A Prebiotic Precursor to Life’s Phosphate Transfer System with an ATP Analog and Histidyl Peptide Organocatalysts

Maguire, Oliver R.; Smokers, Iris B. A.; Oosterom, Bob G.; Zheliezniak, Alla; Huck, Wilhelm T. S.

doi:10.1021/jacs.4c01156

Cited by 4 publications

(2 citation statements)

References 74 publications

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“…In addition to metal ions, coacervates can be rich in peptides with specific catalytic activity . Short histidyl peptides have been shown to catalyze phosphorylation reactions, RNA oligomerization from activated nucleotides and the formation of peptide bonds . Catalytic activity of lysine residues has been shown in self-replicating macrocycle stacks, where several lysine residues are brought in close proximity which lowers their p K a by about 3 units and increases nucleophilicity .…”

Section: Effects On Chemical Reactions: Rate Acceleration and Selecti...mentioning

confidence: 99%

“…In addition to RNA catalysts, other simple molecules and assemblies may have catalyzed reactions. Many of these, including transition metals , and peptides, − are catalysts in the classical sense: they lower the activation energy of a reaction without affecting the overall change in Gibbs free energy. Chemical reactions can, however, be enhanced in multiple other ways that have a similar effect: faster conversion, more product and higher selectivity.…”

Section: Introductionmentioning

confidence: 99%

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How Droplets Can Accelerate Reactions─Coacervate Protocells as Catalytic Microcompartments

Smokers,

Visser,

Slootbeek

et al. 2024

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: Coacervates are droplets formed by liquid−liquid phase separation (LLPS) and are often used as model protocells− primitive cell-like compartments that could have aided the emergence of life. Their continued presence as membraneless organelles in modern cells gives further credit to their relevance. The local physicochemical environment inside coacervates is distinctly different from the surrounding dilute solution and offers an interesting microenvironment for prebiotic reactions. Coacervates can selectively take up reactants and enhance their effective concentration, stabilize products, destabilize reactants and lower transition states, and can therefore play a similar role as micellar catalysts in providing rate enhancement and selectivity in reaction outcome. Rate enhancement and selectivity must have been essential for the origins of life by enabling chemical reactions to occur at appreciable rates and overcoming competition from hydrolysis.In this Accounts, we dissect the mechanisms by which coacervate protocells can accelerate reactions and provide selectivity. These mechanisms can similarly be exploited by membraneless organelles to control cellular processes. First, coacervates can affect the local concentration of reactants and accelerate reactions by copartitioning of reactants or exclusion of a product or inhibitor. Second, the local environment inside the coacervate can change the energy landscape for reactions taking place inside the droplets. The coacervate is more apolar than the surrounding solution and often rich in charged moieties, which can affect the stability of reactants, transition states and products. The crowded nature of the droplets can favor complexation of large molecules such as ribozymes.Their locally different proton and water activity can facilitate reactions involving a (de)protonation step, condensation reactions and reactions that are sensitive to hydrolysis. Not only the coacervate core, but also the surface can accelerate reactions and provides an interesting site for chemical reactions with gradients in pH, water activity and charge. The coacervate is often rich in catalytic amino acids and can localize catalysts like divalent metal ions, leading to further rate enhancement inside the droplets. Lastly, these coacervate properties can favor certain reaction pathways, and thereby give selectivity over the reaction outcome. These mechanisms are further illustrated with a case study on ribozyme reactions inside coacervates, for which there is a fine balance between concentration and reactivity that can be tuned by the coacervate composition. Furthermore, coacervates can both catalyze ribozyme reactions and provide product selectivity, demonstrating that coacervates could have functioned as enzyme-like catalytic microcompartments at the origins of life.

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Section: Effects On Chemical Reactions: Rate Acceleration and Selecti...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

How Droplets Can Accelerate Reactions─Coacervate Protocells as Catalytic Microcompartments

Smokers,

Visser,

Slootbeek

et al. 2024

Acc. Chem. Res.

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The Many‐Chemicals Problem of Systems Chemistry

Maguire

2024

ChemSystemsChem

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An E. coli cell contains ~2500 different chemicals which combine into an ordered biochemical reaction network out of which emerges a living system. A chemist taking 2500 different chemicals from a laboratory chemical cabinet and combining them together will likely cause an explosive disaster and produce an intractable chemical sludge. Systems Chemistry aspires to construct systems whose complexity rivals that of life. However, to do this we will need to learn how to combine hundreds or thousands of different chemicals together to form a functional system without descending into a disordered chemical sludge. This is the Many‐Chemicals Problem of Systems Chemistry. I explore a key strategy life employs to overcome this challenge. Namely, the combination of kinetically stable and thermodynamically activated molecules (e. g. ATP) with enzyme catalysts (e. g. histidine kinases). I suggest how the strategy could have begun at the origin of life. Finally, I assess the implications of this strategy for Systems Chemistry and how it will enable systems chemists to construct systems whose complexity rivals that of life.

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Abiotic Acyl Transfer Cascades Driven by Aminoacyl Phosphate Esters and Self-Assembly

Pol,

Thomann,

Thomann

et al. 2024

J. Am. Chem. Soc.

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Biochemical acyl transfer cascades, such as those initiated by the adenylation of carboxylic acids, are central to various biological processes, including protein synthesis and fatty acid metabolism. Designing cascade reactions in aqueous media remains challenging due to the need to control multiple, sequential reactions in a single pot and manage the stability of reactive intermediates. Herein, we developed abiotic cascades using aminoacyl phosphate esters, the synthetic counterparts of biological aminoacyl adenylates, to drive sequential chemical reactions and self-assembly in a single pot. We demonstrated that the structural elements of amino acid side chains (aromatic versus aliphatic) significantly influence the reactivity and half-lives of aminoacyl phosphate esters, ranging from hours to days. This behavior, in turn, affects the number of couplings we can achieve in the network and the self-assembly propensity of activated intermediate structures. The cascades are constructed using bifunctional peptide substrates featuring side chain nucleophiles. Specifically, aromatic amino acids facilitate the formation of transient thioesters, which preorganized into spherical aggregates and further couple into chimeric assemblies composed of esters and thioesters. In contrast, aliphatic amino acids, which lack the ability to form such structures, predominantly undergo hydrolysis, bypassing further transformations after thioester formation. Additionally, in mixtures containing multiple aminoacyl phosphate esters and peptide substrates, we achieved selective product formation by following a distinct pathway that favors subsequent reactions through reactivity changes and self-assembly. By coupling chemical reactions with molecules of varying reactivity time scales, we can drive multiple reaction clocks with distinct lifetimes and self-assembly dynamics, facilitating precise temporal and structural regulation.

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A Prebiotic Precursor to Life’s Phosphate Transfer System with an ATP Analog and Histidyl Peptide Organocatalysts

Cited by 4 publications

References 74 publications

How Droplets Can Accelerate Reactions─Coacervate Protocells as Catalytic Microcompartments

How Droplets Can Accelerate Reactions─Coacervate Protocells as Catalytic Microcompartments

The Many‐Chemicals Problem of Systems Chemistry

Abiotic Acyl Transfer Cascades Driven by Aminoacyl Phosphate Esters and Self-Assembly

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