Archive for the ‘Uncategorized’ Category

Mutant Enzymes and Frankenstein Catalysts

I know what you’re thinking: “Autumn is here! Who needs sunny weather and optimism? Sign me up for grey skies and vitamin D supplements!”. Oh you weren’t thinking that? Me neither. Well perhaps Halloween gives you more joy, along with the chance to see one of your colleagues dressed up like Freddy Mercury (‘Hg’ emblazoned on their chest, classic) at the departmental party?

In the spirit of Halloween, Simone Morra and Anca Pordea at the University of Nottingham have synthesized a mutant alcohol dehydrogenase enzyme turned Frankenstein catalyst, by replacing the zinc catalytic site with a covalently-bound rhodium(III) complex. The resulting mutant/transition-metal composite was used in combination with the wild-type enzyme to synthesize the chiral alcohol (S)-4-phenyl-2-butanol.

Like many hybrid systems, the purpose of combining enzymatic with transition metal catalysis is to take advantage of the benefits of each. Millions of years of evolution have produced enzymatic catalysts that function under mild conditions, in aqueous solvents, with impressive selectivity and high catalytic efficiency. But the narrow range of conditions that enzymes operate under can be disadvantageous in a synthetic setting. On the other hand, transition metal catalysts are versatile and can be easily customised, reacting with a liberty that would make the most promiscuous of enzymes blush.

Unfortunately, developing multi-component systems that utilise both transition metal and enzymatic catalysis is not as simple as combining them in a single mixture, as mutual deactivation often results. The authors found that encasing the transition metal complex in an enzyme provided a physical shield against inhibition, and preserved the activity of both the wild type enzyme and the rhodium(III) complex.

Synthesis of chiral alcohols via two interconnected cycles: the wild type enzyme (native ADH) reduces the ketone to the alcohol using NADPH as a reducing agent. NADPH is regenerated using the mutant enzyme containing a rhodium active site (chemically modified ADH) with formic acid as the terminal reductant. Alcohol dehydrogenase

Synthesis of chiral alcohols via two interconnected cycles: the wild type enzyme (native ADH) reduces the ketone using NADPH as a reducing agent. NADPH is regenerated by the mutant enzyme containing a catalytically-active rhodium complex (chemically modified ADH) with formic acid as the terminal reductant.

Two interconnected catalytic cycles were responsible for synthesis of the chiral alcohol. In the first, the wild type enzyme effected reduction of 4-phenyl-2-butanol, a process that relies on the biological reductant nicotinamide adenine dinucleotide phosphate (NADPH). In the second cycle, NADPH was recycled using the composite rhodium(III) complex/mutant enzyme, with formic acid as the stoichiometric reductant. The rate of alcohol formation was slow (turnover frequency of 0.02 s-1) and the transition-metal catalysed process was deemed to be rate limiting (compare to turnover frequencies of 4.8 s-1 for enzymatic systems). However, near perfect enantioselectivity was obtained (>99% ee).

This research demonstrates one way that transition metal catalysts can augment the scope of co-factor-dependent enzymes. Furthermore, devising strategies to prepare metal-complex/enzyme bioconjugates might have value for small molecule synthesis due to the second coordination sphere that enzymes offer; an encased steric environment to guide the reaction outcome is a valuable approach to improving selectivity in catalytic reactions.

To find out more please read:

Biocatalyst-artifical metalloenzyme cascade based on alcohol dehydrogenase

Simone Morra, Anca Pordea.
Chem. Sci., 2018, 9, 7447-7454
DOI: 10.1039/c8sc02371a

About the author

Zoë Hearne is a PhD candidate in chemistry at McGill University in Montréal, Canada, under the supervision of Professor Chao-Jun Li. She hails from Canberra, Australia, where she completed her undergraduate degree. Her current research focuses on transition metal catalysis to effect novel transformations, and out of the lab she is an enthusiastic chemistry tutor and science communicator.

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HOT Chemical Science articles for September

We are happy to present a selection of our HOT articles over the past month. To see all of our HOT referee-recommended articles from 2018, please find the collection here.

As always, Chemical Science articles are free to access.

Selective and catalytic carbon dioxide and heteroallene activation mediated by cerium N-heterocyclic carbene complexes
Polly Louise Arnold, Ryan Kerr, Catherine Weetman, Scott Doherty, Julia Rieb, Kai Wang, Christian Jandl, Max McMullon, Alexander Pöthig, Fritz Elmar Kühn and Andrew D Smith
Chem. Sci., 2018, Accepted Manuscript
DOI: 10.1039/C8SC03312A, Edge Article

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Ratiometric fluorescent probes for capturing endogenous hypochlorous acid in the lungs of mice
Xinfu Zhang, Weiyu Zhao, Bin Li, Wenqing Li, Chengxiang Zhang, Xucheng Hou, Justin Jiang and Yizhou Dong
Chem. Sci., 2018, Advance Article
DOI: 10.1039/C8SC03226B, Edge Article

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Surprising solvent-induced structural rearrangements in large [N⋯I+⋯N] halogen-bonded supramolecular capsules: an ion mobility-mass spectrometry study
Ulrike Warzok, Mateusz Marianski, Waldemar Hoffmann, Lotta Turunen, Kari Rissanen, Kevin Pagel and Christoph A. Schalley
Chem. Sci., 2018, Advance Article
DOI: 10.1039/C8SC03040E, Edge Article

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Advanced microRNA-based cancer diagnostics using amplified time-gated FRET
Xue Qiu, Jingyue Xu, Jiajia Guo, Akram Yahia-Ammar, Nikiforos-Ioannis Kapetanakis, Isabelle Duroux-Richard, Julia J. Unterluggauer, Nicole Golob-Schwarzl, Christophe Regeard, Catherine Uzan, Sébastien Gouy, Michael DuBow, Johannes Haybaeck, Florence Apparailly, Pierre Busson and Niko Hildebrandt
Chem. Sci., 2018, Advance Article
DOI: 10.1039/C8SC03121E, Edge Article

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Atomic structure of boron resolved using machine learning and global sampling
Si-Da Huang, Cheng Shang, Pei-Lin Kang and Zhi-Pan Liu
Chem. Sci., 2018, Advance Article
DOI: 10.1039/C8SC03427C, Edge Article

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Spontaneous growth of 2D coordination polymers on functionalized ferromagnetic surfaces 
Michele Mattera, Víctor Rubio-Giménez, Sophie Delprat, Richard Mattana, Pierre Seneor, Sergio Tatay, Alicia Forment-Aliaga and Eugenio Coronado
Chem. Sci., 2018, Advance Article
DOI: 10.1039/C8SC03067G, Edge Article

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TPCB Symposium poster prize winner

The 14th Annual Tri-Institutional Chemical Biology Symposium took place on 11th September at The Rockefeller University in New York. The Symposium was a great success and we look forward to supporting it again next year.

The winner of the Chemical Science poster prize was Chen Chen, pictured below.  Congratulations to Chen!

You can keep up to date with the plans for 2019 by following the TPCB website here.

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EuroBIC 14

This August saw the occasion of the 14th European Biological Inorganic Chemistry Conference (EuroBIC), held at the University of Birmingham in the UK. With an excellent line up of internationally renowned plenary and keynote speakers the event was a huge success, attracting around 400 attendees.

The Royal Society of Chemistry was pleased to support the event, offering poster prizes of books and book vouchers. The winners of RSC vouchers were:

  • Raul Berrocal-Martin (University of Glasgow) – Dalton Transactions Poster Prize
  • Wilma Neumann (Massachusetts Institute of Technology) – Metallomics Poster Prize
  • Ying Zhou (University of Hong Kong) – ChemComm Poster Prize
  • Leon Jenner (University of East Anglia) – Chemical Science Poster Prize

The following presenters also won the RSC Highly Commended Poster Awards:

  • Gloria Vigueras Bautista (University of Murcia)
  • Nicolai Burzlaff (Friedrich-Alexander University)
  • Samya Banerjee (University of Warwick)
  • Riccardo Bonsignore (Cardiff University)
  • Philip Ash (University of Oxford)

Dalton Transactions associate editor Nils Metzler-Nolte (Ruhr-Universität Bochum) and Chemical Science assistant editor William King were on hand to award the prizes.

Raul Berrocal-Martin (left) receiving the Dalton Transactions prize from Nils Metzler-Nolte (right) Ying Zhou (left) receiving the ChemComm prize from Nils Metzler-Nolte (right)
Leon Jenner (left) receiving the Chemical Science prize from William King (right) Gloria Vigueras Bautista (left) receiving a Highly Commended Poster Prize from William King (right)
Riccardo Bonsignore (left) receiving a Highly Commended Poster Prize from William King (right) Philip Ash (left) receiving a Highly Commended Poster Prize from William King (right)

The RSC offers a hearty congratulations to all poster prize winners!

Next year the 19th International Conference on Biological Inorganic Chemistry (ICBIC 19) will be held in Interlaken, Switzerland – August 11th to 16th. The next European Biological Inorganic Chemistry Conference (EuroBIC 15) will be held in Reykjavik, Iceland, in August 2020. 

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HOT Chemical Science articles for August

We are happy to present a selection of our HOT articles over the past month. To see all of our HOT referee-recommended articles from 2018, please find the collection here.

As always, Chemical Science articles are free to access.

Conformational selectivity and high-affinity binding in the complexation of N-phenyl amides in water by a phenyl extended calix[4]pyrrole
L. Escobar, A. Díaz-Moscoso and P. Ballester
Chem. Sci., 2018, Advance Article
DOI: 10.1039/C8SC03034K, Edge Article

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ZrMOF nanoparticles as quenchers to conjugate DNA aptamers for target-induced bioimaging and photodynamic therapy
Yuan Liu, Weijia Hou, Lian Xia, Cheng Cui, Shuo Wan, Ying Jiang, Yu Yang, Qiong Wu, Liping Qiu and Weihong Tan
Chem. Sci., 2018, Advance Article
DOI: 10.1039/C8SC02210K, Edge Article

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Oxidative dehalogenation and denitration by a flavin-dependent monooxygenase is controlled by substrate deprotonation
Panu Pimviriyakul, Panida Surawatanawong and Pimchai Chaiyen
Chem. Sci., 2018, Advance Article
DOI: 10.1039/C8SC01482E, Edge Article

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Biocatalyst–artificial metalloenzyme cascade based on alcohol dehydrogenase
Simone Morra and Anca Pordea
Chem. Sci., 2018, Advance Article
DOI: 10.1039/C8SC02371A, Edge Article

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Design and synthesis of a 4-aminoquinoline-based molecular tweezer that recognizes protoporphyrin IX and iron(III) protoporphyrin IX and its application as a supramolecular photosensitizer
Yosuke Hisamatsu, Naoki Umezawa, Hirokazu Yagi, Koichi Kato and Tsunehiko Higuchi
Chem. Sci., 2018, Advance Article
DOI: 10.1039/C8SC02133C, Edge Article

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Genome Mining, Isolation, Chemical Synthesis and Biological Evaluation of a Novel Lanthipeptide, Tikitericin and N-Truncated Analogues, from the Extremophilic Microorganism Thermogemmatispora Strain T81
Margaret A Brimble, Buzhe Xi, Emma Aitken, Benjamin Baker, Claire Turner, Joanne Harvey, Matthew Stott, Jean Power, Paul Harrs and Rob Keyzers
Chem. Sci., 2018, Accepted Manuscript
DOI: 10.1039/C8SC02170H, Edge Article

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Gaunt Lab and the Holy Grail: Synthesis of Lactams via C-H Activation

A small consolation when marking undergraduate organic chemistry exams is that occasionally you come across an answer so ridiculous it is almost brilliant. Penned to complete a far-fetched synthesis, the student managed to propose a reaction that is completely without precedent, not only in the course, but in the chemistry literature as a whole. Sadly for the student it is completely wrong, 0 marks.

I imagine that 50 years ago if an undergraduate student had proposed a one-step synthesis of γ-lactams starting with a linear alkylamine, which proceeded by clipping off an N-H bond and a C-H bond, then stitching it together with a carbon monoxide molecule at the junction, they too may have got 0 marks. Yet Matthew Gaunt and researchers in his laboratory at the University of Cambridge have achieved just this via palladium-catalysed C-H activation.

Transition metal-catalysed C-H activation refers to the cleavage of a C-H bond by a transition metal, followed by functionalisation of the metal-bound organic fragment and regeneration of the catalyst. This strategy is counter to the classical approach of organic synthesis: construction of molecular complexity by installing and manipulating reactive functional groups. The object of pre-functionalisation is two-fold: it makes a molecule more reactive (for example, installation of a halide can enable oxidative addition to a transition metal or substitution by a nucleophile) and it directs reactivity to a specific location in the molecule under construction. For C-H activation the challenge is to promote reaction of thermodynamically and kinetically stable C-H bonds, and achieve site-selectivity in a molecule containing many chemically-similar C-H bonds.

Figure 1: Optimised reaction conditions and selected products of the C-H activation of linear alkylamines for the synthesis of lactams by palladium catalyzed C-H activation

Figure 1: Optimised reaction conditions

The authors found that a catalytic system consisting of palladium pivalate and copper acetate, in combination with acidic and basic additives under a CO/air atmosphere, transformed a variety of secondary amines with primary C-H bonds at the γ-position into 5-membered lactones (Figure 1). Good yields and diastereoselectivities were obtained, and a variety of substituents such as carbocycles, tetrahydropyran, piperadine, fluorocycloalkanes and dioxolanes were well tolerated.

Figure 2: Mechanistic hypothesis illustrating: C-H activation step, H-bond between the amine and pivalate, intramolecular base-assisted deprotonation, and preference for formation of the trans diastereomer.

Figure 2: Mechanistic hypothesis showing organisation of the transition state and C-H activation.

The reacting components in the C-H activation step are highly organised in the transition state by coordination of the amine to the palladium centre, and formation of a hydrogen bond between the amine and the carbonyl group of a pivalate ligand bound to palladium (Figure 2). Palladium insertion into the C-H bond (one of the pivalate ligands serves as an intramolecular base) forms a palladacycle with the entropic and enthalpic preference for a 5-membered ring, necessitating abstraction of a proton in the γ-position with respect to the amine directing group.

C-H activation has been referred to as the ‘holy grail’ of catalysis, and the efficiency gains are clear: reduction in reaction steps and use of catalysis minimises energy use, formation of stoichiometric by-products and waste from isolation and purification processes, excess reagents, solvents and additives. This aside, the most exciting thing about the development of C-H activation methods is the promise of discovery: novel reactivity can lead to novel products, inaccessible by other means.

 

 

To find out more please read:

Diastereoselective C-H carbonylative annulation of aliphatic amines: a rapid route to functionalized γ-lactams

Png Zhuang Mao, Jaime R. Cabrera-Pardo, Jorge Piero Cadahia and Matthew J. Gaunt.
Chem. Sci., 2018, Edge Article
DOI: 10.1039/c8sc02855a

About the author

Zoë Hearne is a PhD candidate in chemistry at McGill University in Montréal, Canada, under the supervision of Professor Chao-Jun Li. She hails from Canberra, Australia, where she completed her undergraduate degree. Her current research focuses on transition metal catalysis to effect novel transformations, and out of the lab she is an enthusiastic chemistry tutor and science communicator.

 

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Meet Stephen Goldup: Chemical Science Associate Editor

We are happy to introduce Professor Stephen Goldup as Chemical Science Associate Editor, handling submissions in the area of supramolecular chemistry.

Steve obtained an MChem degree from the University of Oxford where he began his research career with a Part II project in the group of Sir Prof. Jack Baldwin. He continued his research training with a PhD in natural product synthesis under the supervision of Prof. Tony Barrett before shifting focus to apply his synthetic skills to the realisation of mechanically interlocked non-natural products during post doctoral work with Prof. David Leigh at the University of Edinburgh where in 2007 he was appointed as Fixed Term Lecturer in Organic Chemistry. In 2008 he moved to Queen Mary with the award of a Leverhulme Trust Early Career Fellowship and in October 2009 he was awarded a Royal Society University Research Fellowship.

In October 2014 the group moved to the University of Southampton where Steve took up the position of Associate Professor. In August 2017, Steve was promoted to Professor of Chemistry. Research in the Goldup Group focusses on the synthesis of novel mechanically interlocked molecules and their application as sensors, catalysts and materials.

Steve is keen to receive submissions in his area of expertise, particularly in supramolecular chemistry, interlocked molecules, molecular machines, stimuli responsive systems, and sensing. Below is a list of Chemical Science articles which Steve would like to highlight – all free to read! We hope you enjoy them.

Variations in the fuel structure control the rate of the back and forth motions of a chemically fuelled molecular switch
Chiara Biagini, Simone Albano, Rachele Caruso, Luigi Mandolini, José Augusto Berrocal and Stefano Di Stefano
Chem. Sci., 2018,9, 181-188
DOI: 10.1039/C7SC04123C, Edge Article

Self-assembled orthoester cryptands: orthoester scope, post-functionalization, kinetic locking and tunable degradation kinetics
Henrik Löw, Elena Mena-Osteritz and Max von Delius
Chem. Sci., 2018,9, 4785-4793
DOI: 10.1039/C8SC01750F, Edge Article

Interfacing porphyrins and carbon nanotubes through mechanical links
Leire de Juan-Fernández, Peter Münich, Arjun Puthiyedath, Belén Nieto-Ortega, Santiago Casado, Luisa Ruiz-Gonzales, Emilio M Perez and Dirk M. Guldi
Chem. Sci., 2018, Accepted Manuscript
DOI: 10.1039/C8SC02492H, Edge Article

White-light emission from a single organic compound with unique self-folded conformation and multistimuli responsiveness
Dengfeng Li, Wende Hu, Jie Wang, Qiwei Zhang, Xiao-Ming Cao, Xiang Ma and He Tian
Chem. Sci., 2018,9, 5709-5715
DOI: 10.1039/C8SC01915K, Edge Article

Mechanochemistry of the mechanical bond
Guillaume De Bo
Chem. Sci., 2018,9, 15-21
DOI: 10.1039/C7SC04200K, Minireview

 

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Bioelectrochemistry with nitrogenase-loaded electrodes for nitrogen fixation

We happily breathe our dinitrogen-rich atmosphere all day, but to access nitrogen for the biosynthesis of molecules such as DNA, RNA and proteins, we rely on nitrogen fixation to reduce dinitrogen into bioavailable molecules like ammonia. In nature, nitrogen-fixing bacteria and archaea equipped with nitrogenase enzymes are responsible for providing plants with reduced nitrogen, which makes its way back to us. Nitrogenase is an enzyme complex of two proteins. The first consists of an iron-containing reductase that supplies electrons to the iron/molybdenum-containing catalytic protein, which carries out the N2 to NH3 conversion.

The Haber Bosch process, an industrial method for fixing dinitrogen into ammonia, was first applied in the early 1900’s and generated a huge supply of nitrogen-based fertilizers to synthetically provide plants with this essential nutrient. The population boom that resulted, and with it the global importance of this reaction, has yet to abate. Albeit an efficient reaction, this iron-catalysed process requires high temperatures (450 °C) and pressures (200 atm). In comparison, enzymes can operate under conditions synthetic chemists can only dream of, as researchers at the University of Utah have demonstrated in their work on the bioelectrochemical reduction of dinitrogen under ambient conditions using the catalytic nitrogenase protein.

The researchers synthesised an electrode/enzyme aggregate by trapping the nitrogenase enzyme in a hydrogel, then binding the hydrogel via π-stacking of incorporated pyrene motifs to carbon paper electrodes coated in multi-walled carbon nanotubes. If the enzyme is oriented in the hydrogel in such a way that the distance between the catalytic iron/molybdenum centre of the enzyme and the electrode is within 14 Å, direct electron transfer can take place. Direct electrical contact with enzymes allows researchers to take advantage of the high efficiency and selectivity of enzymes for conducting chemical reactions under mild conditions.

Two methods for immobilization of proteins on an electrode: the docking strategy (upper) and the hydrogel strategy (middle). Active protein is green, while inactive/denatured protein is grey. Pi-stacking of pyrene moieties to bind the hydrogel to the carbon nanotubes (lower).

Two methods for immobilization of proteins on an electrode: the docking strategy (upper) and the hydrogel strategy (middle). Active protein is green, while inactive/denatured protein is grey. π-stacking of pyrene moieties within the polymer binds the hydrogel to the carbon nanotubes (lower).

To minimise the distance between the enzyme’s redox centre and the electrode, prior strategies have focused on docking enzymes in the desired configuration; however low enzyme activities can result due to protein denaturation. The authors of this work designed a system under the hypothesis that if they focussed on preserving enzymatic activity, the statistical mixture of configurations adopted by enzymes in the hydrogel would still contain a large proportion capable of participating in direct electron transfer.

Bioelectrical activity of the electrode/nitrogenase aggregate was assessed under bubbling N2 at room temperature, and 180 nmol of NH3 (1.1 μmol/mg nitrogenase enzyme) was produced, marking the first bioelectrochemical reduction of N2 in the absence of ATP. The bioelectrical activity of laccase for the reduction of O2 was also measured using the same method. In this experiment 15% of laccase proteins remained active, compared to 0.3% using a reference method applying an enzyme docking technique. This translated to increased current densities of 390 – 1880 μA cm-2 mg-1 (depending on the enzyme concentration, 1-10 mg mL-1) compared to 45 μA cm-1 mg-1 for the reference docking method.

Without being too grandiose, synthetic nitrogen fixation is vital for the continued survival of people on the planet (how did I do?). Beyond nitrogen fixation, this research offers a general method to achieve contact between a conductive electrode and the highly complex catalytic machinery that nature offers: enzymes. Beyond synthesis, opportunities broaden; technology such as this might pave the way for the production of biosensors, biofuel cells and biomolecular electronic components.

 

 

To find out more please read:

Pyrene hydrogel for promoting direct bioelectrochemistry: ATP-independent electroenzymatic reduction of N2

David P. Hickey, Koun Lim, Rong, Cai, Ashlea R. Patterson, Mengwei Yuan, Selmihan Sahin, Sofiene Abdellaoui, Shelley D. Minteer
Chem. Sci., 2018, 9, 5172-5177
DOI: 10.1039/c8sc01638k

About the author:

Zoë Hearne is a PhD candidate in chemistry at McGill University in Montréal, Canada, under the supervision of Professor Chao-Jun Li. She hails from Canberra, Australia, where she completed her undergraduate degree. Her current research focuses on transition metal catalysis to effect novel transformations, and out of the lab she is an enthusiastic chemistry tutor and science communicator.

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Outstanding Reviewers for Chemical Science in 2017

We would like to highlight the Outstanding Reviewers for Chemical Science in 2017, as selected by the editorial team, for their significant contribution to the journal. The reviewers have been chosen based on the number, timeliness and quality of the reports completed over the last 12 months.

We would like to say a big thank you to those individuals listed here as well as to all of the reviewers that have supported the journal. Each Outstanding Reviewer will receive a certificate to give recognition for their significant contribution.

Dr Lutz Ackermann, Georg-August-Universitaet, ORCID: 0000-0001-7034-8772
Dr Mircea Dinca, MIT, ORCID: 0000-0002-1262-1264
Professor Frank Glorius, University of Muenster
Dr Takashi Hisatomi, The University of Tokyo, ORCID: 0000-0002-5009-2383
Professor Rei Kinjo, Nanyang Technological University, ORCID: 0000-0002-4425-3937
Professor Jun Kubota, Fukuoka University
Professor Akihiko Kudo, Tokyo University of Science
Dr Armido Studer, WWU Muenster, ORCID: 0000-0002-1706-513X
Dr Bo Tang, Shangdong Normal University, ORCID: 0000-0002-8712-7025
Dr Jay Winkler, California Institute of Technology

We would also like to thank the Chemical Science Board and the general chemical sciences community for their continued support of the journal, as authors, reviewers and readers.

If you would like to become a reviewer for our journal, just email us with details of your research interests and an up-to-date CV or résumé. You can find more details in our author and reviewer resource centre.

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Customised peptides via nickel/photoredox-catalysed bioconjugation

Proteins have an expansive utility in the structure, function, replication and regulation of all cells, and developing tools to study each role is to the benefit of our continued health and wellbeing. One tool is protein bioconjugation, the covalent pairing of a molecule with a protein. Molecule-protein combinations are endless, provided there are efficient methods available to couple molecules with amino acids. Among bioconjugation methods, cysteine functionalisation is a popular choice because the primary thiol is highly nucleophilic thus aiding chemoselectivity. Furthermore, cysteine is rare, reducing the likelihood of many competing, reactive residues.

Transition metal catalysed transformations are uncommon in bioconjugations, despite prominence in other areas of synthetic chemistry. This is because only the most robust methods can overcome the challenges of this chemistry: the solubility of substrates in solvents other than aqueous media, the presence of other amino acids bearing reactive functional groups, and the requirement for low temperatures, low concentrations and mild pH to preserve protein structure.

Catalytic cycle for the nickel/phororedox catalysed synthesis of cysteine bioconjugates

Catalytic cycle for the nickel/phororedox catalysed synthesis of cysteine bioconjugates

A group of researchers from the University of Pennsylvania headed by Professor Gary Molander have developed a bioconjugation method in which aryl halides are cross-coupled with cysteine residues in peptides. Two complexes catalyse the reaction in two connected cycles: the photoredox cycle by a ruthenium-bipyridine complex, and the catalytic cycle by a nickel-bipyridine complex.

The reaction is efficient at room temperature and does not require prior functional group protection. The reaction can also be performed under dilute conditions (10 mM) and on gram scale (3.5 mmol). The scope table includes more than 35 reactions coupling a broad range of aryl halides with small peptides (4 and 9 amino acids) and biologically relevant molecules such as coenzyme A and sulphur-containing pharmaceuticals.

Protecting-group free functionalisation of small peptides under dilute conditions using nickel and ruthenium photoredox catalysis for cysteine functionalization

Protecting group free functionalisation of small peptides under dilute conditions

Included in the reaction scope are a number of substrates which highlight how this work can adapt to established techniques for studying proteins. Coupling of a coumarin generates a fluorescent molecule, which could be used to study the cellular localisation of a protein. Reaction with an aryl-bound biotin derivative demonstrates that affinity tags can be coupled, and utilising aryl-containing pharmaceutical agents is relevant to the synthesis of antibody-drug conjugates.

With this research the authors have contributed a robust catalytic system, which convincingly shows the value of combining a transition metal and photoredox catalyst to functionalise cysteine residues in biomolecules. A necessary next step for this chemistry, and no small task, is to further optimise the reaction conditions for whole proteins.

Read the research article:

Scalable thioarylation of unprotected peptides and biomolecules under Ni/photoredox catalysis

Chem. Sci., 2018, DOI: 10.1039/C7SC04292B

Brandon A. Vara, Xingpin Li, Simon Berritt, Christopher R. Walters, E. James Petersson, Gary A. Molander.


About the Author: 

Zoë Hearne is a PhD candidate in chemistry at McGill University in Montréal, Canada, under the supervision of Professor Chao-Jun Li. She hails from Canberra, Australia, where she completed her undergraduate degree. Her current research focuses on transition metal catalysis to effect novel transformations, and out of the lab she is an enthusiastic chemistry tutor and science communicator.

 

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