Biochemistry articles within Nature Chemistry

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  • Article |

    Despite their intriguing photochemical activities, natural photoenzymes have not yet been repurposed for new-to-nature activities. Now, by leveraging the strongly oxidizing excited-state flavoquinone cofactor, fatty acid photodecarboxylases were engineered to catalyse unnatural decarboxylative radical cyclization with excellent chemo-, enantio- and diastereoselectivities.

    • Shuyun Ju
    • , Dian Li
    •  & Yang Yang

  • In Your Element |

    Serotonin is known by many names — in science as 5-hydroxytryptamine (5-HT) or enteramine, and in popular culture as the ‘feel good’ chemical or the ‘happy hormone’. Cameron Movassaghi and Anne Andrews discuss the knowns and unknowns of this well-studied yet elusive neurotransmitter.

    • Cameron S. Movassaghi
    •  & Anne Milasincic Andrews

  • Article
    | Open Access

    Negatively charged lysine acylations—malonylation, succinylation and glutarylation—impact protein structure and function, which can affect cellular processes. Now temporarily masked thioester derivatives of succinylation and glutarylation can be used for site-specific modification of diverse bacterial and mammalian proteins, which can facilitate the study of how these lysine modifications impact enzymatic activity and control protein–protein and protein–DNA interactions.

    • Maria Weyh
    • , Marie-Lena Jokisch
    •  & Kathrin Lang

  • Article |

    Ribosomally synthesized and post-translationally modified peptides (RiPPs) can have vast structural diversity and biological functions enabled by disparate post-translational modifications (PTMs). However, unconventional PTMs derived from non-RiPP biosynthesis are rarely reported. Now a class of lipopeptides featuring a distinct fatty-acyl-modified N terminus and the responsible RiPP/fatty-acid hybrid biosynthetic machinery have been characterized.

    • Hengqian Ren
    • , Chunshuai Huang
    •  & Huimin Zhao

  • Article
    | Open Access

    The underlying mechanism for how heterotypic protein–RNA interactions modulate the liquid to amyloid transition of hnRNPA1A, a protein involved in amyotrophic lateral sclerosis, has so far remained elusive. Now characterization of hnRNPA1A condensate formation and aggregation in vitro reveals that the RNA/protein stoichiometry affects the molecular pathways leading to amyloid formation.

    • Chiara Morelli
    • , Lenka Faltova
    •  & Paolo Arosio

  • Article |

    Lipidomics aims to uncover lipid functions in biological systems and disease. Quantifying lipids is challenging due to highly diverse chemical structures. Here a diazobutanone-assisted isobaric labelling method is developed that relies on diazobutanone and isobaric mass tags to target phosphate- and sulfate-containing lipids, enabling multiplexed lipidomic quantification in complex mixtures.

    • Ting-Jia Gu
    • , Peng-Kai Liu
    •  & Lingjun Li

  • Article |

    The use of biocatalysis to support early-stage drug discovery campaigns remains largely untapped. Here, engineered biocatalysts enable the synthesis of sp3-rich polycyclic compounds through an intramolecular cyclopropanation of benzothiophenes, affording a class of complex scaffolds potentially useful for fragment-based drug discovery campaigns.

    • David A. Vargas
    • , Xinkun Ren
    •  & Rudi Fasan

  • News & Views |

    Cryptic halogenation reactions result in natural products with diverse structural motifs and bioactivities. However, these halogenated species are difficult to detect with current analytical methods because the final products are often not halogenated. An approach to identify products of cryptic halogenation using halide depletion has now been discovered, opening up space for more effective natural product discovery.

    • Ludek Sehnal
    • , Libera Lo Presti
    •  & Nadine Ziemert

  • Article |

    Many natural products are produced by non-ribosomal peptide synthetases in an assembly-line fashion. How these molecular machines orchestrate the biochemical sequences has remained elusive. It is now understood that an extended-conformation ensemble is needed to coordinate chemical-transformation steps whereas the biosynthesis directionality is driven by the enzyme’s innate conformational free energies.

    • Xun Sun
    • , Jonas Alfermann
    •  & Haw Yang

  • Article |

    The inherent rigidity of the azaarene ring structure has made it challenging to achieve remote stereocontrol through asymmetric catalysis on these substrates. Now, through a photoenzymatic process, an ene-reductase system facilitates the production of diverse azaarenes with distant γ-stereocentres, highlighting the potential of biocatalysts for stereoselectivity at remote sites.

    • Maolin Li
    • , Wesley Harrison
    •  & Huimin Zhao

  • Article |

    The physicochemical driving forces of protein-free, RNA-driven phase transitions were previously unclear, but it is now shown that RNAs undergo entropically driven liquid–liquid phase separation upon heating in the presence of magnesium ions. In the condensed phase, RNAs can undergo an enthalpically favourable percolation transition that leads to arrested condensates.

    • Gable M. Wadsworth
    • , Walter J. Zahurancik
    •  & Priya R. Banerjee

  • Article
    | Open Access

    Understanding of the molecular mechanisms underlying the maturation of protein condensates into amyloid fibrils associated with neurodegenerative diseases has so far remained elusive. Now it has been shown that in condensates formed by the low-complexity domain of the amyotrophic lateral sclerosis-associated protein hnRNPA1, fibril formation is promoted at the interface, which provides a potential therapeutic target for counteracting aberrant protein aggregation.

    • Miriam Linsenmeier
    • , Lenka Faltova
    •  & Paolo Arosio

  • Article
    | Open Access

    Shifts in temperature alter the structure and dynamics of macromolecules. Now, infra-red laser-induced temperature jump is combined with X-ray crystallography to observe protein structural dynamics in real time. Using this method, motions related to the catalytic cycle of lysozyme, a model enzyme, are visualized at atomic resolution and across broad timescales.

    • Alexander M. Wolff
    • , Eriko Nango
    •  & Michael C. Thompson

  • Article
    | Open Access

    Biological membranes are asymmetric bilayers, but little is known about how this asymmetry modulates membrane protein folding or stability. Now, folding and stability assays with bacterial outer membrane proteins reveal an exquisite sensitivity to asymmetric membrane charge distribution and a required matching of protein charge for efficient folding.

    • Jonathan M. Machin
    • , Antreas C. Kalli
    •  & Sheena E. Radford

  • News & Views |

    Medicinal chemistry efforts typically focus on drug–protein interactions and overlook RNA binding as a source of off-target pharmacology. Now, a new method has been developed to map the interactions of small-molecule drugs with RNA in cells and characterize how these interactions can exert functional effects.

    • Christopher R. Fullenkamp
    •  & John S. Schneekloth Jr

  • Article
    | Open Access

    Ribozyme-mediated post-transcriptional RNA modification is a powerful method for site-specific RNA labelling and analysis of RNA functions. Now, an alkyltransferase ribozyme—termed SAMURI—has been shown to catalyse the transfer of a propargyl group from a stabilized synthetic S-adenosylmethionine analogue to a specific adenosine on the target RNA within cells.

    • Takumi Okuda
    • , Ann-Kathrin Lenz
    •  & Claudia Höbartner

  • Article
    | Open Access

    Molecular systems with coincident cyclic and superhelical symmetry axes have considerable advantages for materials design as they can be lengthened or shortened by changing the length of the monomers. Now a systematic approach to generate modular repeat protein oligomers with combined symmetry that can be extended by repeat propagation has been developed.

    • Neville P. Bethel
    • , Andrew J. Borst
    •  & David Baker

  • Article |

    Covalent inhibitors offer high potency but their potential is hindered by off-target reactivity. Now, an in vitro selection method has been developed to enable the discovery of covalent inhibitors from trillions of oligonucleotides endowed with the sulfur(VI) fluoride exchange chemistry. This strategy generates covalent inhibitors of protein–protein interactions with optimally balanced selectivity and reactivity.

    • Zichen Qin
    • , Kaining Zhang
    •  & Yu Xiang

  • Article |

    The design and improvement of enzymes based on physical principles remain challenging. Now, the vibrational Stark effect has been used to demonstrate how an electrostatic model can unify the catalytic effects of distinct chemical forces in a quantitative manner and guide the design of enzyme variants that outperform their natural counterpart.

    • Chu Zheng
    • , Zhe Ji
    •  & Steven G. Boxer

  • News & Views |

    Tandem cycloaddition reactions have significant applications in organic synthetic chemistry. Now, two enzymes are shown to catalyse tandem hetero-Diels–Alder reactions with a synergistic interplay between a calcium cofactor and N-glycan post-translational modifications during the biosynthesis of bistropolone-sesquiterpene secondary metabolites.

    • Richiro Ushimaru
    •  & Ikuro Abe

  • Article |

    Most chemoproteomic screening approaches are indirect. Now, a chemoproteomic platform based on chiral sulfonyl fluoride probes has been developed for the direct identification of probe-modified tyrosines and lysines in live cells. Stereoselective modification by structurally diverse probes was observed for 634 tyrosines and lysines across functionally diverse protein sites.

    • Ying Chen
    • , Gregory B. Craven
    •  & Jack Taunton

  • Article
    | Open Access

    Allostery produces concerted functions of protein complexes by orchestrating the cooperative work between the constituent subunits. By restoring functions of pseudo-active sites that have been lost through evolution, allosteric sites have now been designed into a rotary molecular motor, V1-ATPase, resulting in its rotation being boosted allosterically.

    • Takahiro Kosugi
    • , Tatsuya Iida
    •  & Nobuyasu Koga

  • News & Views |

    Genetic code expansion beyond α-amino acids is a major challenge, in which stitching together non-natural building blocks within the ribosome is a critical barrier. Now, the molecular determinants for the efficient incorporation of non-natural amino acids into the ribosome have been unlocked, accelerating ribosomal synthesis.

    • Souvik Sinha
    • , Mohd Ahsan
    •  & Giulia Palermo

  • Article |

    Microtubules carry patterns of post-translational modifications that are important for the regulation of key cellular processes. Now a semi-synthetic method facilitates the production of tubulins with defined post-translational modifications. Using these designer tubulins, polyglutamylation of α-tubulin is found to promote its detyrosination by enhancing the activity of the carboxypeptidase vasohibin/small vasohibin-binding protein.

    • Eduard Ebberink
    • , Simon Fernandes
    •  & Charlotte Aumeier

  • Article |

    Two glycosylated enzymes, EupfF and PycR1, have now been characterized and shown to independently catalyse the tandem intermolecular [4 + 2] cycloaddition in the biosynthesis of bistropolone-sesquiterpenes. Through analysis of enzyme–substrate co-crystal structures, together with computational and mutational studies, the origins of their catalytic activity and stereoselectivity were elucidated.

    • Jiawang Liu
    • , Jiayan Lu
    •  & Youcai Hu

  • Research Briefing |

    Challenges in the synthesis of heparan sulfate (HS) glycosaminoglycans have limited access to defined HS oligosaccharides bearing a diverse array of sulfation sequences. A concise, divergent synthetic approach now provides a library of 64 HS tetrasaccharides displaying a comprehensive set of sulfation sequences, offering insight into the elusive sulfation code of glycosaminoglycans.

  • Article
    | Open Access

    The metal-dependent, bifunctional isoprenyl diphosphate synthase PcIDS1 from the leaf beetle Phaedon cochleariae integrates substrate, product and metal-ion concentrations to tune its dynamic reactivity. Now structural and functional analyses reveal that this enzyme uses both catalytic centres to form geranyl pyrophosphate, while one domain is inactivated during farnesyl pyrophosphate production.

    • Felix Ecker
    • , Abith Vattekkatte
    •  & Michael Groll

  • Article |

    Incorporating polar residues into hydrophobic protein channel pores facilitates selective proton transport. Now, classical and multiscale reactive molecular dynamics simulations of designed channels reveal dynamic water wires within the channel lumen that are proton conductive according to structural and functional validation. These results provide some guiding principles for biological and engineered proton conduction.

    • Huong T. Kratochvil
    • , Laura C. Watkins
    •  & William F. DeGrado

  • Article |

    Generating aptamers for use as affinity reagents in analytical applications is important, but SELEX, the standard method for aptamer generation, is unable to select for pre-defined binding affinities. Now, by combining efficient particle display, high-performance microfluidic sorting and high-content bioinformatics, the method ‘Pro-SELEX’ can afford the quantitative generation of aptamers with programmable binding affinities.

    • Dingran Chang
    • , Zongjie Wang
    •  & Shana O. Kelley

  • News & Views |

    Complexity is a hallmark of biological systems, but scientific experiments are typically conducted in simplified conditions. Now, diverse polymers that mimic the local environments of complex biological mixtures have been shown to improve protein folding, stability and function.

    • Alana P. Gudinas
    •  & Danielle J. Mai

  • Article |

    The biosynthesis of the methylated sesquiterpene sodorifen, which features a cryptic methylation pattern, has now been studied through extensive labelling experiments and computational chemistry. The methyl group formation is now understood to come from methylene carbons of the substrate farnesyl diphosphate and the absolute configuration of the biosynthetic intermediate presodorifen diphosphate has been revised.

    • Houchao Xu
    • , Lukas Lauterbach
    •  & Jeroen S. Dickschat

  • Article |

    Cellular membranes contain numerous lipids, and efforts to understand the biological functions of individual lipids demand approaches for controlled modulation of membrane composition in situ. Now, click chemistry-based directed evolution of a microbial phospholipase within mammalian cells affords an editor for optogenetic, targeted modification of phospholipids in cell membranes.

    • Reika Tei
    • , Saket R. Bagde
    •  & Jeremy M. Baskin

  • Article
    | Open Access

    In vitro screening of a ribosomally synthesized macrocyclic peptide library containing cyclic γ2,4-amino acids (cγAA) afforded the discovery of potent inhibitors of the SARS-CoV-2 main protease (Mpro). A co-crystal structure revealed the contribution of this cγAA to Mpro binding and the proteolytic stability of these macrocycles.

    • Takashi Miura
    • , Tika R. Malla
    •  & Hiroaki Suga

  • In Your Element |

    Organisms that glow are perhaps eerie. Vadim Viviani ponders on the luciferin–luciferase systems responsible for their intriguing bioluminescence.

    • Vadim R. Viviani

  • Article |

    The molybdenum nitrogenase catalytic cofactor is composed of seven high-spin Fe sites making it difficult to study spectroscopically. Now it has been shown that 57Fe can be incorporated into a single site and that such site-selectively labelled samples provide insights into the cofactor’s electronic structure and the mechanism of biological nitrogen fixation.

    • Edward D. Badding
    • , Suppachai Srisantitham
    •  & Daniel L. M. Suess

  • Article
    | Open Access

    The alkaloids crocagins are derived from a ribosomal peptide through a series of enzymatic post-translational modifications. A combination of biochemistry and structural biology techniques has now been used to elucidate this biosynthetic pathway, propose a mechanism for the formation of the tetracyclic core structure and enable genome mining for related natural products.

    • Sebastian Adam
    • , Dazhong Zheng
    •  & Jesko Koehnke

  • Article |

    A nanopore framework has been developed to reveal the crosstalk effect on the renin–angiotensin system. By reading the single-amino-acid differences in angiotensin peptides with high accuracy and high efficiency, the selective inhibition of angiotensin-converting enzyme by angiotensin-converting enzyme 2 was revealed. This activity was shown to be suppressed by the spike protein of SARS-CoV-2.

    • Jie Jiang
    • , Meng-Yin Li
    •  & Yi-Tao Long

  • 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 |

    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 |

    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 |

    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 |

    Enteropeptins are peptide natural products produced by the gut microbe Enterococcus cecorum. Now, the structure, biosynthesis and function of enteropeptins have been determined. After ribosomal biosynthesis, enteropeptins are post-translationally modified in three reactions carried out by a radical S-adenosylmethionine enzyme, an Mn2+-dependent arginase, and an Fe–S-containing methyltransferase, respectively, to form the N-methylornithine-containing peptide natural products.

    • Kenzie A. Clark
    • , Brett C. Covington
    •  & Mohammad R. Seyedsayamdost

  • 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 |

    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

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