Tracing the Evolution of Substrate Specificity in Low-Molecular-Weight Protein Tyrosine Phosphatases and Arsenate reductases
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Dixon, Sara
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Abstract
At the origin of evolution, ancient enzymes were thought to be versatile and promiscuous. Through genetic mutation, proteins evolve to acquire activity with new substrates, higher efficiency, or novel functions. Our current research explores the hypothesis that, despite differing functions, sequences, and substrate affinities, low molecular weight protein tyrosine phosphatases (LMW-PTPs) and thioredoxin-coupled arsenate reductases (ArsCs) share a common ancestor that later evolved substrate specificity, as shown by their similar mechanisms and structure, including the conserved active site P-loop CX R(S/T). We performed ancestral sequence reconstruction (ASR) on LMW-PTPs, ArsCs, and a pool of the combined families to investigate the development of specificity for phosphate derivatives or arsenate ions. Analyzing key sites for structural conservation and catalytic residues revealed that the reconstructed common ancestor contained ArsC-specific reducing cysteines, which only mutated in the single ancestor from which all LMW-PTPs evolved. Although the P-loop remained mostly conserved, ancestors with the ArsC cysteines consistently featured a serine at a key position, while those without often had a bulkier, nonpolar residue, suggesting the active-site serine may play a critical role in distinguishing between phosphate derivatives and arsenate. Further conventional molecular dynamics (MD) studies investigate substrate affinity across ancestors as well as the relationship between the P-loop dynamics and selectivity. By bridging evolutionary insights with practical applications, this research can drive enzyme engineering for efficient and sustainable bioremediation of arsenic and phosphate pollutants.
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2026-05
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Text
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Undergraduate Thesis