates, 4 and 5 , established the pathways leading to the tricyclic analogues and bicyclic analogues, and demonstrated the importance of stereochemistry in determining the pathways.…”

Section: Figurementioning

confidence: 67%

“…It is only when the first ring has the “correct” stereochemistry (as in 4 ) that OX2 and OX4 can process it to form the second ring (as in 5 ) and the third ring (as in 11 , which is tautomerized to 1 ; Figure ). Both in vivo and in vitro studies establish that OX4 catalyzes the reductive cyclization of the third ring in the tricyclic system, which is homologous to the function of IkaC for ikarugamycin and PtmC for pactamides . In vitro, OX4 is also able to reduce a double bond in the two‐ring compound 2 that does not have the “correct” stereochemistry in the rings.…”

Section: Figurementioning

confidence: 99%

“…The formation of the inner 5‐memebered ring was shown to be catalyzed by a redox enzyme (IkaC), and evidence also showed that the formation of the outer 5‐6 rings was catalyzed by a single redox enzyme, IkaB. The Zhang group also showed that three redox enzyme genes, ptmB2 , ptmB1 , and ptmC , are responsible for formation of the 5‐5‐6 tricycle of pactamides in Streptomyces pactum SCSIO 02999 …”

Section: Figurementioning

confidence: 99%

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Biosynthesis of the Polycyclic System in the Antifungal HSAF and Analogues from Lysobacter enzymogenes

Wang

Liu

et al. 2018

Angewandte Chemie

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The biocontrol agent Lysobacter enzymogenes produces polycyclic tetramate macrolactams (PoTeMs), including the antifungal HSAF.T oe lucidate the biosynthesis of the cyclic systems,w ei dentified eleven HSAF precursors/ analogues with zero,o ne,t wo,o rt hree rings through heterologous expression of the HSAF gene cluster.Aseries of combinatorial gene expression and deletion experiments showed that OX3i st he "gatekeeper" responsible for the formation of the first 5-membered ring from lysobacterene A, OX1and OX2are responsible for formation of the second ring but with different selectivity,a nd OX4i sr esponsible for formation of the 6-membered ring. In vitro experiments showed that OX4i sa nN ADPH-dependent enzyme that catalyzest he reductive cyclization of 3-dehydroxy alteramide Ctoform 3-dehydroxy HSAF.Thus,the multiplicity of OX genes is the basis for the structural diversity of the HSAF family,w hich is the only characterized PoTeMc luster that involves four redox enzymes in the formation of the cyclic system.

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Section: Figurementioning

confidence: 67%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

Biosynthesis of the Polycyclic System in the Antifungal HSAF and Analogues from Lysobacter enzymogenes

Wang

Liu

et al. 2018

Angewandte Chemie

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“…K310, representing the first example of a microbial producer of ikarugamycins other than the Streptomyces species; however, it only displayed fragile antibacterial activity (MIC ≥ 50 µg/mL) [114]. The following year, three new ikarugamycins, 28-N-methylikarugamycin (111), iso-ikarugamycin 112 suggesting that the presence of a double bond in the A ring of the 5/5/6 ring system significantly decreased their cytotoxicity [120].…”

Section: Macrocyclic Tetramic Acidsmentioning

confidence: 99%

The Biological and Chemical Diversity of Tetramic Acid Compounds from Marine-Derived Microorganisms

Jiang

Chen

et al. 2020

Marine Drugs

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Tetramic acid (pyrrolidine-2,4-dione) compounds, isolated from a variety of marine and terrestrial organisms, have attracted considerable attention for their diverse, challenging structural complexity and promising bioactivities. In the past decade, marine-derived microorganisms have become great repositories of novel tetramic acids. Here, we discuss the biological activities of 277 tetramic acids of eight classifications (simple 3-acyl tetramic acids, 3-oligoenoyltetramic acids, 3-decalinoyltetramic acid, 3-spirotetramic acids, macrocyclic tetramic acids, N-acylated tetramic acids, α-cyclopiazonic acid-type tetramic acids, and other tetramic acids) from marine-derived microbes, including fungi, actinobacteria, bacteria, and cyanobacteria, as reported in 195 research studies up to 2019.

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“…The PTM gene clusters are conserved and widely distributed among bacterial genomes but normally remain silent. The activation of six new PTM congeners, pactamides A-F (Figure 3), was achieved through the expression of PTM cluster isolated from a deep-sea S. pactum strain SCSIO 02999 (Saha et al, 2017). A hybrid PKS/NRPS gene cluster of approximately 90-kb was captured in a single pSBAC clone through a straightforward restriction enzyme digestion and cloning approach; expression of the construct in S. lividans produced meridamycin (Figure 3); its productivity was enhanced by feeding precursors and using the strong constitutive ermE* promoter (Liu et al, 2009).…”

Section: Streptomyces Lividans As a Heterologous Hostmentioning

confidence: 99%

Streptomycetes: Surrogate hosts for the genetic manipulation of biosynthetic gene clusters and production of natural products

Nepal

Wang

2019

Biotechnology Advances

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Due to the worldwide prevalence of multidrug-resistant pathogens and high incidence of diseases such as cancer, there is an urgent need for the discovery and development of new drugs. Nearly half of the FDA-approved drugs are derived from natural products that are produced by living organisms, mainly bacteria, fungi, and plants. Commercial development is often limited by the low yield of the desired compounds expressed by the native producers. In addition, recent advances in whole genome sequencing and bioinformatics have revealed an abundance of cryptic biosynthetic gene clusters within microbial genomes. Genetic manipulation of clusters in the native host is commonly used to awaken poorly expressed or silent gene clusters, however, the lack of feasible genetic manipulation systems in many strains often hinders our ability to engineer the native producers. The transfer of gene clusters into heterologous hosts for expression of partial or entire biosynthetic pathways is an approach that can be used to overcome this limitation. Heterologous expression also facilitates the chimeric fusion of different biosynthetic pathways, leading to the generation of “unnatural” natural products. The genus Streptomyces is especially known to be a prolific source of drugs/antibiotics, its members are often used as heterologous expression hosts. In this review, we summarize recent applications of Streptomyces species, S. coelicolor, S. lividans, S. albus, S. venezuelae and S. avermitilis, as heterologous expression systems.

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Activation and characterization of a cryptic gene cluster reveals a cyclization cascade for polycyclic tetramate macrolactams

Abstract: We report the activation of a PTM gene cluster in marine-derived Streptomyces pactum, leading to the discovery of six new PTMs, the pactamides A-F.

Cited by 85 publications

References 33 publications

Biosynthesis of the Polycyclic System in the Antifungal HSAF and Analogues from Lysobacter enzymogenes

Biosynthesis of the Polycyclic System in the Antifungal HSAF and Analogues from Lysobacter enzymogenes

The Biological and Chemical Diversity of Tetramic Acid Compounds from Marine-Derived Microorganisms

Streptomycetes: Surrogate hosts for the genetic manipulation of biosynthetic gene clusters and production of natural products

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