Refactoring the Cryptic Streptophenazine Biosynthetic Gene Cluster Unites Phenazine, Polyketide, and Nonribosomal Peptide Biochemistry

Bauman, Katherine D.; Li, Jie; Murata, Katsuyuki; Mantovani, Simone M.; Dahesh, Samira; Nizet, Victor; Luhavaya, Hanna; Moore, Bradley S.

doi:10.1016/j.chembiol.2019.02.004

Cited by 51 publications

(59 citation statements)

References 74 publications

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“…S3). The benchmark set also included a number of unusual or multifunctional adenylateforming enzymes involved in diazo-group formation (9), formylation (18), and amide-bond formation (19,20).…”

Section: Adenylpred Validation With Widely-distributed Anl Superfamilmentioning

confidence: 99%

Global analysis of adenylate-forming enzymes reveals β-lactone biosynthesis pathway in pathogenic Nocardia

Robinson

Terlouw

Smith

et al. 2020

Journal of Biological Chemistry

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Enzymes that cleave ATP to activate carboxylic acids play essential roles in primary and secondary metabolism in all domains of life. Class I adenylate-forming enzymes share a conserved structural fold but act on a wide range of substrates to catalyze reactions involved in bioluminescence, nonribosomal peptide biosynthesis, fatty acid activation, and β-lactone formation. Despite their metabolic importance, the substrates and functions of the vast majority of adenylate-forming enzymes are unknown without tools available to accurately predict them. Given the crucial roles of adenylate-forming enzymes in biosynthesis, this also severely limits our ability to predict natural product structures from biosynthetic gene clusters. Here we used machine learning to predict adenylate-forming enzyme function and substrate specificity from protein sequences. We built a web-based predictive tool and used it to comprehensively map the biochemical diversity of adenylate-forming enzymes across >50,000 candidate biosynthetic gene clusters in bacterial, fungal, and plant genomes. Ancestral phylogenetic reconstruction and sequence similarity networking of enzymes from these clusters suggested divergent evolution of the adenylate-forming superfamily from a core enzyme scaffold most related to contemporary CoA ligases towards more specialized functions including β-lactone synthetases. Our classifier predicted β-lactone synthetases in uncharacterized biosynthetic gene clusters conserved in >90 different strains of Nocardia. To test our prediction, we purified a candidate β-lactone synthetase from Nocardia brasiliensis and reconstituted the biosynthetic pathway in vitro to link the gene cluster to the β-lactone natural product, nocardiolactone. We anticipate our machine learning approach will aid in functional classification of enzymes and advance natural product discovery.

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Section: Adenylpred Validation With Widely-distributed Anl Superfamilmentioning

confidence: 99%

Global analysis of adenylate-forming enzymes reveals β-lactone biosynthesis pathway in pathogenic Nocardia

Robinson

Terlouw

Smith

et al. 2020

Journal of Biological Chemistry

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“…N -formylglycine is known as peptide derived from enzymic formylation of melittin—main component of honeybee (e.g ., Apis mellifera ) venom and antimicrobial peptide 35 , 36 . The bioactivities of this metabolite were further emphasised in the research of biosynthetic pathway from marine Streptomyces bacteria, reporting that the metabolic product, streptophenazines, with the attachment of N -formylglycine provides the strong antibiotic activity 37 . Thus, N -formylglycine could be employed in BSF to cope with bacterial infection through either AMP modification or gut microbiota metabolism.…”

Section: Discussionmentioning

confidence: 99%

Bacterial challenge-associated metabolic phenotypes in Hermetia illucens defining nutritional and functional benefits

Klanrit

Hanboonsong

et al. 2021

Sci Rep

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Black soldier fly (BSF, Hermetia illucens) is popular for its applications in animal feed, waste management and antimicrobial peptide source. The major advantages of BSF larva include their robust immune system and high nutritional content that can be further developed into more potential agricultural and medical applications. Several strategies are now being developed to exploit their fullest capabilities and one of these is the immunity modulation using bacterial challenges. The mechanism underlying metabolic responses of BSF to different bacteria has, however, remained unclear. In the current study, entometabolomics was employed to investigate the metabolic phenoconversion in response to either Escherichia coli, Staphylococcus aureus, or combined challenges in BSF larva. We have, thus far, characterised 37 metabolites in BSF larva challenged with different bacteria with the major biochemical groups consisting of amino acids, organic acids, and sugars. The distinct defense mechanism-specific metabolic phenotypes were clearly observed. The combined challenge contributed to the most significant metabolic phenoconversion in BSF larva with the dominant metabolic phenotypes induced by S. aureus. Our study suggested that the accumulation of energy-related metabolites provided by amino acid catabolism is the principal metabolic pathway regulating the defense mechanism. Therefore, combined challenge is strongly recommended for raising BSF immunity as it remarkably triggered amino acid metabolisms including arginine and proline metabolism and alanine, aspartate and glutamate metabolism along with purine metabolism and pyruvate metabolism that potentially result in the production of various nutritional and functional metabolites.

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“…In another case, the silent streptophenazine BGC in marine Streptomyces S.sp is non-transcriptional active in heterologous environment. After introducing four constitutive promoters ( ermE ∗ p/actIp/sp44/p21 ) at different positions in the BGC, the production of streptophenazine was detected ( Bauman et al, 2019 ).…”

Section: Heterologous Expression Of Target Bgcsmentioning

confidence: 99%

Recent Advances in Silent Gene Cluster Activation in Streptomyces

Liu

Zhao

Huang

et al. 2021

Front. Bioeng. Biotechnol.

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Natural products (NPs) are critical sources of drug molecules for decades. About two-thirds of natural antibiotics are produced by Streptomyces. Streptomyces have a large number of secondary metabolite biosynthetic gene clusters (SM-BGCs) that may encode NPs. However, most of these BGCs are silent under standard laboratory conditions. Hence, activation of these silent BGCs is essential to current natural products discovery research. In this review, we described the commonly used strategies for silent BGC activation in Streptomyces from two aspects. One focused on the strategies applied in heterologous host, including methods to clone and reconstruct BGCs along with advances in chassis engineering; the other focused on methods applied in native host which includes engineering of promoters, regulatory factors, and ribosomes. With the metabolic network being elucidated more comprehensively and methods optimized more high-thoroughly, the discovery of NPs will be greatly accelerated.

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Refactoring the Cryptic Streptophenazine Biosynthetic Gene Cluster Unites Phenazine, Polyketide, and Nonribosomal Peptide Biochemistry

Cited by 51 publications

References 74 publications

Global analysis of adenylate-forming enzymes reveals β-lactone biosynthesis pathway in pathogenic Nocardia

Global analysis of adenylate-forming enzymes reveals β-lactone biosynthesis pathway in pathogenic Nocardia

Bacterial challenge-associated metabolic phenotypes in Hermetia illucens defining nutritional and functional benefits

Recent Advances in Silent Gene Cluster Activation in Streptomyces

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