Integrating abiotic chemical catalysis and enzymatic catalysis in living cells

Adamson, Christopher; Kanai, Motomu

doi:10.1039/d0ob01898h

Cited by 15 publications

(8 citation statements)

References 66 publications

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“…We believe the ability to correlate the co-operative factor with catalytic property alongside other functionality is a pathway to quantitative deconvolution of the complex patterning in a selforganized system. [27][28][29][30][31][32][33] Thus, it demonstrates potential in achieving future biologically relevant complex synthetic selforganized systems where functional properties related to cooperativity can be regulated by an exogenous module, which also has broader significance in therapeutic purpose. [34] Experimental Section…”

Section: Discussionmentioning

confidence: 99%

Analyzing Catalytic Co‐operativity and Membrane Parameters in a Substrate‐driven Vesicular Assembly Modified by Nucleotides

2022

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Rationalizing changes in functional properties by an exogenous module in a synthetic nanoscale self-organized system has broader significance in designing responsive biomimic materials having application in catalysis to therapeutics. Herein, we have developed a substrate-driven nanoscale vesicular assembly of a metallosurfactant (with dipicolylamine co-ordinated with zinc ion as headgroup) which simultaneously acts as a cooperative catalyst for the hydrolysis of the RNA-model substrate, 2-hydroxypropyl-4nitrophenylphosphate (HPNPP). We have found out that both purine and pyrimidine-based nucleoside monophosphates interact differently with the assembly, modulating the rate of catalytic cleavage. The different means of recognition of the nucleobases leads to alteration in membrane fluidity as well as surface charge of the vesicular aggregates whether the assembly is in catalytically active or inactive state. Then a systematic pattern for different nucleotides mediated vesicular nanoscale assembly composed of a catalytically-active surfactant by statistically corelating alteration in dynamic membrane parameters (fluidity, surface charge) with its cooperative phosphodiester hydrolyzing ability has been generated using principal component analysis as statistical tool. Overall, it showed a unique response pathway of a cooperative functional assembly to different exogenous modules, and this perception of the deconvolution of collective property opens up an avenue for future development of advanced adaptive systems.

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Section: Discussionmentioning

confidence: 99%

Analyzing Catalytic Co‐operativity and Membrane Parameters in a Substrate‐driven Vesicular Assembly Modified by Nucleotides

2022

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“…This is an intriguing example of competition between endogenous and synthetic PTMs in living cells. 44 Alternatively, from a synthetic chemist's viewpoint, this is a protecting group strategy to prevent an undesired pathologic pathway in a structure transformation of proteins occurring in living cells. Taken together, the artificial introduction of H2BK120Ac by the synthetic catalyst system in living cells would be a useful tool for PTM cross-talk analysis between H2BK120 and H3K79, as well as a treatment strategy for MLL-rearranged leukemia.…”

Section: Chemical Catalyst-promotedmentioning

confidence: 99%

“…The H2BK120Ub level in cells chemically acetylated by 15 / 13 decreased significantly. This is an intriguing example of competition between endogenous and synthetic PTMs in living cells . Alternatively, from a synthetic chemist’s viewpoint, this is a protecting group strategy to prevent an undesired pathologic pathway in a structure transformation of proteins occurring in living cells.…”

Section: Chemical Catalyst-promoted Regioselective Histone Globular A...mentioning

confidence: 99%

Chemical Catalysis Intervening to Histone Epigenetics

Nozaki

Kanai

2021

Acc. Chem. Res.

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Conspectus Life emerges from complicated and sophisticated chemical networks comprising numerous biomolecules (e.g., nucleic acids, proteins, sugars, and lipids) and chemical reactions catalyzed by enzymes. Dysregulation of these chemical networks is linked to the emergence of diseases. Our research goal is to develop abiotic chemical catalysts that can intervene into life’s chemical networks by complementing, surrogating, or exceeding enzymes in living cells or multicellular organisms such as animals or plants. Mending dysregulated networks in pathological states by the chemical catalysts will lead to a new medicinal strategy, catalysis medicine. This research direction will also advance catalysis science, because highly active and selective chemical catalysts must be developed to promote the intended reactions in a complex mixture of life in aqueous solution at body temperature. Epigenetics exists at the crossroads of chemistry, biology, and medicine and is a suitable field to pursue this idea. Post-translational modifications (PTMs) of histones epigenetically regulate chromatin functions and gene transcription and are intimately related to various diseases. Investigating the functions and cross-talk of histone PTMs is crucial for mechanistic elucidation of diseases and their treatments. We launched a program to develop chemical catalysts enabling endogenous histone modifications in living cells without relying on enzymes. We reported two types of chemical catalyst systems so far for synthetic histone acylation. The first system comprised a DNA-binding oligo-4-dimethylaminopyridine (DMAP) catalyst and a phenyl ester acyl donor, PAc-gly. This system promoted histone hyperacetylation in Xenopus laevis sperm chromatin. Using the thus-synthesized hyperacetylated sperm chromatin, we found a novel relationship between histone acetylation and DNA replication. The second system involved a histone-binding catalyst, LANA-DSH, composed of a catalytic motif (DSH) and a histone-binding peptide ligand (LANA), and thioester acyl donors, including endogenous acyl-CoA. This system regioselectively (i.e., selectively to a lysine residue at a specific position) acylated lysine 120 of histone H2B (H2BK120), a lysine residue proximal to the DSH motif defined by binding of the LANA ligand to a nucleosome substrate. This catalyst system was optimized to achieve H2BK120-selective acetylation in living cells without genetic manipulation. The synthetically introduced H2BK120Ac inhibited enzyme-catalyzed ubiquitination at the same lysine residue, acting as a protecting group. H2BK120Ub is a mark recognized by methyltransferase that plays an essential role in mixed-lineage leukemia (MLL)-rearranged leukemia, suggesting the potential of the catalyst system as an epigenetic tool and a cancer therapy. We also discuss the prospects of chemical catalyst-promoted synthetic epigenetics for future PTM studies and therapeutic uses.

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“…Furthermore, they possess an extraordinary catalytic power that accelerates the targeted chemical reactions. The process of catalyzing biochemical reactions takes place in aqueous solutions under very mild conditions of temperature and pH [3].…”

Section: Introductionmentioning

confidence: 99%

Enzyme Therapy: Current Challenges and Future Perspectives

Fuente

Lombardero²,

Gómez-González

et al. 2021

IJMS

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In recent years, enzymes have risen as promising therapeutic tools for different pathologies, from metabolic deficiencies, such as fibrosis conditions, ocular pathologies or joint problems, to cancer or cardiovascular diseases. Treatments based on the catalytic activity of enzymes are able to convert a wide range of target molecules to restore the correct physiological metabolism. These treatments present several advantages compared to established therapeutic approaches thanks to their affinity and specificity properties. However, enzymes present some challenges, such as short in vivo half-life, lack of targeted action and, in particular, patient immune system reaction against the enzyme. For this reason, it is important to monitor serum immune response during treatment. This can be achieved by conventional techniques (ELISA) but also by new promising tools such as microarrays. These assays have gained popularity due to their high-throughput analysis capacity, their simplicity, and their potential to monitor the immune response of patients during enzyme therapies. In this growing field, research is still ongoing to solve current health problems such as COVID-19. Currently, promising therapeutic alternatives using the angiotensin-converting enzyme 2 (ACE2) are being studied to treat COVID-19.

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Integrating abiotic chemical catalysis and enzymatic catalysis in living cells

Abstract: Life emerges from networks of multiple chemical reactions mediated by enzymes. If abiotic chemical catalysis is implanted into the reaction network of life, such an integration would produce organisms generating...

Cited by 15 publications

References 66 publications

Analyzing Catalytic Co‐operativity and Membrane Parameters in a Substrate‐driven Vesicular Assembly Modified by Nucleotides

Analyzing Catalytic Co‐operativity and Membrane Parameters in a Substrate‐driven Vesicular Assembly Modified by Nucleotides

Chemical Catalysis Intervening to Histone Epigenetics

Enzyme Therapy: Current Challenges and Future Perspectives

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