Mutational and computational analysis demonstrates reversible substrate selectivity in fungal sesterterpene synthases, suggesting a predictive framework for rational enzyme engineering.
Bifunctional fungal terpene synthases exhibit significant catalytic plasticity, yet the mechanisms governing substrate chain-length selectivity remain to be fully defined. We identified the α1-loop within the catalytic functional plasticity zone (CAPZ) as a primary determinant of substrate preference. Targeted α1-loop substitutions in three enzymes redirected specificity from GFPP (C25) to GGPP (C20), while compensatory D-helix mutations restored C25 selectivity. Molecular dynamics simulations revealed that the α1-loop/D-helix axis constructs a subpocket specifically accommodating the distal terminal-olefin of the precursor. This coordinated machinery modulates the active-site cavity and substrate preorganization to discriminate precursors, providing a predictive paradigm for rational engineering in terpene biosynthesis.
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Zhang et al. (2026) studied this question.
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