How modern enzymes evolved as complex catalytic machineries to facilitate diverse chemical transformations is an open question for the emerging field of systems chemistry. Inspired by Nature’s ingenuity in creating...
Extant proteins exploit thermodynamically activated negatively
charged coenzymes and hydrotropes to temporally access mechanistically
important conformations that regulate vital biological functions,
from metabolic reactions to expression modulation. Herein, we show
that a short amyloid peptide can bind to a small molecular coenzyme
by exploiting reversible covalent linkage to polymerize and access
catalytically proficient nonequilibrium amyloid microphases. Subsequent
hydrolysis of the activated coenzyme leads to depolymerization, realizing
a variance of the surface charge of the assembly as a function of
time. Such temporal change of surface charge dynamically modulates
catalytic activities of the transient assemblies as observed in highly
evolved modern-day biocatalysts.
Through millions of years of the evolutionary journey,
contemporary
enzymes observed in extant metabolic pathways have evolved to become
specialized, in contrast to their ancestors, which displayed promiscuous
activities with wider substrate specificities. However, there remain
critical gaps in our understanding of how these early enzymes could
show such catalytic versatility despite lacking the complex three-dimensional
folds of the existing modern-day enzymes. Herein, we report the emergence
of a promiscuous catalytic triad by short amyloid peptide based nanofibers
that access paracrystalline folds of β-sheets to expose three
residues (lysine, imidazole, and tyrosine) toward solvent. The ordered
folded nanostructures could simultaneously catalyze two metabolically
relevant chemical transformations via C–O and C–C bond
manipulations, displaying both hydrolase and retro-aldolase-like activities.
Further, the latent catalytic capabilities of the short peptide based
promiscuous folds also helped in processing a cascade transformation,
suggesting the important role they might have played in protometabolism
and early evolutionary processes.
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