Structural basis of nonribosomal peptide macrocyclization in fungi

Zhang, Jinru; Liu, Nicholas; Cacho, Ralph A.; Gong, Zhou; Zhu, Liping; Qin, Wenming; Tang, Chun; Tang, Yi; Zhou, Jiahai

doi:10.1038/nchembio.2202

Cited by 58 publications

(91 citation statements)

References 31 publications

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“…Many examples of assembly line ACPs docking with cognate enzymes are known, even though all are from NRPS modules. Representative interactions between ACPs and embedded assembly line enzymes have been observed for the C domain (donor site: PDB 5EJD, acceptor site: PDB 4ZXH), the A domain (PDBs 4DG9), the epimerization (E) domain (PDB 5ISX), and the thioesterase (TE) domain (PDB 3TEJ). Representative interactions between an ACP and a non‐embedded P450 monooxygenase have also been observed (PDB 4PXH).…”

Section: Resultsmentioning

confidence: 99%

“…assembly line ACPs was investigated.Many examples of assembly line ACPs docking with cognate enzymes are known, even though all are from NRPS modules. Representative interactions between ACPs and embedded assembly line enzymes have been observed for the C domain (donor site: PDB 5EJD,27 acceptor site: PDB 4ZXH28 ), the A domain (PDBs 4DG929 ), the epimerization (E) domain (PDB 5ISX30 ), and the thioesterase (TE)FIG URE 3 Cladograms of KSs Upstream and Downstream of ACPs Support the Updated Module Boundaries. A, The lack of clustering for KSs upstream of ACPs that clade together, with the anticipated exception of KSs from the first module of bimodules, indicates ACPs do not usually evolutionarily co-migrate with the KS upstream of them.…”

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confidence: 97%

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The modules of trans‐acyltransferase assembly lines redefined with a central acyl carrier protein

Wood

Keatinge‐Clay

2018

Proteins

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Here, the term "module" is redefined for trans-acyltransferase (trans-AT) assembly lines to agree with how its domains cooperate and evolutionarily co-migrate. The key domain in both the polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) modules of assembly lines is the acyl carrier protein (ACP). ACPs not only relay growing acyl chains through the assembly line but also collaborate with enzymes in modules, both in cis and in trans, to add a specific chemical moiety. A ketosynthase (KS) downstream of ACP often plays the role of gatekeeper, ensuring that only a single intermediate generated by the enzymes of a module is passed downstream. Bioinformatic analysis of 526 ACPs from 33 characterized trans-AT assembly lines reveals ACPs from the same module type generally clade together, reflective of the co-evolution of these domains with their cognate enzymes. While KSs downstream of ACPs from the same module type generally also clade together, KSs upstream of ACPs do not-in disagreement with the traditional definition of a module. Beyond nomenclature, the presented analysis impacts our understanding of module function, the evolution of assembly lines, pathway prediction, and assembly line engineering.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 97%

The modules of trans‐acyltransferase assembly lines redefined with a central acyl carrier protein

Wood

Keatinge‐Clay

2018

Proteins

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“…Instead, the free TE gene may fulfill an editing function during metabolite biosynthesis (22). We found that the terminal C domain of SimA could be grouped together with those C T domains being functionally verified to catalyze the cyclization of macrocycles, e.g., the C T domain of the NRPS TqaA from Penicillium aethiopicum (21, 23). It is suggested therefore that the terminal C domain of SimA might contribute to the release and cyclization of CSNs.…”

Section: Discussionmentioning

confidence: 99%

“…Additional C domains were also retrieved from the nonribosomal peptide synthetase (NRPS) DtxS1 for destruxin biosynthesis in Metarhizium spp. (27), and the beauvericin nonribosomal cyclodepsipeptide synthetase (BEAS) for the production of beauvericin in B. bassiana (29) as well as the cyclization C T domains of Penicillium aethiopicum TqaA (21, 23) and Emericella rugula EcdA (41). The A- or C-domain sequences were aligned with the program Clustal X (ver.…”

Section: Methodsmentioning

confidence: 99%

Cyclosporine Biosynthesis in Tolypocladium inflatum Benefits Fungal Adaptation to the Environment

Yang

Peng

Yin

et al. 2018

mBio

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The cyclopeptide cyclosporin A was first isolated from the filamentous fungus Tolypocladium inflatum showing antifungal activity and was later developed as an immunosuppressant drug. We report the biosynthetic mechanism of cyclosporines that are mediated by a cluster of genes encoding NRPS and PKS controlled by a bZIP-type transcriptional regulator. The two unusual amino acids Bmt and d-Ala are produced by the PKS pathway and alanine racemase, respectively. The cyclophilin and transporter genes jointly contribute to fungal self-protection against cyclosporines. Cyclosporine confers on T. inflatum the abilities to outcompete other fungi in competitive interactions and to facilitate fungal infection of insect hosts, which therefore benefits fungal adaptations to different environments.

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“…Recent structures have been obtained with pantetheine chains bound to the acceptor site. 56, 58 While no structures exist of a condensation domain bound to a donor PCP, structures of TqaA, the homologous terminal cyclization domain of fungal NRPSs, 62 and an epimerization domain of the gramicidin synthetase GrsA 57 provide models for the binding of the PCP to the condensation domain donor site.…”

Section: The Biochemistry and Structural Biology Of The Nonribosommentioning

confidence: 99%

Nonribosomal peptide synthetase biosynthetic clusters of ESKAPE pathogens

Gulick

2017

Nat. Prod. Rep.

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Overview Natural products are important secondary metabolites produced by bacterial and fungal species that play important roles in cellular growth and signaling, nutrient acquisition, intra- and interspecies communication, and virulence. A subset of natural products is produced by nonribosomal peptide synthetases (NRPSs), a family of large, modular enzymes that function in an assembly line fashion. Because of the pharmaceutical activity of many NRPS products, much effort has gone into the exploration of their biosynthetic pathways and the diverse products they make. Many interesting NRPS pathways have been identified and characterized from both terrestrial and marine bacterial sources. Recently, several NRPS pathways in human commensal bacterial species have been identified that produce molecules with antibiotic activity, suggesting another source of interesting NRPS pathways may be the commensal and pathogenic bacteria that live on the human body. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) have been identified as a significant cause of human bacterial infections that are frequently multidrug resistant. The emerging resistance profile of these organisms has prompted calls from multiple international agencies to identify novel antibacterial targets and develop new approaches to treat infections from ESKAPE pathogens. Each of these species contains several NRPS biosynthetic gene clusters. While some have been well characterized and produce known natural products with important biological roles in microbial physiology, others have yet to be investigated. This review catalogs the NRPS pathways of ESKAPE pathogens. The exploration of novel NRPS products may lead to a better understanding of the chemical communication used by human pathogens and potentially to the discovery of novel therapeutic approaches.

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Structural basis of nonribosomal peptide macrocyclization in fungi

Cited by 58 publications

References 31 publications

The modules of trans‐acyltransferase assembly lines redefined with a central acyl carrier protein

The modules of trans‐acyltransferase assembly lines redefined with a central acyl carrier protein

Cyclosporine Biosynthesis in Tolypocladium inflatum Benefits Fungal Adaptation to the Environment

Nonribosomal peptide synthetase biosynthetic clusters of ESKAPE pathogens

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