Targeted and Logical Discovery of Piperazic Acid-Bearing Natural Products Based on Genomic and Spectroscopic Signatures

Shin, Daniel; Byun, Woong Sub; Kang, Sangwook; Kang, Ilnam; Bae, Eun Seo; An, Joon Soo; Im, Ji Hyeon; Park, Jiyoon; Kim, Eunji; Ko, Keebeom; Hwang, Sunghoon; Lee, Honghui; Kwon, Yun; Ko, Yoon-Joo; Hong, Suckchang; Nam, Sang-Jip; Kim, Seung Bum; Fenical, William; Yoon, Yeo Joon; Cho, Jang-Cheon; Lee, Sang Kook; Oh, Dong-Chan

doi:10.1021/jacs.3c04699

Cited by 7 publications

(5 citation statements)

References 59 publications

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“…3 b). MomK is predicted as l -lysine-6-monooxygenase and MomL is supposed to catalyze the formation of N – N bonds, potentially being responsible for the synthesis of piperazic acid [ [19] , [20] , [21] , [22] , [23] ] ( Fig. 3 f); The enzymes MomO, Mom5, and MomP are responsible for the synthesis of 3-hydroxy-3-methylproline ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Analyzing and engineering of the biosynthetic pathway of mollemycin A for enhancing its production

Jin,

Chen,

Zhang

et al. 2024

Synthetic and Systems Biotechnology

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Section: Resultsmentioning

confidence: 99%

Analyzing and engineering of the biosynthetic pathway of mollemycin A for enhancing its production

Jin,

Chen,

Zhang

et al. 2024

Synthetic and Systems Biotechnology

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“…[64] Although this detection method is currently limited to NÀ N functional groups prone to acid hydrolysis, the development of more broadly applicable chemical probe-or spectroscopy-based detection methods will contribute to the further expansion of this fruitful field of natural product chemistry. [65]…”

Section: Discussionmentioning

confidence: 99%

Bacterial Hydrazine Biosynthetic Pathways Featuring Cupin/Methionyl tRNA Synthetase‐like Enzymes

Matsuda,

Wakimoto

2024

ChemBioChem

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Nitrogen‐Nitrogen (N–N) bond‐containing functional groups in natural products and synthetic drugs play significant roles in exerting biological activities. The mechanisms of N–N bond formation in natural organic molecules have garnered increasing attention over the decades. Recent advances have illuminated various enzymatic and nonenzymatic strategies, and our understanding of natural N–N bond construction is rapidly expanding. A group of didomain proteins with zinc‐binding cupin/methionyl‐tRNA synthetase (MetRS)‐like domains, also known as hydrazine synthetases, generates amino acid‐based hydrazines, which serve as key biosynthetic precursors of diverse N–N bond‐containing functionalities such as hydrazone, diazo, triazene, pyrazole, and pyridazinone groups. In this review, we summarize the current knowledge on hydrazine synthetase mechanisms and the various pathways employing this unique bond‐forming machinery.

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“…As mentioned above, the biosynthesis of L-piperazic acid requires hydroxylation of L-ornithine followed by the cyclization of the resultant L-N 5 -OH-ornithine [5,6]. Similarly to the way it occurs in other BGCs encoding piperazic acid-bearing peptides [8], the dpn BGC contains two genes encoding the DpnO2 ornithine N-monooxygenase and the DpnZ diperazate synthase for the biosynthesis of L-piperazic acid (Figure 6). Noticeably, in the art BGC from Streptomyces aurantiacus JA 4570 and the polyoxypeptin A BGC from Streptomyces sp.…”

Section: Analysis Of Diperamycin Biosynthetic Gene Cluster and Propos...mentioning

confidence: 95%

“…Quite recently, a similar approach was carried out using the same probe to screen bacterial genomes in the National Center for Biotechnology Information (NCBI) database, resulting in the identification of the incarnatapeptine BGC [15]. More recently, the use of another strategy based on the Polymerase Chain Reaction (PCR) amplification of ktzIand ktzT-homologous genes from the bacterial genomic DNA of strains isolated in different environments has led to the identification of putative BGCs for depsidomycins and lenziamides [8]. By using KtzT as probe against the "CS" genomes in a Basic Local Alignment Search Tool (BLAST) analysis, we could identify a protein similar to KtzT (WP_087803920.1; 54.67% identical amino acids) in Streptomyces sp.…”

Section: Identification Of the Dpn Biosynthetic Gene Clustermentioning

confidence: 99%

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Unearthing a Cryptic Biosynthetic Gene Cluster for the Piperazic Acid-Bearing Depsipeptide Diperamycin in the Ant-Dweller Streptomyces sp. CS113

García-Gutiérrez,

Pérez-Victoria,

Montero

et al. 2024

IJMS

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Piperazic acid is a cyclic nonproteinogenic amino acid that contains a hydrazine N-N bond formed by a piperazate synthase (KtzT-like). This amino acid, found in bioactive natural products synthesized by non-ribosomal peptide synthetases (NRPSs), confers conformational constraint to peptides, an important feature for their biological activities. Genome mining of Streptomyces strains has been revealed as a strategy to identify biosynthetic gene clusters (BGCs) for potentially active compounds. Moreover, the isolation of new strains from underexplored habitats or associated with other organisms has allowed to uncover new BGCs for unknown compounds. The in-house “Carlos Sialer (CS)” strain collection consists of seventy-one Streptomyces strains isolated from the cuticle of leaf-cutting ants of the tribe Attini. Genomes from twelve of these strains have been sequenced and mined using bioinformatics tools, highlighting their potential to encode secondary metabolites. In this work, we have screened in silico those genomes, using KtzT as a hook to identify BGCs encoding piperazic acid-containing compounds. This resulted in uncovering the new BGC dpn in Streptomyces sp. CS113, which encodes the biosynthesis of the hybrid polyketide–depsipeptide diperamycin. Analysis of the diperamycin polyketide synthase (PKS) and NRPS reveals their functional similarity to those from the aurantimycin A biosynthetic pathway. Experimental proof linking the dpn BGC to its encoded compound was achieved by determining the growth conditions for the expression of the cluster and by inactivating the NRPS encoding gene dpnS2 and the piperazate synthase gene dpnZ. The identity of diperamycin was confirmed by High-Resolution Mass Spectrometry (HRMS) and Nuclear Magnetic Resonance (NMR) and by analysis of the domain composition of modules from the DpnP PKS and DpnS NRPS. The identification of the dpn BGC expands the number of BGCs that have been confirmed to encode the relatively scarcely represented BGCs for depsipeptides of the azinothricin family of compounds and will facilitate the generation of new-to-nature analogues by combinatorial biosynthesis.

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Targeted and Logical Discovery of Piperazic Acid-Bearing Natural Products Based on Genomic and Spectroscopic Signatures

Cited by 7 publications

References 59 publications

Analyzing and engineering of the biosynthetic pathway of mollemycin A for enhancing its production

Analyzing and engineering of the biosynthetic pathway of mollemycin A for enhancing its production

Bacterial Hydrazine Biosynthetic Pathways Featuring Cupin/Methionyl tRNA Synthetase‐like Enzymes

Unearthing a Cryptic Biosynthetic Gene Cluster for the Piperazic Acid-Bearing Depsipeptide Diperamycin in the Ant-Dweller Streptomyces sp. CS113

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