Mechanistic Insights into NAD+ Driven Activation of Phosphite Dehydrogenase: Preclinical Findings

Synopsis

Research shows that the energy from the ADP part of the NAD+ molecule helps drive a shape change in phosphite dehydrogenase (PTDH), which activates the enzyme to transfer a hydride from phosphite to NAD+. The ADP fragment alone provides over 8.5 kcal/mol of stabilization to the transition state of this reaction. Both the ADP and AMP parts of NAD+ can also activate PTDH to transfer a hydride to nicotinamide riboside (NR), stabilizing the transition state by 5.1 and 2.7 kcal/mol, respectively, through interactions with the α- and β-phosphates. In contrast, the adenosine part of NAD+ does not stabilize the transition state. Activation appears to occur because a cation–anion interaction involving the K76 residue stabilizes the closed form of PTDH by bridging the α- and β-phosphates. Comparatively, other enzymes like formate dehydrogenase and glycerol phosphate dehydrogenase mainly rely on interactions with only the α-phosphate for activation. These findings indicate that different dehydrogenases have evolved diverse ways to use cofactor interactions to trigger the conformational changes needed for hydride transfer.

Journal

Biochemistry