Molecular insights into the regulation of coenzyme selection in NADP-specific glutamate dehydrogenase from Saccharomyces cerevisiae

K272R and S250E mutations in Saccharomyces cerevisiae GDH3 shift coenzyme specificity toward NAD(H), with 15–55-fold and 3–14-fold increased preference, respectively.

• Why it matters: Coenzyme selection in glutamate dehydrogenase is central to coordinating carbon and nitrogen metabolism, but the molecular rules governing NADP versus NAD(H) use remain unclear.
• What they did: They engineered ScGDH3 mutants (K272R, S250E), measured coenzyme preference and affinities, and solved a 2.50 Å crystal structure of the K272R–NADP+ complex plus molecular dynamics to interpret NADH binding.
• The result: The K272R–NADP+ structure shows open and super-closed subunit conformations, and simulations support increased NADH affinity, outlining an evolutionarily conserved coenzyme-regulation mechanism in fungal GDHs.

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