NAD⁺ as a Hydride Donor and Reductant

Abstract

Reduced nicotinamide adenine dinucleotide (NADH) can generate a ruthenium-hydride intermediate that catalyzes the reduction of O to HO, which endows it with potent anticancer properties. A catalyst that could access a Ru-H intermediate using oxidized nicotinamide adenine dinucleotide (NAD) as the H source, however, could draw upon a supply of reducing equivalents 1000-fold more abundant than NADH, which would enable significantly greater HO production. Herein, it is demonstrated, using the reduction of ABTS to ABTS, that NAD can function as a reductant. Mechanistic evidence is presented that suggests a Ru-H intermediate is formed via β-hydride elimination from a ribose subunit in NAD. The insight gained from the heretofore unknown ability of NAD to function as a reductant and H donor may lead to undiscovered biological carbohydrate oxidation pathways and new chemotherapeutic strategies.

The NAD+/NADH Redox Couple—Insights from the Perspective of Electrochemical Energy Transformation and Biomimetic Chemistry

“…Recently, the reduction of NAD + was studied from the viewpoint of its orientation at the solution or electrode interfaces. Studies showed that there is a perpendicular orientation of NAD + on a glassy carbon as determined from charge consumed on the application of a potential sweep and such is in good agreement with the sequence of chemical reactions (Santhanam and Elving, 1973;Htet and Tennyson, 2016). Figure 4 are different anodic waves for the oxidation of NADH in various electrodes including glassy carbon (GC), platinum (Pt), and gold (Au).…”

“…The processes involved in the electrochemical reduction of NAD + and the electrochemical oxidation of its reduced form NADH are summarized in Figure 4. The process starts with a one-electron reduction of NAD + to give a free radical NAD • seen at the cathodic wave at approximately -1 V. The free radical NAD • dimerizes to form (NAD)₂ followed with the subsequent one-electron reduction to form NADH at a potential of -1.6 V (Elving et al, 1982;Htet and Tennyson, 2016). The dimer (NAD)₂ is oxidized to give NAD + at around -0.4 V. Furthermore, the (NAD)₂ can undergo a proton-assisted disproportionation to NAD + and NADH (Bresnahan and Elving, 1981;Huang and Liu, 2014).…”

“…The mechanistic pathway for the electrochemical reduction of NAD + to the radical NAD • is dependent on several factors like the existence of competing adsorption, time-scale of the experiment, the electrode surface and its initial condition, and the background solution defined by its ionic strength and surface activity (Bresnahan and Elving, 1981;Huang and Liu, 2014). Experimentally, it has been suggested that there is a need for a protonation process before any charge transfer occurs since NAD • is not reduced in aprotic media (Santhanam andElving, 1973, Htet andTennyson, 2016). The measured k d for this process, Figure 5, was 2.7 × 10⁶ M -¹ s -¹ from voltammetric analysis (Bresnahan and Elving, 1981).…”

Hydrogen peroxide as a hydride donor and reductant under biologically relevant conditions

“…Interestingly, this value was nearly identical to the O–H/D KIE of 1.45 measured with NAD + 21. Although H 2 O 2 and NAD + are structurally dissimilar, their O–H p K a values (11.6 for H 2 O 2 and 11.8 for NAD + ) are nearly identical,48,49 therefore their O–H bond polarizations will be highly conserved.…”

“…We recently reported a Ru complex ( Ru1 , Scheme 1B) that catalyzed the 1e – reduction of ABTS˙ – (Scheme 1C) with biologically-relevant alcohols (ascorbate, glucose, NAD + , etc. , Scheme 1D) as terminal reductants 21,22. Importantly, ABTS˙ – undergoes 1e – reduction at a potential ( E 1/2 = +0.68 V vs. NHE) comparable to the ROS generated during oxidative stress,23–25 therefore the one-electron redox reactivity of ABTS˙ – can thermodynamically approximate the corresponding reactivity of oxidizing species in living systems.…”