Biological sciences articles within Nature Chemistry

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  • Thesis |

    Winter brings a spike in mortality rates, but rather than simply having more parties to divert our attention, Bruce Gibb suggests that perhaps we should be looking to the misunderstood mushroom to give us a boost.

    • Bruce C. Gibb

  • News & Views |

    2+2-cycloaddition reactions have long been considered key transformations in the biosynthesis of cyclobutane-containing natural products, but enzymes for these reactions have not yet been identified. Now, a 2+2 cyclase has been discovered, characterized and bioengineered to catalyse cycloadditions with different selectivity.

    • Bo Zhang
    •  & Hui Ming Ge

  • Article |

    Cycloaddition reactions are among the most useful reactions in chemical synthesis, but biosynthetic enzymes with 2 + 2 cyclase activity have yet to be observed. Now it is shown that a β-barrel-fold protein catalyses competitive 2 + 2 and 4 + 2 cycloaddition reactions. This protein can be engineered to preferentially produce the exo-2 + 2, exo-4 + 2 or endo-4 + 2 product.

    • Hongbo Wang
    • , Yike Zou
    •  & K. N. Houk

  • Article |

    A Diels–Alderase that catalyses the inherently disfavoured cycloaddition and forms a bicyclo[2.2.2]diazaoctane scaffold with a strict α-anti-selectivity has now been discovered. This Diels–Alderase, called CtdP, is an NmrA-like protein. Isotopic labelling, structural biology and computational studies reveal that the CtdP-catalysed Diels–Alder reaction involves a NADP+/NADPH-dependent redox mechanism.

    • Zhiwen Liu
    • , Sebastian Rivera
    •  & Xue Gao

  • News & Views |

    Ribosomes cannot synthesize peptides using hydroxy acids to replace canonical amino acids as no codons encode hydroxy acid building blocks. Now, this challenge has been addressed by rewriting the genetic code, enabling the direct cellular biosynthesis of non-natural depsipeptides containing non-canonical amino acids.

    • Jian Li

  • News & Views |

    Molecular computing programmed with complementary nucleic acid strands allows the construction of sophisticated biomolecular circuits. Now, systems with partially complementary strands have been shown to enable more compact and faster molecular circuits, and may illuminate biological processes.

    • Philip Petersen
    •  & Grigory Tikhomirov

  • News & Views |

    Interactions between proteins and non-proteinaceous biopolymers are essential for life; however, many methods used to characterize these interactions lack precision and display significant biases. Now, a genetically encoded method employing sulfur(vi) fluoride exchange (SuFEx)-based chemical crosslinking has been developed for capturing and analysing protein–RNA and protein–carbohydrate interactions in vivo.

    • Christopher P. Watkins
    •  & Ryan A. Flynn

  • Article |

    The complementarity of the two strands in the DNA double helix provides a mechanism for the storage and processing of genetic information. Now, an alternative ‘strand commutation’ mechanism of data processing with DNA/RNA has been revealed based on the reversible low-affinity interactions of essentially non-complementary nucleic acids.

    • Maxim P. Nikitin

  • Article
    | Open Access

    Macrocyclic peptides can be genetically encoded and synthesized in cells; however, the programmable diversity is limited. Now, macrocycles containing two non-canonical amino acids have been genetically encoded and synthesized in codon-reassigned Syn61Δ3 cells. Incorporating diverse hydroxy acids in Syn61Δ3 cells enables the synthesis of non-natural depsipeptides containing either one or two ester bonds.

    • Martin Spinck
    • , Carlos Piedrafita
    •  & Jason W. Chin

  • Article |

    Enzymes with identical sequences of amino acids can display varying activities when encoded with mRNA with different properties, but why this is the case has been a mystery. Now, it has been shown that synonymous mutations in mRNA alter the partitioning of proteins into long-lived soluble misfolded states with varying activities.

    • Yang Jiang
    • , Syam Sundar Neti
    •  & Edward P. O’Brien

  • Article
    | Open Access

    Native mass spectrometry has been used to interrogate both biased signalling and allosteric modulation of the β1-adrenergic receptor. Simultaneously capturing the effects of ligand binding and receptor coupling to different G proteins has enabled the relative importance of specific interactions to be investigated.

    • Hsin-Yung Yen
    • , Idlir Liko
    •  & Carol V. Robinson

  • Article |

    Despite recent advances in engineering of in vitro translation systems, direct ribosomal incorporation of hydroxyhydrocarbon moieties—which can endow peptides with unique biochemical/folding properties—remains challenging. Now, incorporation of translation-compatible azide/hydroxy acids and their post-translational tandem backbone-acyl shifts have enabled in vitro ribosomal synthesis of peptides containing various hydroxyhydrocarbon units.

    • Tomohiro Kuroda
    • , Yichao Huang
    •  & Hiroaki Suga

  • Article |

    Identifying and quantifying the biodistribution of synthetic polymeric nanoparticles in biological milieu is crucial for biomedical applications. Now, it has been shown that encoded polymeric amphiphiles with discrete molar masses undergo sequence- and length-dependent self-assembly into precise digital micelles that can be used in direct sequence reading and ex vivo label-free quantification assays.

    • Qiangqiang Shi
    • , Hao Yin
    •  & Shiyong Liu

  • Article |

    Synthesis of peptidyl-tRNAs is challenging because there are no enzymes that can directly attach the desired peptide to tRNA. Now it has been shown that a chemoenzymatic approach based on native chemical ligation can be used for the semi-synthesis of peptidyl-tRNAs for structural/biochemical studies of arrested and non-arrested ribosome complexes.

    • Egor A. Syroegin
    • , Elena V. Aleksandrova
    •  & Yury S. Polikanov

  • Article |

    Peptide design remains a challenge owing to the large library of amino acids. Rational design approaches, although successful, result in a peptide design bias. Now it has been shown that AI techniques can be used to overcome such bias and discover unusual peptides as efficiently as humans.

    • Rohit Batra
    • , Troy D. Loeffler
    •  & Subramanian K. R. S. Sankaranarayanan

  • Article |

    Creating hierarchical synthetic materials that can modulate microbial communities remains a great challenge due to the complex interactions between microbiota and their colonized environments. Now, a soil-inspired chemical system that responds to chemical, optical and mechanical stimuli has been developed. The soil-inspired chemical system can enhance microbial cultures and biofuel production, enrich gut bacterial diversity and alleviate ulcerative colitis symptoms.

    • Yiliang Lin
    • , Xiang Gao
    •  & Bozhi Tian

  • News & Views |

    DNA nanotechnology and synthetic biology both aim to expand the range of dynamic behaviours exhibited by rationally programmed biomolecules. Now, the programmability of synthetic transcriptional circuits has been improved to enable synthesis of dynamic biomolecular circuits with unmatched complexity.

    • Jongmin Kim
    •  & Friedrich C. Simmel

  • Article |

    Sterically demanding 2′-modified nucleotides used in antisense therapeutics have thus far been challenging to synthesise enzymatically. Now, it has been shown that mutation of two gatekeeper residues in an archaeal DNA polymerase unlocks efficient synthesis of the modified nucleic acid oligomers 2′-O-methyl-RNA and 2′-O-(2-methoxyethyl)-RNA and enables the evolution of 2′-O-methyl-RNA enzymes.

    • Niklas Freund
    • , Alexander I. Taylor
    •  & Philipp Holliger

  • Article |

    Protein–carbohydrate interactions remain challenging to study due to their low binding affinity and non-covalent nature. Now, a genetically encoded bioreactive unnatural amino acid containing sulfonyl fluoride has been shown to crosslink a protein with its bound glycan, offering a solution to probe and exploit protein–carbohydrate interactions.

    • Shanshan Li
    • , Nanxi Wang
    •  & Lei Wang

  • Article |

    Technologies for profiling biological environments with high spatiotemporal resolution are in demand to enable the discovery of new targets for addressing unmet clinical needs. Now, a deep red light-mediated photocatalytic strategy for the targeted activation of aryl azides has been developed. This platform enables mapping of protein microenvironments in physiologically relevant systems.

    • Nicholas Eng Soon Tay
    • , Keun Ah Ryu
    •  & Tomislav Rovis

  • Article |

    Protein–RNA interactions regulate RNA fate and function, and are generally non-covalent and reversible. Genetically introducing a latent bioreactive amino acid into a protein is now shown to enable the protein to covalently crosslink a bound RNA molecule in vivo. This method offers innovative avenues for developing protein–RNA research and applications.

    • Wei Sun
    • , Nanxi Wang
    •  & Lei Wang

  • Article |

    Tigilanol tiglate is a therapeutic lead for the treatment of a broad range of cancers. Now, it has been shown that tigilanol tiglate can be synthesized in a time and step economical fashion from phorbol—its naturally abundant biosynthetic precursor. This synthesis provides rapid access to analogues with unprecedented protein kinase C binding activity.

    • Paul A. Wender
    • , Zachary O. Gentry
    •  & Edward Njoo

  • News & Views |

    Quantitatively studying the partitioning of biomolecules and reaction equilibria in cellular systems is an enormous challenge. Now, a multiphase coacervate model system provides insight into this complex biological problem, illustrating how coexisting phases influence RNA partitioning and duplex dissociation.

    • Shuqi Wu
    •  & Liangfei Tian

  • Article
    | Open Access

    Proteins rich in phenylalanine-glycine (FG) repeats can phase separate through FG–FG interactions. The molecular interactions of an important FG-repeat protein, nucleoporin 98, have now been studied in liquid-like transient and amyloid-like cohesive states. These interactions underlie the behaviour of FG-repeat proteins and their function in physiological and pathological cell activities.

    • Alain Ibáñez de Opakua
    • , James A. Geraets
    •  & Markus Zweckstetter

  • Article |

    The total synthesis and complete stereochemical assignment of the cyclic peptide natural product SR-A3—which has potential as a cancer therapeutic—has now been reported. Single-molecule biophysical and cellular experiments reveal a crucial, stereospecific role for a side-chain hydroxyl in SR-A3, which confers enhanced target residence time and efficacy in a mouse tumour model.

    • Hao-Yuan Wang
    • , Haojun Yang
    •  & Jack Taunton

  • Article |

    A method has been developed to identify RNA transcript isoforms at the single-molecule level using solid-state nanopore microscopy. In this method, target RNA is refolded into RNA identifiers with designed sets of complementary DNA strands. Each reshaped molecule carries a unique sequence of structural (pseudo)colours that enables identification and quantification using solid-state nanopore microscopy.

    • Filip Bošković
    •  & Ulrich Felix Keyser

  • Article |

    Oligonucleotide catalysts such as ribozymes and DNAzymes can cleave RNA efficiently and specifically but are typically dependent on high concentrations of divalent cations, limiting their biological applications. A modular XNAzyme catalyst composed of 2′-deoxy-2′-fluoro-β-d-arabino nucleic acid (FANA) has now been developed that can cleave long (>5 kb), highly structured mRNAs under physiological conditions and enables allele-specific catalytic RNA knockdown inside cells.

    • Alexander I. Taylor
    • , Christopher J. K. Wan
    •  & Philipp Holliger

  • Article |

    In silico chemical prediction of a polyketide synthase gene cluster in the bacterium Gynuella sunshinyii has led to the discovery of a class of natural products called janustatins. The absolute configuration of the stereocentres in these compounds was determined by a combination of techniques including DFT calculations and 2D NMR experiments—and finally confirmed by total synthesis. Janustatins were found to cause delayed, synchronized cell death at subnanomolar concentrations.

    • Reiko Ueoka
    • , Philipp Sondermann
    •  & Jörn Piel

  • Article |

    The biosynthesis of fuscimiditide, a ribosomally synthesized post-translationally modified peptide, has now been reported. Heterologous expression and analysis of fuscimiditide showed it contained two side-chain–side-chain ester linkages and an aspartimide in its backbone. The aspartimide moiety is unexpectedly stable, suggesting this structure is the intended natural product.

    • Hader E. Elashal
    • , Joseph D. Koos
    •  & A. James Link

  • Article |

    The β1-adrenergic receptor (β1AR) contains empty cavities in its preactive conformation, which disappear in the active one. Now, using X-ray crystallography of xenon-derivatized β1AR crystals, a cavity has been shown to be in contact with the cholesterol-binding pocket. Monitoring the binding of a cholesterol analogue in solution has explained the function of cholesterol as a negative allosteric modulator of β1AR.

    • Layara Akemi Abiko
    • , Raphael Dias Teixeira
    •  & Stephan Grzesiek

  • Article
    | Open Access

    Most proteins must fold co-translationally on the ribosome to adopt biologically active conformations, yet structural, mechanistic descriptions are lacking. Using 19F NMR spectroscopy to study a nascent multi-domain protein has now enabled the identification of two co-translational folding intermediates that are significantly more stable than intermediates formed off the ribosome, suggesting that the ribosome may thermodynamically regulate folding.

    • Sammy H. S. Chan
    • , Tomasz Włodarski
    •  & John Christodoulou

  • Article |

    Synthetic chemical networks with far-from-equilibrium dynamics akin to genetic regulatory networks in living cells could precisely regulate the kinetics of chemical synthesis or self-assembly. Now standardized excitable chemical regulatory elements, termed genelets, that enable predictive bottom-up construction of in vitro networks with designed temporal and multistable behaviour have been developed.

    • Samuel W. Schaffter
    • , Kuan-Lin Chen
    •  & Rebecca Schulman

  • News & Views |

    Malleicyprols are highly reactive polyketides responsible for virulence in some pathogenic bacteria. Now, the enzyme that constructs the cyclopropanol warhead of malleicyprols has been identified. This enzyme could represent a useful target for developing new antivirulence therapeutics.

    • Elijah Abraham
    •  & Rebecca A. Butcher

  • Article
    | Open Access

    Burkholderia pseudomallei is a species of bacteria that poses a global health threat and, more generally, bacteria of the Burkholderia pseudomallei group cause severe diseases that are recalcitrant to treatment with antibiotics. Now, it has been shown how these infamous pathogens repurpose the widespread enzyme BurG to produce a reactive cyclopropanol head group found in the virulence-promoting malleicyprol toxins. Interrupting the synthesis of the cyclopropanol warhead is a potential route for developing antivirulence treatments.

    • Felix Trottmann
    • , Keishi Ishida
    •  & Christian Hertweck

  • Perspective |

    Droplet interface bilayers (DIBs) are a type of artificial bilayer that can act as cell membrane mimics. This Perspective surveys how DIBs can be used to mimic key cellular features (such as bilayer asymmetry) and processes (such as drug movement), and discusses challenges that need to be overcome to enable DIBs to reach their full potential as biomimetic model membranes.

    • Elanna B. Stephenson
    • , Jaime L. Korner
    •  & Katherine S. Elvira

  • Article |

    The introduction of fluorine into a drug molecule can alter the biological responses to it, including modulating bioavailability, pharmacokinetics and selectivity. Now, a hybrid polyketide/fatty acid synthase multienzyme has been designed to incorporate fluorinated precursors during polyketide biosynthesis in an approach that provides new chemoenzymatic access to fluorinated natural compounds.

    • Alexander Rittner
    • , Mirko Joppe
    •  & Martin Grininger

  • Article
    | Open Access

    The design of photoactivatable fluorophores—which are required for some super-resolution fluorescence microscopy methods—usually relies on light-sensitive protecting groups imparting lipophilicity and generating reactive by-products. Now, it has been shown that by exploiting a unique intramolecular photocyclization, bright and highly photostable fluorophores can be rapidly generated in situ from appropriately substituted 1-alkenyl-3,6-diaminoxanthone precursors.

    • Richard Lincoln
    • , Mariano L. Bossi
    •  & Stefan W. Hell

  • Article |

    A genetically encoded phototrigger based on a xanthone amino acid can expand the scope of time-resolved serial femtosecond crystallography beyond naturally photoactive proteins. This approach has been used to uncover metastable reaction intermediates that occur prior to C–H bond activation in a human liver fatty-acid-binding protein mutant.

    • Xiaohong Liu
    • , Pengcheng Liu
    •  & Jiangyun Wang

  • Article |

    The composition of toxic protein aggregates associated with neurodegenerative diseases is difficult to determine. Now, a method has been developed that can capture amyloid-containing aggregates in human biofluids using a structure-specific chemical dimer. This method—known as amyloid precipitation—enables unbiased determination of the molecular composition and structural features of the in vivo aggregates.

    • M. Rodrigues
    • , P. Bhattacharjee
    •  & D. Klenerman

  • News & Views |

    Amino-containing four-carbon threose nucleic acids (TNAs) have long been considered to be prebiotically irrelevant due to their difficult formation. Now, a prebiotically plausible route to 3′-amino-TNA nucleoside triphosphate has been developed, raising the possibility of 3′-amino-TNA as a non-canonical nucleic acid during the origin of life.

    • Yingyu Liu
    •  & Yajun Wang

  • News & Views |

    Antibody-mediated delivery of therapeutics has been primarily limited to agents containing amine, alcohol or thiol functional groups. Now, an approach has been developed to create stable and bio-reversible prodrugs that mask ortho-quinones. Drug release requires both protease activation followed by acid-assisted elimination.

    • Thomas Pillow

  • Article |

    Nucleotides are essential to the origins of life, and their synthesis is a key challenge for prebiotic chemistry. Contrary to prior expectation, non-canonical 3′-amino-TNA nucleosides are shown to be synthesized diastereoselectively and regiospecifically under prebiotically plausible conditions. The enhanced reactivity of 3′-amino-TNAs also promotes their selective non-enzymatic triphosphorylation in water.

    • Daniel Whitaker
    •  & Matthew W. Powner

  • Article |

    The biochemical roles and mechanisms of multiphase membraneless organelles are not yet well understood. Now, multiphase peptide droplets have been shown to sort RNA based on whether it is single- or double-stranded, as well as impact RNA duplexation through in-droplet thermodynamic equilibria. This work provides insight into possible primitive mechanisms for multicompartment intracellular condensates and can aid in the design of functional artificial membraneless organelles.

    • Saehyun Choi
    • , McCauley O. Meyer
    •  & Christine D. Keating

  • Article
    | Open Access

    A strategy for protecting redox-active ortho-quinones, which show promise as anticancer agents but suffer from redox-cycling behaviour and systemic toxicity, has been developed. The ortho-quinones are derivatized to redox-inactive para-aminobenzyl ketols. Upon amine deprotection, an acid-promoted, self-immolative C–C bond-cleaving 1,6-elimination releases the redox-active hydroquinone. The strategy also enables conjugation to a carrier for targeted delivery of ortho-quinone species.

    • Lavinia Dunsmore
    • , Claudio D. Navo
    •  & Gonçalo J. L. Bernardes

  • Article
    | Open Access

    Analogues of mRNA 5′ caps containing a photo-cleavable group have now been developed. These so-called FlashCaps can be used for routine in vitro transcription to make long mRNAs containing a cap. In cells, the capped mRNAs are translationally muted; however, upon irradiation by light, the photo-cleavable group is removed without leaving any remaining modification and mRNA is then translated into the corresponding protein.

    • Nils Klöcker
    • , Florian P. Weissenboeck
    •  & Andrea Rentmeister

  • Article
    | Open Access

    Cytoskeletons are essential components of cells that perform a variety of tasks, and artificial cytoskeletons that perform these functions are required for the bottom-up assembly of synthetic cells. Now, a multi-functional cytoskeleton mimic has been engineered from DNA, consisting of confined DNA filaments that are capable of reversible self-assembly and transport of gold nanoparticles and vesicular cargo.

    • Pengfei Zhan
    • , Kevin Jahnke
    •  & Kerstin Göpfrich

  • Article |

    Amino acids are one of the major building blocks of life, but the ways in which they respond to light excitation are not fully understood. Now, the photochemistry of tyrosine has been studied using physically inspired deep neural networks, leading to the observation of unconventional dynamically controlled reactivity that involves ‘roaming’ radicals that can cause photodamage.

    • Julia Westermayr
    • , Michael Gastegger
    •  & Philipp Marquetand

  • Article |

    SynGAP and PSD-95 are two abundant proteins that form a complex and undergo liquid–liquid phase separation (LLPS) in the postsynaptic density of neurons. Now, O-GlcNAcylation of SynGAP has been found to suppress LLPS of the SynGAP/PSD-95 complex, and O-GlcNAc-dependent LLPS was also shown to be dynamically regulated by the enzymes O-GlcNAc transferase and O-GlcNAcase.

    • Pinou Lv
    • , Yifei Du
    •  & Xing Chen

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