Biochemistry articles within Nature Chemistry

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  • News & Views |

    Tailor-made reverse transcriptases are used in molecular biology and synthetic genetics. However, re-engineering these enzymes to work with non-natural nucleic acids is difficult and requires powerful directed evolution strategies. Now, an adaptable selection approach has been demonstrated for the evolution of new reverse transcriptases.

    • Melanie Henkel
    •  & Andreas Marx

  • Article |

    Engineering reverse transcriptases for modified or unnatural nucleic acids is challenging, but now a versatile method has been developed that enables the discovery of efficient reverse transcriptases. The method works with a wide range of template structures, including xeno-nucleic acids and can also be used to produce high-fidelity reverse transcriptases for RNA.

    • Gillian Houlihan
    • , Sebastian Arangundy-Franklin
    •  & Philipp Holliger

  • Article |

    Many bacterial pathogens release effector enzymes belonging to the large Fic family, which modify host targets with nucleotide monophosphates. Now, recombinantly produced Fic enzymes have been equipped with synthetic thiol-reactive nucleotide derivatives to make covalent binary probes. The reaction of modified Fic enzymes with their targets permits covalent substrate capture and the structural determination of low-affinity ternary enzyme–nucleotide–substrate complexes.

    • Burak Gulen
    • , Marie Rosselin
    •  & Aymelt Itzen

  • Article |

    Proteins that interact with histone post-translational modifications have now been identified using an approach based on split-intein mediated histone semisynthesis. Histone modifications and disease-relevant mutations were installed into native chromatin with an adjacent photocross-linker to enable in situ cross-linking. This strategy enabled the determination of chromatin-relevant interactomes and represents a powerful tool for exploring epigenetic regulation and dysregulation at the molecular level.

    • Antony J. Burton
    • , Michael Haugbro
    •  & Tom W. Muir

  • Article |

    Oxygen is a potent inhibitor of radical polymerization reactions, but the facultative bacterium Shewanella oneidensis has now been shown to facilitate aerobic radical polymerizations by first consuming dissolved oxygen and then directing extracellular electron flux to a metal catalyst. Aerobic polymerization activity is dependent on the S. oneidensis genotype and can be initiated using lyophilized or spent cells.

    • Gang Fan
    • , Austin J. Graham
    •  & Benjamin K. Keitz

  • Thesis |

    Bruce C. Gibb takes a look at the chemistry and biochemistry of intermittent fasting.

    • Bruce C. Gibb

  • Article |

    Single-molecule nanopore measurements have revealed ligand-induced conformational changes in the catalytic cycle of dihydrofolate reductase, and showed that the enzyme adopts distinctive conformers, which have different affinities for substrates and products. Crossing the transition state facilitates conformer exchange, suggesting that the chemical step catalyses the switch between conformers to obtain a more efficient product release.

    • Nicole Stéphanie Galenkamp
    • , Annemie Biesemans
    •  & Giovanni Maglia

  • Article |

    A method to fabricate heterotrimeric three-stranded coiled-coil peptide structures has now been developed using coordination around a Pb(ii) centre. The heterotrimeric structures require only three cysteines that bind to Pb(ii) to form a trigonal pyramidal structure, and the formation of an adjacent cavity in which water can hydrogen bond to the cysteine sulfur atoms.

    • Audrey E. Tolbert
    • , Catherine S. Ervin
    •  & Vincent L. Pecoraro

  • Perspective |

    The complexity of proteins has inspired chemists to seek artificial mimetics of protein structure and function. Historically, most such work has focused on analogues of small, isolated segments; however, there is growing interest in mimicry of larger, intact tertiary folds. This Perspective surveys the emerging body of work on these agents, termed ‘proteomimetics’, discusses their construction and outlines some of the remaining challenges.

    • W. Seth Horne
    •  & Tom N. Grossmann

  • Article |

    The Varkud satellite ribozyme, which catalyses site-specific RNA cleavage and ligation, is an important model to understand RNA catalysis. Now, a combination of theoretical and experimental work has revealed new details about its catalytic mechanism. Mg2+ is shown to play an important role in organizing the active site, and the proton transfers in the transition state have also been identified.

    • Abir Ganguly
    • , Benjamin P. Weissman
    •  & Darrin M. York

  • News & Views |

    Biological receptors distinguish between S- and R-enantiomers and these subtle differences in chirality can lead to vastly different protein affinities. Now, a proteomics approach has been developed that capitalizes on chirality to map enantiomeric probe pairs and provides a rapid and global view of protein ligandability within the cell.

    • Yuka Amako
    •  & Christina M. Woo

  • Article |

    A flavin-dependent halogenase with a remarkable preference for iodination has now been discovered. The halogenase (VirX1) was discovered using a bioinformatics-based approach and comes from a cyanophage. Structural characterization and kinetic studies show that VirX1 possesses broad substrate tolerance, making it an attractive tool for synthesis.

    • Danai S. Gkotsi
    • , Hannes Ludewig
    •  & Rebecca J. M. Goss

  • Article |

    Enacyloxin IIa is an antibiotic, assembled by a modular polyketide synthase, with promising activity against the Gram-negative bacterium Acinetobacter baumannii. Now, it has been shown that the enacyloxin IIa polyketide chain is released via transfer to a separately encoded carrier protein by a non-elongating ketosynthase domain, followed by condensation with 3,4-dihydroxycyclohexane carboxylic acid by a non-ribosomal peptide synthetase condensation domain.

    • Joleen Masschelein
    • , Paulina K. Sydor
    •  & Gregory L. Challis

  • Article |

    The antibiotic enacyloxin IIa is assembled by a modular polyketide synthase, and released from it by condensation of the enacyloxin acyl chain with 3,4-dihydroxycyclohexane carboxylic acid. A multipronged approach shows the structural basis for recognition between the peptidyl carrier protein domain that bears the acyl chain and the non-ribosomal peptide synthetase condensation domain that ligates it with the carboxylic acid.

    • Simone Kosol
    • , Angelo Gallo
    •  & Józef R. Lewandowski

  • Article |

    The complete biosynthesis of the fungal indole alkaloid malbrancheamide, which culminates in an intramolecular [4+2] hetero-Diels–Alder cyclization to produce the bicyclo[2.2.2]diazaoctane scaffold, has now been discovered. Chemical synthesis and protein structural analysis were used to provide mechanistic insight into this enzyme-dependent diastereo- and enantioselective cycloaddition.

    • Qingyun Dan
    • , Sean A. Newmister
    •  & Robert M. Williams

  • Article |

    The emergence of pristine RNA and DNA on the early Earth would have been hindered by a lack of specificity in their prebiotic syntheses. Now, it has been shown that chimeric sequences—with a mixture of RNA and DNA backbones—mediate the template-directed ligation of oligomers present in mixtures of nucleic acids, enabling the simultaneous appearance of RNA and DNA.

    • Subhendu Bhowmik
    •  & Ramanarayanan Krishnamurthy

  • Article |

    The UbiD family of reversible decarboxylases interconvert propenoic or aromatic acids with the corresponding alkenes or aromatic compounds, using a transient 1,3-dipolar cycloaddition between the substrate and the prenylated flavin mononucleotide cofactor. Atomic-resolution crystallography shows targeted destabilization of the intermediate covalent adducts, allowing the enzyme to harness 1,3-dipolar cycloaddition as a readily reversible reaction.

    • Samuel S. Bailey
    • , Karl A. P. Payne
    •  & David Leys

  • News & Views |

    Proteins are biosynthesized from α-amino acids using hefty biological machinery, but the origin of this process on the early Earth is unclear. Now, a bottom-up approach for forming peptides, taking place under mild, prebiotically-plausible conditions, has been developed. This strategy uses α-aminonitrile precursors, bypassing α-amino acids entirely.

    • Robert Pascal
    •  & Irene A. Chen

  • Article |

    LepI is an S-adenosylmethionine-dependent pericyclase that catalyses the dehydration, hetero-Diels–Alder reaction and retro-Claisen rearrangement reactions that occur in the formation of the 2-pyridone natural product leporin C. Now, the mechanistic details that underpin this range of catalytic reactions have been uncovered from the crystal structures of LepI and LepI in complex with ligands.

    • Yujuan Cai
    • , Yang Hai
    •  & Yi Tang

  • Article |

    A method for engineering chemically modified proteins has now been developed using a chemoenzymatic cascade of sortase-mediated transpeptidation and protein trans-splicing. Using this one-pot approach enabled the generation of site-specifically modified proteins in vitro and in isolated cell nuclei.

    • Robert E. Thompson
    • , Adam J. Stevens
    •  & Tom. W. Muir

  • Article |

    Abasic sites are amongst the most common forms of DNA damage. Despite their biological significance, little is known regarding the distribution of these sites within DNA. Now a method to sequence abasic sites at single-nucleotide resolution has been developed. This method allows the location of abasic sites to be mapped genome-wide.

    • Zheng J. Liu
    • , Sergio Martínez Cuesta
    •  & Shankar Balasubramanian

  • Article |

    Fractal topologies are ubiquitous, and synthetic fractal objects provide unique functional advantages by virtue of their high surface area:volume ratios. Now, a computationally guided bottom-up design approach for constructing protein-based fractal assemblies in response to phosphorylation has been developed. Designed assemblies are shown to perform reversible and efficient molecular capture.

    • Nancy E. Hernández
    • , William A. Hansen
    •  & Sagar D. Khare

  • Article |

    Modulating particular ubiquitin chains using binding molecules is challenging given the diversity of chain lengths and linkages found in vivo. Now, tight binding modulators that are specific to K48-linked ubiquitin chains have been found by combining protein synthesis and screening of macrocyclic peptide ligands.

    • Mickal Nawatha
    • , Joseph M. Rogers
    •  & Ashraf Brik

  • Article |

    Non-ribosomal peptide synthetases have now been modified and de novo non-ribosomal peptide synthetases constructed using new assembly points within condensation domains. This approach enabled the production of new-to-nature peptides, including some carrying synthetic amino acids, as well as the generation of peptide libraries.

    • Kenan A. J. Bozhüyük
    • , Annabell Linck
    •  & Helge B. Bode

  • Article |

    Natural hydrogenases exclusively utilize Ni and/or Fe to activate or produce hydrogen. Now, a catalytically active [Mn]-hydrogenase has been prepared by incorporating a synthetic Mn complex into the apoenzyme of [Fe]-Hydrogenase. The semi-synthetic [Mn]-hydrogenase shows higher activity than the corresponding Fe analogue.

    • Hui-Jie Pan
    • , Gangfeng Huang
    •  & Xile Hu

  • News & Views |

    Methods for generating molecular diversity provide a route to screen a wider section of chemical space, to discover compounds with useful biological properties. Now, a complexity-to-diversity strategy has enabled the discovery of a multi-cyclic structure from a complex natural product that induces ferroptotic cell death in cancer cells.

    • Tatiana Cañeque
    •  & Raphaël Rodriguez

  • Article |

    A set of stereochemically complex and structurally diverse compounds were created from the diterpene natural product pleuromutilin using the complexity-to-diversity strategy. Phenotypic screening identified a compound that induces rapid ferroptotic death of cancer cells. Experiments to probe the mechanism revealed the compound to be an inhibitor of thioredoxin.

    • Evijola Llabani
    • , Robert W. Hicklin
    •  & Paul J. Hergenrother

  • Article |

    Bacteria communicate through excretion of minute amounts of chemical signalling molecules that affect virulence, biofilm formation and colonization. In staphylococci, these molecules, called autoinducing peptides, are macrocyclic thiolactone-containing peptides. Now, a simple enrichment method, based on chemoselective capture on polymer beads, has been developed that enables the identification of previously unknown autoinducing peptides.

    • Bengt H. Gless
    • , Martin S. Bojer
    •  & Christian A. Olsen

  • Article |

    RNA is usually considered to be the first genetic polymer, with DNA a product of a biochemical pathway that arose after the origin of life. Now, studies into the prebiotic phosphorylation of an RNA nucleoside reveal pathways for the synthesis of DNA building blocks, providing experimental support for a prebiotic link between RNA and DNA.

    • Jianfeng Xu
    • , Nicholas J. Green
    •  & John D. Sutherland

  • Article |

    Two chemical probes, YnF and YnGG, that enable the identification of prenylated peptides and global analysis of protein prenylation using quantitative chemical proteomics have now been developed. Prenylation dynamics in response to pharmacological inhibition of prenyl-transferase enzymes were also studied. As a final demonstration, defective Rab prenylation in a model of the retinal degenerative disease choroideremia was also quantified.

    • Elisabeth M. Storck
    • , Julia Morales-Sanfrutos
    •  & Edward W. Tate

  • Article |

    A concise strategy for engineering functional, supramolecular protein complexes has now been developed based on single-mutation-mediated covalent tethering. Metalloproteins designed with this method can sustain large alterations to the metal coordination environment, bind small molecules, exhibit reversible redox activity and sustain large alterations to the protein structure.

    • Jonathan Rittle
    • , Mackenzie J. Field
    •  & F. Akif Tezcan

  • Article |

    Symmetrical protein oligomers perform key structural and catalytic functions in nature, but engineering such oligomers synthetically is challenging. Now, oppositely supercharged synthetic variants of normally monomeric proteins have been shown to assemble via specific, introduced electrostatic contacts into symmetrical, highly well-defined oligomers.

    • Anna J. Simon
    • , Yi Zhou
    •  & Andrew D. Ellington

  • Article |

    Heteromultivalency, which involves the simultaneous interactions of more than one type of ligand with more than one type of receptor, is common in biological systems but challenging to engineer artificially. Now, a heteromultivalent platform prepared by co-assembling cyclodextrin and calixarene amphiphiles has shown self-adaptive peptide binding with high affinity. The platform was used to sequester amyloid β-peptides, reducing amyloid cytotoxicity.

    • Zhe Xu
    • , Shaorui Jia
    •  & Dong-Sheng Guo

  • Article |

    A 27 kDa photosensitizer protein (PSP) has now been developed and used to design a miniature photocatalytic CO2-reducing enzyme. Visible light drives the PSP efficiently to the long-lived triplet excited state (PSP*), and then to a super-reducing radical (PSP•), which is strong enough to reduce many CO2-reducing catalysts. The 3D structure of PSP• at 1.8 Å resolution was determined by X-ray crystallography.

    • Xiaohong Liu
    • , Fuying Kang
    •  & Jiangyun Wang

  • Thesis |

    Bruce Gibb focuses on fatty acids and wonders whether we’ll all be eating cyanobacteria before too long.

    • Bruce C. Gibb

  • Article |

    Triplet–triplet energy transfer activation of disulfides enables the chemoselective anti-Markovnikov hydroalkyl/aryl thiolation of alkenes and alkynes—and can also be used for the biologically important hydromethylthiolation reaction. This fast disulfide–ene reaction is biocompatible and is tolerant of a wide range of functional groups. The triplet–triplet energy transfer sensitization process was studied in detail with transient absorption spectroscopy.

    • Michael Teders
    • , Christian Henkel
    •  & Frank Glorius

  • News & Views |

    Potassium channels rapidly move K+ ions across cell membranes while blocking Na+, but how these two effects are achieved simultaneously has remained unclear. Now, extensive molecular simulations show a single mechanism that features fully dehydrated ions can explain both rapid transport and impeccable selectivity.

    • Ben Corry

  • Article |

    As a consequence of high chemical resistance and low solubility in conventional solvents, deconstructing biomass into fuels and other useful chemical building blocks remains a challenge. Now, through enzyme modification and ionic liquid solvents, it is possible to homogeneously biocatalytically convert cellulose to sugars at a rate 30 times greater than is achievable in water.

    • Alex P. S. Brogan
    • , Liem Bui-Le
    •  & Jason P. Hallett

  • Article |

    The [4Fe4S]2+ cluster-containing DNA-repair enzyme MUTYH helps safeguard the integrity of Watson–Crick base pairing and the human genetic code. The MUTYH [4Fe4S]2+ cluster mediates DNA redox signalling and DNA lesion identification. Now, a MUTYH pathologic variant associated with catastrophic [4Fe4S]2+ cluster redox degradation, impairment of DNA signalling and human colonic tumorigenesis has been identified.

    • Kevin J. McDonnell
    • , Joseph A. Chemler
    •  & Stephen B. Gruber

  • Article |

    Enzymes are powerful catalysts for chemical synthesis because they are capable of providing unparalleled levels of selectivity; however, in nature they only catalyse a limited collection of reactions. Now, it has been shown that non-natural reactions that proceed via free-radical intermediates can be catalysed with high selectivity by using an exogenous photoredox catalyst in conjunction with enzymes.

    • Kyle F. Biegasiewicz
    • , Simon J. Cooper
    •  & Todd K. Hyster

  • News & Views |

    As the most abundant class of biomolecules on Earth, carbohydrates are implicated in a multitude of biological functions. Now, a simple chemical transformation has enabled the direct and selective installation of carbohydrates onto a diverse range of small molecules and peptides.

    • Lara R. Malins

  • Article |

    Living systems rely on externally tuneable and stimuli-responsive conformational changes of proteins and protein assemblies for a wide range of essential functions. A combination of experimental and computational analyses has now enabled the fabrication of a rationally designed, synthetic, stimuli-responsive protein assembly through modulation of its free-energy landscape.

    • Robert Alberstein
    • , Yuta Suzuki
    •  & F. Akif Tezcan

  • Thesis |

    Bruce C. Gibb discusses the biochemistry behind the sensory experiences associated with eating chillies and the lesser-known tingle-inducing ‘sanshools’.

    • Bruce C. Gibb

  • Article |

    The M-cluster in the active site of nitrogenase is derived from an 8Fe core assembled via coupling and rearrangement of two [Fe4S4] clusters concomitant with the insertion of an interstitial carbon and a ninth sulfur. Now, by combining synthetic [Fe4S4] clusters and assembly with a protein template, it has been shown that sulfite gives rise to the ninth sulfur that is inserted into the nitrogenase cofactor after the radical SAM-dependent carbide insertion and cofactor core rearrangement.

    • Kazuki Tanifuji
    • , Chi Chung Lee
    •  & Markus W. Ribbe

  • Article |

    The biosynthesis of the [FeFe] hydrogenase active site H-cluster requires several Fe–S proteins that perform poorly understood reactions. Now, a reaction intermediate trapped in the enzyme HydG is shown to contain a [(Cys)Fe(CO)(CN)] species identified as the first organometallic Fe moiety en route to the catalytic H-cluster.

    • Guodong Rao
    • , Lizhi Tao
    •  & R. David Britt

  • News & Views |

    Mass spectrometry is a powerful technique for analysing proteins, yet linking higher-order protein structure to amino acid sequence and post-translational modifications is far from simple. Now, a native top-down method has been developed that can provide information on higher-order protein structure and different proteoforms at the same time.

    • Kathrin Breuker

  • Article |

    Proteins have the potential to serve as powerful scaffolds that control the catalytic activity and selectivity of organometallic centres; however, new methods are needed to optimize artificial metalloenzymes. Now, an efficient approach for evolving the activity and selectivity of artificial metalloenzymes has been demonstrated using dirhodium cyclopropanases. This approach does not require structural or mechanistic data to guide mutagenesis.

    • Hao Yang
    • , Alan M. Swartz
    •  & Jared C. Lewis

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