Construction of a hybrid gene cluster to reveal coupled ring formation–hydroxylation in the biosynthesis of HSAF and analogues from <i>Lysobacter enzymogenes</i>

Li, Xue; Wang, Haoxin; Li, Yaoyao; Du, Liangcheng

doi:10.1039/c9md00154a

Cited by 12 publications

(28 citation statements)

References 18 publications

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“…These observations further highlight the importance of Streptomyces species as prolific sources for bioactive compounds and they indicate the worth of genome mining in marine-derived Streptomycetes [35]. Similar to the well-established biosynthetic pathway for 5/5/6 type of PTMs [20,23,33], PtmA catalyzes the formation of a common polyene tetramate precursor, which is sequentially cyclized by PtmB2 /PtmB1 into an intermediate with the 5/5 carbocyclic ring system (Figure 2b). It has been hypothesized that OX3, which is a PtmB2 homologous enzyme, is involved in controlling the formation of products with both cisand trans-orientated H-10/H-11 in HSAF (7) biosynthesis [23].…”

Section: Biosynthetic Implicationsmentioning

confidence: 60%

“…It should be noted that a trans-orientation of H-10 and H-11 was assigned for 1, because of the obvious NOESY correlations of H-8/H-10, H10/H-12, and H-11/H-29b ( Figure 3). Previously, a trans-orientation of H-10 and H-11 was reported for pactamide A [20], aburatubolactam A (X-ray crystallography structure available [31]), combamide D [32], deOH alteramides, and lysobacterene B [33]. In the recently reported 5/5 type of PTMs umezawamides, the relative orientation of H-10 and H-11 was not determined [34].…”

Section: Genome Mining Of a Ptm Biosynthetic Gene Clustermentioning

confidence: 96%

“…However, it appears that PtmB2 only generates products with trans-orientated H-10/H-11. Additionally, it has been proposed that C-14 oxidation occurs during the OX2 (PtmB1 analogue)-catalyzed formation of the second five-membered ring [23], and a recent in vivo combinatorial study has confirmed that the second ring formation is coupled with the C-14 hydroxylation in the biosynthesis of HSAF and analogues [33]. However, the detailed biochemistry and enzymology responsible for such transformations have not been elucidated.…”

Section: Biosynthetic Implicationsmentioning

confidence: 99%

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Genome Mining of Marine-Derived Streptomyces sp. SCSIO 40010 Leads to Cytotoxic New Polycyclic Tetramate Macrolactams

Liu

Zhang²,

Jin³

et al. 2019

Marine Drugs

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Polycyclic tetramate macrolactams (PTMs) biosynthetic gene cluster are widely distributed in different bacterial types, especially in Streptomyces species. The mining of the genomic data of marine-derived Streptomyces sp. SCSIO 40010 reveals the presence of a putative PTM-encoding biosynthetic gene cluster (ptm′ BGC) that features a genetic organization for potentially producing 5/5/6 type of carbocyclic ring-containing PTMs. A fermentation of Streptomyces sp. SCSIO 40010 led to the isolation and characterization of six new PTMs 1–6. Comprehensive spectroscopic analysis assigned their planar structures and relative configurations, and their absolute configurations were deduced by comparing the experimental electronic circular dichroism (ECD) spectra with the reported spectra of the known PTMs. Intriguingly, compounds 1–6 were determined to have a trans-orientation of H-10/H-11 at the first 5-membered ring, being distinct from the cis-orientation in their known PTM congeners. PTMs 1–5 displayed cytotoxicity against several cancer cell lines, with IC50 values that ranged from 2.47 to 17.68 µM.

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Section: Biosynthetic Implicationsmentioning

confidence: 60%

Section: Genome Mining Of a Ptm Biosynthetic Gene Clustermentioning

confidence: 96%

Section: Biosynthetic Implicationsmentioning

confidence: 99%

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Genome Mining of Marine-Derived Streptomyces sp. SCSIO 40010 Leads to Cytotoxic New Polycyclic Tetramate Macrolactams

Liu

Zhang²,

Jin³

et al. 2019

Marine Drugs

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“…SGR812 or PtmB2 or OX3 was demonstrated to catalyze the formation of the first five-membered ring [ 8 , 30 ], whereas the formation of the second five-membered ring appeared to be catalyzed by SGR813 or PtmB1 or OX1/OX2 [ 8 , 30 ]. Notably, it has been confirmed that formation of the second ring is coupled to C14 hydroxylation during HSAF biosynthesis [ 33 ]. The presence of two oxidoreductases in the sko gene cluster is consistent with the 5/5 ring system seen in 1 and 2 .…”

Section: Resultsmentioning

confidence: 99%

Genome Mining and Metabolic Profiling Uncover Polycyclic Tetramate Macrolactams from Streptomyces koyangensis SCSIO 5802

Ding

Zhang

et al. 2021

Marine Drugs

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We have previously shown deep-sea-derived Streptomyces koyangensis SCSIO 5802 to produce two types of active secondary metabolites, abyssomicins and candicidins. Here, we report the complete genome sequence of S. koyangensis SCSIO 5802 employing bioinformatics to highlight its potential to produce at least 21 categories of natural products. In order to mine novel natural products, the production of two polycyclic tetramate macrolactams (PTMs), the known 10-epi-HSAF (1) and a new compound, koyanamide A (2), was stimulated via inactivation of the abyssomicin and candicidin biosynthetic machineries. Detailed bioinformatics analyses revealed a PKS/NRPS gene cluster, containing 6 open reading frames (ORFs) and spanning ~16 kb of contiguous genomic DNA, as the putative PTM biosynthetic gene cluster (BGC) (termed herein sko). We furthermore demonstrate, via gene disruption experiments, that the sko cluster encodes the biosynthesis of 10-epi-HSAF and koyanamide A. Finally, we propose a plausible biosynthetic pathway to 10-epi-HSAF and koyanamide A. In total, this study demonstrates an effective approach to cryptic BGC activation enabling the discovery of new bioactive metabolites; genome mining and metabolic profiling methods play key roles in this strategy.

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“…The lafE (OX3) gene product is responsible for the formation of the first pentameric ring, while genes lafC (OX1) and lafD (OX2) are involved in the formation of the second pentameric ring, and lafF (OX4) mediates the formation of the hexameric ring (Li et al ., 2014). The ftdA gene (ORF7) encoding a homologue of a sterol desaturase is responsible for 3‐hydroxylation of the polycyclic tetramate macrolactam structure (Li et al ., 2019).…”

Section: Hsaf the Long‐range Antifungal Weapon Of L Enzymogenesmentioning

confidence: 99%

Antifungal weapons of Lysobacter, a mighty biocontrol agent

Lin

Shen

et al. 2021

Environmental Microbiology

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Bacteria interact with fungi in a variety of ways to inhibit fungal growth, while the underlying mechanisms remain only partially characterized. The plantbeneficial Bacillus and Pseudomonas species are well-known antifungal biocontrol agents, whereas Lysobacter are far less studied. Members of Lysobacter are easy to grow in fermenters and are safe to humans, animals and plants. These environmentally ubiquitous bacteria use a diverse arsenal of weapons to prey on other microorganisms, including fungi and oomycetes. The small molecular toxins secreted by Lysobacter represent long-range weapons effective against filamentous fungi. The secreted hydrolytic enzymes act as intermediaterange weapons against non-filamentous fungi. The contact-dependent killing devices are proposed to work as short-range weapons. We describe here the structure, biosynthetic pathway, action mode and applications of one of the best-characterized longrange weapons, the heat-stable antifungal factor (HSAF) produced by Lysobacter enzymogenes. We discuss how the flagellar type III secretion system has evolved into an enzyme secretion machine for the intermediate-range antifungal weapons. We highlight an intricate mechanism coordinating the production of the long-range weapon, HSAF and the proposed contact-dependent killing device, type VI secretion system. We also overview the regulatory mechanisms of HSAF production involving specific transcription factors and the bacterial second messenger c-di-GMP.

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Construction of a hybrid gene cluster to reveal coupled ring formation–hydroxylation in the biosynthesis of HSAF and analogues from Lysobacter enzymogenes

Abstract: HSAF and analogues are polycyclic tetramate macrolactams (PoTeMs) isolated from Lysobacter enzymogenes.

Cited by 12 publications

References 18 publications

Genome Mining of Marine-Derived Streptomyces sp. SCSIO 40010 Leads to Cytotoxic New Polycyclic Tetramate Macrolactams

Genome Mining of Marine-Derived Streptomyces sp. SCSIO 40010 Leads to Cytotoxic New Polycyclic Tetramate Macrolactams

Genome Mining and Metabolic Profiling Uncover Polycyclic Tetramate Macrolactams from Streptomyces koyangensis SCSIO 5802

Antifungal weapons of Lysobacter, a mighty biocontrol agent

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