Au(I) Catalyzed HF Transfer: Tandem Alkyne Hydrofluorination and Perfluoroarene Functionalisation

HF transfer reactions between organic substrates are an incredibly rare class of transformation. Such reactions require the development of new catalytic systems that can promote both defluorination and fluorination steps in a single reaction sequence. Herein, we report a novel catalytic protocol in which an equivalent of HF is generated from a perfluoroarene | nucleophile pair and transferred directly to an alkyne. The reaction is catalysed by [Au(IPr)NiPr2] (IPr = N,N’-1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene) and is 100 % atom efficient. HF transfer generates two useful products in the form of functionalised fluoroarenes and fluoroalkenes. Mechanistic studies (rate laws, KIEs, DFT calculations, competition experiments) are consistent with the Au(I) catalyst facilitating a catalytic network involving both concerted SNAr and hydrofluorination steps. The nature of the nucleophile impacts the turnover-limiting step. The cSNAr step is turnover-limiting for phenol-based nucleophiles while proteodeauration likely becomes turnover-limiting for aniline-based nucleophiles. The new approach removes the need for direct handling of HF reagents in hydrofluorination and offers new possibilities to manipulate the fluorine content of organic molecules through catalysis.

Chaotic oscillations, dissipation and mirror symmetry breaking in a chiral catalytic network

The entropy production per unit volume in the chaotic regime of a chiral hypercycle in an open-flow reactor.

A systematic survey of PRMT interactomes reveals key roles of arginine methylation in the global control of RNA splicing and translation

Thousands of proteins undergo arginine methylation, a widespread post-translational modification catalyzed by various protein arginine methyltransferases (PRMTs). However, a full picture of the catalytic network for each PRMT is lacking and the global understanding of their biological roles remains limited. Here we systematically identified interacting proteins for all human PRMTs and demonstrated that they are functionally important for mRNA splicing and translation. We showed that the interactomes of human PRMTs are significantly overlapped with the known methylarginine containing proteins, and different PRMTs are functionally complementary with a high degree of overlap in their substrates and high similarities between their putative methylation motifs. Importantly, arginine methylation is significantly enriched in RNA binding proteins involved in regulating RNA splicing and translation, and inhibition of PRMTs leads to global alteration of alternative splicing and suppression of translation. In particular, ribosomal proteins are pervasively modified with methylarginine, and mutations on their methylation sites suppress ribosome assembly, translation, and eventually cell growth. Collectively, our study provides a novel global view of different PRMT networks and uncovers critical functions of arginine methylation in the regulation of mRNA splicing and translation.

Multiscale dynamics of an adaptive catalytic network

We study the multiscale structure of the Jain–Krishna adaptive network model. This model describes the co-evolution of a set of continuous-time autocatalytic ordinary differential equations and its underlying discrete-time graph structure. The graph dynamics is governed by deletion of vertices with asymptotically weak concentrations of prevalence and then re-insertion of vertices with new random connections. In this work, we prove several results about convergence of the continuous-time dynamics to equilibrium points. Furthermore, we motivate via formal asymptotic calculations several conjectures regarding the discrete-time graph updates. In summary, our results clearly show that there are several time scales in the problem depending upon system parameters, and that analysis can be carried out in certain singular limits. This shows that for the Jain–Krishna model, and potentially many other adaptive network models, a mixture of deterministic and/or stochastic multiscale methods is a good approach to work towards a rigorous mathematical analysis.

Systems protobiology: origin of life in lipid catalytic networks

Life is that which replicates and evolves, but there is no consensus on how life emerged. We advocate a systems protobiology view, whereby the first replicators were assemblies of spontaneously accreting, heterogeneous and mostly non-canonical amphiphiles. This view is substantiated by rigorous chemical kinetics simulations of the graded autocatalysis replication domain (GARD) model, based on the notion that the replication or reproduction of compositional information predated that of sequence information. GARD reveals the emergence of privileged non-equilibrium assemblies (composomes), which portray catalysis-based homeostatic (concentration-preserving) growth. Such a process, along with occasional assembly fission, embodies cell-like reproduction. GARD pre-RNA evolution is evidenced in the selection of different composomes within a sparse fitness landscape, in response to environmental chemical changes. These observations refute claims that GARD assemblies (or other mutually catalytic networks in the metabolism first scenario) cannot evolve. Composomes represent both a genotype and a selectable phenotype, anteceding present-day biology in which the two are mostly separated. Detailed GARD analyses show attractor-like transitions from random assemblies to self-organized composomes, with negative entropy change, thus establishing composomes as dissipative systems—hallmarks of life. We show a preliminary new version of our model, metabolic GARD (M-GARD), in which lipid covalent modifications are orchestrated by non-enzymatic lipid catalysts, themselves compositionally reproduced. M-GARD fills the gap of the lack of true metabolism in basic GARD, and is rewardingly supported by a published experimental instance of a lipid-based mutually catalytic network. Anticipating near-future far-reaching progress of molecular dynamics, M-GARD is slated to quantitatively depict elaborate protocells, with orchestrated reproduction of both lipid bilayer and lumenal content. Finally, a GARD analysis in a whole-planet context offers the potential for estimating the probability of life's emergence. The invigorated GARD scrutiny presented in this review enhances the validity of autocatalytic sets as a bona fide early evolution scenario and provides essential infrastructure for a paradigm shift towards a systems protobiology view of life's origin.

Target-triggered cascade assembly of a catalytic network as an artificial enzyme for highly efficient sensing

A hemin-based enzymatic network is constructed with high catalytic activity that is comparable to natural horseradish peroxidaseviatriple signal amplification.

Implications of Stisa2 catalytic residue restoration through site directed mutagenesis

Objective:Restoration of catalytic activity of Isa2 fromMethods:The six conserved amino acid residues absent in the Stisa2 gene were restored by mutation using the overlap extension PCR and the asymmetrical overlap extension PCR methods. Next, mutant Stisa2 with restored catalytic residues was expressed inResults:Both qualitative and quantitative analysis showed that the restoration of the conserved residues in the catalytic site did not restore starch debranching activity. Molecular modeling showed greater than expected distances between the catalytic triad in mutant Stisa2. These additional distances are likely to prevent hydrogen bonding which stabilizes the reaction intermediate, and are critical for catalytic activity.Conclusions:These results suggest that during evolution, mutations in other highly conserved regions have caused significant changes to the structure and function of the catalytic network. Catalytically inactive Isa2, which is conserved in starch-producing plants, has evolved important non-catalytic roles such as in substrate binding and in regulating isoamylase activity.