Genome mining approach for harnessing the cryptic gene cluster in Alternaria solani: production of PKS–NRPS hybrid metabolite, didymellamide B

Ugai, Takahiro; Minami, Atsushi; Gomi, Katsuya; Oikawa, Hideaki

doi:10.1016/j.tetlet.2016.05.043

Cited by 19 publications

(19 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Detailed features of Diels-Alderases used for the modification enzyme search are discussed in the following section. Notably, as in the case of didymellamide 21 , a spontaneous [4 + 2] cycloaddition also affords the same decalin skeleton. Therefore, lack of the DAase gene in the target BGC does not mean that the corresponding hybrid NPs have a linear PK chain.…”

Section: Resultsmentioning

confidence: 85%

“…On the other hand, when focusing on the NP structure biosynthesized from functionally characterized hybrids, we found that phylogenetically related hybrids synthesize structurally and biosynthetically related NPs. For example, functionally characterized hybrids that synthesize 2-pyridone containing hybrid NPs such as aspyridone (hybrid name: ApdA 18 ), tenellin (TenS 19 ), desmethylbassianin (DmbS 20 ), didymellamide (AsolS 21 ), leporin (LepA 22 ), and illicicolin (IccA 23 ), are located in a specific region defined as the pyridone family clade (Ia-D) (Fig. 2 ).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Predicting the chemical space of fungal polyketides by phylogeny-based bioinformatics analysis of polyketide synthase-nonribosomal peptide synthetase and its modification enzymes

Minami

Ugai

Ozaki

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

Fungal polyketide synthase (PKS)–nonribosomal peptide synthetase (NRPS) hybrids are key enzymes for synthesizing structurally diverse hybrid natural products (NPs) with characteristic biological activities. Predicting their chemical space is of particular importance in the field of natural product chemistry. However, the unexplored programming rule of the PKS module has prevented prediction of its chemical structure based on amino acid sequences. Here, we conducted a phylogenetic analysis of 884 PKS–NRPS hybrids and a modification enzyme analysis of the corresponding biosynthetic gene cluster, revealing a hidden relationship between its genealogy and core structures. This unexpected result allowed us to predict 18 biosynthetic gene cluster (BGC) groups producing known carbon skeletons (number of BGCs; 489) and 11 uncharacterized BGC groups (171). The limited number of carbon skeletons suggests that fungi tend to select PK skeletons for survival during their evolution. The possible involvement of a horizontal gene transfer event leading to the diverse distribution of PKS–NRPS genes among fungal species is also proposed. This study provides insight into the chemical space of fungal PKs and the distribution of their biosynthetic gene clusters.

show abstract

Section: Resultsmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Predicting the chemical space of fungal polyketides by phylogeny-based bioinformatics analysis of polyketide synthase-nonribosomal peptide synthetase and its modification enzymes

Minami

Ugai

Ozaki

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…The BGC of N-hydroxyapiosporamide (2, R = OH) consists of a polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) pathway. 21 The lack of the C12 methyl substituent in fischerin 1 predicted by calculations scanning of the PKS-NRPS MT domain was then performed on the candidate BGCs, especially at the conserved MT active site GXGTG motif that binds S-adenosyl-methionine (SAM). 22 Gratifyingly, we were able to identify one such PKS-NRPS, from a cluster in Aspergillus carbonarius (renamed fin), to contain a MT domain with a mutated and presumably inactivating GXGAG motif (Fig.…”

Section: Main Textmentioning

confidence: 99%

Structural Determination of an Orphan Natural Product Using Microcrystal Electron Diffraction and Genome Mining

Kim¹,

Ohashi²,

D³

et al. 2020

Preprint

View full text Add to dashboard Cite

<p>More than 60% of pharmaceuticals are related to natural products (NPs), chemicals produced by living organisms.<a></a> Hence, new methods that accelerate natural product discovery are poised to profoundly impact human health. Of the many challenges that remain in natural product discovery, none are as pervasive as structural elucidation, as determination of the molecular structure of a newly discovered natural product can take months, years, or in some cases be altogether unachievable. This challenge can be fueled by lack of sufficient material for spectroscopic analysis, or difficulties in sourcing the producing organism. Even in cases where the analyte is abundant, its physical properties, including molecular structure, can prevent unambiguous structural determination. Here we report the use of microcrystal electron diffraction (MicroED),<a></a> an emerging cryogenic electron microscopy (CryoEM) technique, in combination with genome mining, to address these challenges. As proof-of-principle, we apply these techniques to fischerin (<b>1</b>), an orphan NP isolated more than 30 years ago, with potent cytotoxicity but ambiguous structural assignment.<a></a> We utilize genome mining methods to reconstruct its biosynthetic pathway and highlight the sensitivity of MicroED through the precise determination of the solid-state structure of <b>1</b> from sub-micron thick crystals. This structural solution serves as a powerful demonstration of the synergy of MicroED and synthetic biology in NP discovery, technologies that when taken together will ultimately accelerate the rate at which new drugs are discovered.</p><div><div><p> </p></div></div>

show abstract

“…The polyketide biosynthesis pathway for the marine-derived telomerase inhibitor griseorhodin A was productively transferred to Streptomyces lividans from an environmental Streptomyces isolate (Li and Piel, 2002 ). Ugai et al ( 2016 ) got success in heterologous expression of the cryptic gene cluster found in A. solani to obtain a marine-derived antifungal agent didymellamide B from the A. oryzae transformant introducing PKS–NRPS, trans -ER, and P450 genes asolSCA (Ugai et al, 2016 ). Likewise many other successful examples are available in literature (Fortman and Sherman, 2005 ; Luo et al, 2016 ; Winn et al, 2016 ).…”

Section: Role Of Genomics Proteomics and Bioinformatics In Discoverymentioning

confidence: 99%

Nonribosomal Peptides from Marine Microbes and Their Antimicrobial and Anticancer Potential

et al. 2017

View full text Add to dashboard Cite

Marine environments are largely unexplored and can be a source of new molecules for the treatment of many diseases such as malaria, cancer, tuberculosis, HIV etc. The Marine environment is one of the untapped bioresource of getting pharmacologically active nonribosomal peptides (NRPs). Bioprospecting of marine microbes have achieved many remarkable milestones in pharmaceutics. Till date, more than 50% of drugs which are in clinical use belong to the nonribosomal peptide or mixed polyketide-nonribosomal peptide families of natural products isolated from marine bacteria, cyanobacteria and fungi. In recent years large numbers of nonribosomal have been discovered from marine microbes using multi-disciplinary approaches. The present review covers the NRPs discovered from marine microbes and their pharmacological potential along with role of genomics, proteomics and bioinformatics in discovery and development of nonribosomal peptides drugs.

show abstract

Genome mining approach for harnessing the cryptic gene cluster in Alternaria solani: production of PKS–NRPS hybrid metabolite, didymellamide B

Cited by 19 publications

References 31 publications

Predicting the chemical space of fungal polyketides by phylogeny-based bioinformatics analysis of polyketide synthase-nonribosomal peptide synthetase and its modification enzymes

Predicting the chemical space of fungal polyketides by phylogeny-based bioinformatics analysis of polyketide synthase-nonribosomal peptide synthetase and its modification enzymes

Structural Determination of an Orphan Natural Product Using Microcrystal Electron Diffraction and Genome Mining

Nonribosomal Peptides from Marine Microbes and Their Antimicrobial and Anticancer Potential

Contact Info

Product

Resources

About