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Function of pathway specific regulators in the ACE1 and pyrichalasin H biosynthetic gene clusters.

ABSTRACT: Ectopic expression of BC1 which encodes a putative pathway specific transcription factor from the ACE1 biosynthetic gene cluster of the rice pathogen Pyricularia oryzae Guy11 did not lead to the production of ACE1-related compounds. However the known compound hinnulin A was formed. A putative partial gene cluster potentially involved in the biosynthesis of hinnulin A and DHN melanin was validated by RT-PCR and a possible biosynthetic pathway is proposed. Ectopic expression of pyiR which encodes a pathway specific transcription factor from the pyrichalasin H biosynthetic gene cluster in Magnaporthe grisea NI980 led to the apparent up-regulation of the pyi cluster and a 3-fold increase in pyrichalasin production under standard fermentation conditions, but did not lead to the formation of new compounds.

SUBMITTER: Hantke V

PROVIDER: S-EPMC9074748 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Function of pathway specific regulators in the ACE1 and pyrichalasin H biosynthetic gene clusters.

Hantke Verena V Wang Chongqing C Skellam Elizabeth J EJ Cox Russell J RJ

RSC advances 20191001 61

Ectopic expression of BC1 which encodes a putative pathway specific transcription factor from the ACE1 biosynthetic gene cluster of the rice pathogen Pyricularia oryzae Guy11 did not lead to the production of ACE1-related compounds. However the known compound hinnulin A was formed. A putative partial gene cluster potentially involved in the biosynthesis of hinnulin A and DHN melanin was validated by RT-PCR and a possible biosynthetic pathway is proposed. Ectopic expre ...[more]

PMID: 35528102

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Project description:BackgroundBiosynthetic gene clusters produce a wide range of metabolites with activities that are of interest to the pharmaceutical industry. Specific interest is shown towards those metabolites that exhibit antimicrobial activities against multidrug-resistant bacteria that have become a global health threat. Genera of the phylum Firmicutes are frequently identified as sources of such metabolites, but the biosynthetic potential of its Virgibacillus genus is not known. Here, we used comparative genomic analysis to determine whether Virgibacillus strains isolated from the Red Sea mangrove mud in Rabigh Harbor Lagoon, Saudi Arabia, may be an attractive source of such novel antimicrobial agents.ResultsA comparative genomics analysis based on Virgibacillus dokdonensis Bac330, Virgibacillus sp. Bac332 and Virgibacillus halodenitrificans Bac324 (isolated from the Red Sea) and six other previously reported Virgibacillus strains was performed. Orthology analysis was used to determine the core genomes as well as the accessory genome of the nine Virgibacillus strains. The analysis shows that the Red Sea strain Virgibacillus sp. Bac332 has the highest number of unique genes and genomic islands compared to other genomes included in this study. Focusing on biosynthetic gene clusters, we show how marine isolates, including those from the Red Sea, are more enriched with nonribosomal peptides compared to the other Virgibacillus species. We also found that most nonribosomal peptide synthases identified in the Virgibacillus strains are part of genomic regions that are potentially horizontally transferred.ConclusionsThe Red Sea Virgibacillus strains have a large number of biosynthetic genes in clusters that are not assigned to known products, indicating significant potential for the discovery of novel bioactive compounds. Also, having more modular synthetase units suggests that these strains are good candidates for experimental characterization of previously identified bioactive compounds as well. Future efforts will be directed towards establishing the properties of the potentially novel compounds encoded by the Red Sea specific trans-AT PKS/NRPS cluster and the type III PKS/NRPS cluster.

Project description:The field of secondary metabolism has greatly benefitted from computational advances in recent years. This has been particularly true for fungal natural product studies. Strides in genome mining have led to the identification of an extraordinary number of secondary metabolite biosynthetic gene clusters (BGCs) across the fungal Kingdom and metabologenomic platforms can group BGCs into gene cluster families and link them to initial chemical structures. Missing are computational applications focused on identifying BGC regulatory networks. Here, we applied the new online gene regulatory network resource, GRAsp (Gene Regulation of Aspergillus fumigatus), to identify unknown and unpredictable BGC trans-acting transcriptional/metabolite production modules. GRAsp correctly predicted a two-component regulatory module composed of the transcription factors (TFs), RogA (regulation of gliotoxin) and HsfA, which negatively regulate the gliotoxin BGC and are also involved in gliotoxin self-protection. RogA functions through the repression of gliZ, the pathway-specific gliotoxin TF, and HsfA functions by activating rogA expression. Furthermore, GRAsp identified TFs that regulate the production of two BGCs lacking pathway-specific TFs, the helvolic acid and fumitremorgin BGCs, respectively. Finally, the known TF, NsdD, was predicted and found to regulate the hexadehydroastechrome BGC. These advances highlight the power of inference algorithms to uncover unpredictable networks in specialized metabolite synthesis.IMPORTANCEToxic secondary metabolites are virulence factors of the opportunistic fungal pathogen Aspergillus fumigatus, yet the transcriptional networks regulating secondary metabolite production remain elusive. Uncovering novel regulators without any prior information is challenging. Computational programs have gained prominence in the field of secondary metabolite research due to their accuracy and ability to handle vast amounts of data, including DNA, RNA, and protein data. In this study, a newly developed online computer platform, Gene Regulation of A. fumigatus, was used to identify five regulators involved in the production of several A. fumigatus toxins, including gliotoxin, helvolic acid, fumitremorgin, and hexadehydroastechrome. This work illustrates the potential for discovering new trans-acting regulators and mechanisms of secondary metabolite regulation through the examination of computational gene regulatory networks.

Dataset Information

Function of pathway specific regulators in the ACE1 and pyrichalasin H biosynthetic gene clusters.

Publications

Function of pathway specific regulators in the <i>ACE1</i> and pyrichalasin H biosynthetic gene clusters.

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