Sugar phosphatases as biocatalysts for biomanufacturing: Recent advances and applications

Phosphatases, the largest subgroup within the haloacid dehydrogenase (HAD) superfamily, catalyze the irreversible dephosphorylation of phosphate biomolecules. In in vitro synthetic enzymatic biosystems, sugar phosphatases drive the pathways of phosphorylation, transformation (isomerization, epimerization, dehydrogenation, and/or transamination), and dephosphorylation towards product formation through irreversible and exothermic reactions. This process enables enzymatic cascades based on phosphorylation-dephosphorylation to overcome the thermodynamic limitations of traditional functional sugar production methods that rely on isomerases or epimerases, potentially leading to high theoretical conversion rates. However, sugar phosphatases often exhibit broad substrate scope, which can result in dephosphorylation of intermediates within enzymatic biosystems. In this review, we begin by reviewing the classification, structural features, and catalytic mechanisms of phosphatases, followed by the molecular mechanisms underlying substrate promiscuity. The current research on the substrate specificity engineering of phosphatases is then discussed, with particular focus on the production of functional sugars using sugar phosphatase-driven in vitro synthetic enzymatic biosystems. Our goal is to provide a comprehensive overview of the current research status, challenges, and future trends related to sugar phosphatases-mediated biomanufacturing, offers valuable insights into the enzymatic modification and application of these enzymes.