Chemistry articles within Nature Chemical Biology

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  • Article |

    Enediyne natural products are potent antitumor antibiotics but the biosynthesis of their 1,5-diyne-3-ene core has remained enigmatic for decades. Here a diiodotetrayne is reported as a universal enediyne biosynthetic intermediate of this core, obtained upon cryptic iodination.

    • Chun Gui
    • , Edward Kalkreuter
    •  & Ben Shen

  • Article
    | Open Access

    A de novo-designed protein that precisely assembles a chlorophyll dimer has been developed. The design matches the conformation of the native ‘special pair’ of chlorophylls that functions as the primary electron donor in natural photosynthetic reaction centers. In the designed protein, excitonically coupled chlorophylls participate in energy transfer. The proteins were also redesigned to assemble into 24-chlorophyll nanocages.

    • Nathan M. Ennist
    • , Shunzhi Wang
    •  & David Baker

  • Article |

    Cathepsins are relevant therapeutic targets in cancer and other diseases. Here, the authors developed a different approach to block the activity of cathepsins in specific cellular contexts by combining non-natural peptide inhibitors with antibodies, enhancing therapeutic efficacy while reducing side effects.

    • Aaron Petruzzella
    • , Marine Bruand
    •  & Elisa Oricchio

  • News & Views |

    Targeted protein degradation has emerged as a promising approach in drug discovery, harnessing a cell’s intrinsic machinery to eliminate disease-related proteins. Now, a study paves the way to translating this technology into potential anti-mycobacterial therapies, by exploiting the bacterial protein-degradation complex.

    • Delia Preti
    • , Valentina Albanese
    •  & Peggy Carla Raffaella Marconi

  • News & Views |

    An integrative approach has now enabled elucidation of the complete biosynthetic pathway of a prominent saponin adjuvant. Reconstruction of the whole biosynthetic pathway in a heterologous host provides new perspectives for the biotechnological supply of this immunostimulant.

    • Vincent Courdavault
    •  & Nicolas Papon

  • News & Views |

    Reprogramming of the genetic code allows the synthesis of proteins using new building blocks, thus opening the door to the development of a wider variety of medicines and biocatalysts; however, it is currently limited to α-amino acids. A new study has now reported the incorporation of β-linked and α,α-disubstituted monomers into a ribosome-synthesized protein.

    • Ya-Ming Hou
    •  & Yuko Nakano

  • News & Views |

    Chemically reactive metabolites such as formaldehyde are often toxic and are proposed to react promiscuously with biomolecules. New work shows that some reactive sites on proteins are uniquely sensitive to formaldehyde, leading to functionally important regulation of protein and cell functions.

    • Vicki L. Emms
    • , Sara Y. Chothia
    •  & Richard J. Hopkinson

  • Article
    | Open Access

    A proteome-wide thermal profiling study of osmolyte action on E. coli and human proteins within the cellular milieu reveals mechanisms of protein thermal stabilization by osmolytes and in situ behavior of intrinsically disordered proteins.

    • Monika Pepelnjak
    • , Britta Velten
    •  & Paola Picotti

  • Article |

    BURP-domain proteins are an unexplored family of plant-specific, copper-dependent peptide cyclases. Here the authors show that a BURP-domain protein has a particular protein fold, investigate its mechanism and provide evidence for intramolecular modification in RiPP biosynthesis.

    • Lisa S. Mydy
    • , Jordan Hungerford
    •  & Roland D. Kersten

  • Article
    | Open Access

    α-Synuclein and tau can form multiple amyloid structures or strains that are associated with different neurodegenerative diseases, suggesting a strain–toxicity relationship. Now, it has been shown that O-GlcNAc modification of α-synuclein results in the formation of an amyloid strain that is largely nonpathogenic in vivo, supporting structure-dependent toxicity and another protective role for O-GlcNAc.

    • Aaron T. Balana
    • , Anne-Laure Mahul-Mellier
    •  & Matthew R. Pratt

  • Article
    | Open Access

    Nonribosomal peptide synthetases produce valuable natural products but are challenging to engineer. Yeast surface display and fluorescence-activated cell sorting have now been combined to reprogram a condensation domain to recognize a noncanonical lipid substrate. This methodology may facilitate molecular tailoring of many biosynthetic assembly lines.

    • Ines B. Folger
    • , Natália F. Frota
    •  & Donald Hilvert

  • Article
    | Open Access

    Vaccine immunoadjuvants are central to vaccine efficiency. Now, the complete characterization of the biosynthetic pathway of QS-21, a potent immunoadjuvant produced by the Chilean soapbark tree, has been reported. These findings open the door to heterologous production of QS-21 and new-to-nature adjuvants.

    • Laetitia B. B. Martin
    • , Shingo Kikuchi
    •  & Anne Osbourn

  • News & Views |

    The rules for designing cyclic peptides with drug-like properties are unclear. Two studies now show how cyclic peptide libraries can be created to optimize properties such as cell permeability before screening for binding activity. The approach has led to a macrocyclic peptide inhibitor for KRAS that has reached clinical trials.

    • Sunit Pal
    •  & Peter ‘t Hart

  • Article
    | Open Access

    Hanswillemenke, Hofacker and colleagues developed a proximity labeling-based method to identify protein interactome of small molecules and RNA drugs within living cells, facilitating the design and development of RNA drugs with enhanced pharmacological properties.

    • Alfred Hanswillemenke
    • , Daniel Tobias Hofacker
    •  & Thorsten Stafforst

  • News & Views |

    Nature has evolved elegant enzymatic strategies to cyclize peptides, resulting in complex macrocyclic compounds with potent biological activities. A study illustrates the diverse chemical versatility of one such remarkable enzyme family, the cytochrome P450 macrocyclases, which form new biaryl crosslinks in ribosomal peptidic natural products.

    • Krushnamurthy Pattanayakanahalli Henjarappa
    • , Simita Das
    •  & Nilkamal Mahanta

  • Article |

    A chemoproteomic workflow was developed to determine the interaction sites of photoaffinity probes in cells, enabling the identification of diverse binding pockets and providing evidence of their tractability to small-molecule action.

    • Jacob M. Wozniak
    • , Weichao Li
    •  & Christopher G. Parker

  • Research Briefing |

    Cyclic peptides can bind challenging disease targets, but their oral application is hindered by digestion and absorption issues. We developed a versatile method for the synthesis and functional screening of vast numbers of synthetic cyclic peptides and identified peptides with high inhibitory activity, stability and oral bioavailability in rats.

  • Article
    | Open Access

    Cyclic peptides show promise for modulating difficult disease targets; however, they often cannot be administered orally. The authors developed a method to synthesize and screen large libraries of small cyclic peptides while enabling the simultaneous interrogation of activity and permeability. This approach was applied to the disease target thrombin to discover peptides with high affinity, stability and oral bioavailability of up to 18% in rats.

    • Manuel L. Merz
    • , Sevan Habeshian
    •  & Christian Heinis

  • News & Views |

    Analyzing glycans is challenging because of their structural diversity and complexity and the lack of analytical techniques capable of resolving pools of similar glycan structures. A new method now enables imaging of single glycans, providing direct observation of individual glycans and glycoconjugates.

    • Martina Delbianco
    •  & Yu Ogawa

  • Article |

    Macrocyclic peptides are promising scaffolds for chemical tools and potential therapeutics, but their synthesis is currently difficult. Here, the authors report the characterization of Ulm16, a peptide cyclase of the penicillin-binding protein (PBP)-type class of thioesterases, that catalyzes head-to-tail macrolactamization of nonribosmal peptides of 4–6 amino acids in length.

    • Zachary L. Budimir
    • , Rishi S. Patel
    •  & Elizabeth I. Parkinson

  • Article |

    A workflow integrating tools from bioinformatics, structural biology and synthetic biology has been developed that enables the rapid design of pili-enabled living materials. This approach allows mining of pili-producing nonpathogenic chassis, understanding of the pili structure and assembly, and engineering of pili-enabled living materials in a systematic and sequential manner.

    • Yuanyuan Huang
    • , Yanfei Wu
    •  & Chao Zhong

  • News & Views |

    Terpenoids bearing carbon skeletons derived from nonisoprene units are rare and considered noncanonical. Now, a genome-mining study has uncovered previously unknown noncanonical C16 terpenes and their biosynthetic pathways from bacteria. The findings suggest that noncanonical terpenoids are diverse and widespread in nature.

    • Shaonan Liu
    • , Darwin Lara
    •  & Yang Hai

  • Article |

    Cofactorless oxygenases are rare in nature and natural product biosynthesis. Here the authors describe the biochemical and structural characterization of two such oxygenases catalyzing deformylation, ring cleavage and epoxidation in the biosynthesis of the enediyne natural product tiancimycin A.

    • Chun Gui
    • , Edward Kalkreuter
    •  & Ben Shen

  • Article |

    NOXs are vital ROS-producing enzymes with roles in cell function and cancer. Here the authors combine computational and experimental methods to validate inhibitors for human NOX enzymes, opening avenues for redox biology-related cancer drug development.

    • Joana Reis
    • , Christoph Gorgulla
    •  & Andrea Mattevi

  • Research Briefing |

    We developed a versatile lipid probe — MAO–SiR — to visualize the structure and dynamics of the inner mitochondrial membrane (IMM). MAO–SiR assembles in situ from two cell-permeant small molecules to image the IMM selectively, continuously and at super resolution for extended periods of time without extensive photobleaching or toxicity.

  • News & Views |

    The quality of chemical tools and their appropriate use determine the quality and reliability of scientific data based on their use. Now, two papers extend criteria to new modalities and critically review adherence to established guidelines.

    • Stefan Knapp
    •  & Susanne Müller

  • News & Views |

    Computational approaches are emerging as powerful tools for the discovery of antibiotics. A study now uses machine learning to discover abaucin, a potent antibiotic that targets the bacterial pathogen Acinetobacter baumannii.

    • Angela Cesaro
    •  & Cesar de la Fuente-Nunez

  • Article
    | Open Access

    The flavoenzyme nicotine oxidoreductase degrades nicotine in the bloodstream. Now, genetic selection in bacteria has been used to improve the catalytic performance of nicotine oxidoreductase, isolating variants with increased O2 reactivity that were more effective at degrading nicotine in the blood of rats.

    • Mark Dulchavsky
    • , Rishav Mitra
    •  & James C. A. Bardwell

  • Article |

    Tryptophan hydroxylases have only been known from eukaryotes and are involved in the biosynthesis of serotonin or melatonin. Here, the authors characterize a family of bacterial tryptophan hydroxylases that differ markedly from their eukaryotic counterpart in cofactor and catalytic mechanism.

    • Xinjie Shi
    • , Guiyun Zhao
    •  & Yi-Ling Du

  • Comment |

    Since its proposition in 2002, the Division of Chemical Biology in the Department of Chemical Sciences at the National Natural Science Foundation of China has implemented a range of constructive initiatives to break down traditional boundaries between chemistry and biology and to further bridge these two fields, in order to boost the development of chemical biology in China.

    • Zhiyi Yu
    • , Peng R. Chen
    •  & Yan Zhang

  • News & Views |

    Modular polyketide synthases are multidomain megasynthases catalyzing polyketide chain elongation, modification and release. New work reveals a full ~360-kDa modular polyketide synthases with just one active domain, ketosynthase, catalyzing an amidation that releases the completed product (a reaction type typically catalyzed by dedicated thioesterases).

    • Zuodong Sun
    •  & Yi Tang

  • News & Views |

    A study has now shown that copper ions can drive inflammation via a mitochondrial signaling pathway that regulates epigenetic states of immune cells. This pathway could offer a new route for treating inflammatory diseases.

    • Christopher J. Chang
    •  & Donita C. Brady

  • Research Briefing |

    Synthetic cells are modular gene-expressing compartments with promising applications in biology and medicine. However, a more diverse toolkit is needed to enhance their capabilities, particularly in terms of controlling their gene expression and employing novel synthetic cell–to–living cell signaling pathways. In this work, photocaged promoters and cell-free synthesis of the acyl homoserine lactone synthase BjaI were used to achieve light-activated communication between synthetic cells and living cells.

  • Article
    | Open Access

    Synthetic cells, modular gene-expressing compartments, have shown promising applications in biology and medicine; however, more diverse tools are required for their control and communication. Now, photocaged promoters and cell-free synthesis of an acyl homoserine lactone have been used to demonstrate light-activated communication between synthetic cells and living cells.

    • Jefferson M. Smith
    • , Denis Hartmann
    •  & Michael J. Booth

  • News & Views |

    Tricyclic peptides have reduced conformational flexibility, making them well suited for ligand development. Researchers have now generated large combinatorial libraries of tricyclic peptides using a disulfide-directing motif. Screening these libraries discovered binders to challenging protein targets.

    • Christian Heinis

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