Redox Coenzymes: NAD+ and FAD

NAD+ and FAD are the workhorse electron carriers of cellular metabolism. As dissociable or bound coenzymes of oxidoreductases, they accept and donate electrons (and, for NAD+, hydride), linking the oxidation of fuels to the reactions of respiration and biosynthesis. Their reduced forms, NADH and FADH2, feed electrons into the respiratory chain.

Definition

NAD+ (nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide) are redox coenzymes that cycle between oxidised and reduced states to carry electrons in enzyme-catalysed oxidation-reduction reactions; the phosphorylated form NADP+ serves analogous chemistry dedicated largely to reductive biosynthesis.

Scope

The topic covers the structure and redox chemistry of the pyridine nucleotide coenzymes NAD+/NADH and NADP+/NADPH and of the flavin coenzymes FAD/FADH2 (and FMN), their roles in catabolic and anabolic pathways, and the distinction between NAD+'s role in catabolism and NADPH's role in biosynthesis. It treats these as redox coenzymes within enzymology, not as clinical guidance.

Core questions

• How do NAD+ and FAD differ in the chemistry of electron transfer they perform?
• Why does the cell maintain separate NAD+ and NADP+ pools?
• How are reduced coenzymes reoxidised, and how does this couple to ATP synthesis?
• How is NAD+ synthesised and turned over beyond its redox role?

Key concepts

• Hydride transfer by NAD+/NADH
• One- and two-electron transfer by flavins
• NADP+/NADPH dedicated to reductive biosynthesis
• Reduced coenzymes feeding the respiratory chain
• Flavins as tightly bound prosthetic groups
• NAD+ as a substrate for sirtuins and other consuming enzymes
• NAD+ biosynthesis and salvage

Mechanisms

NAD+ accepts a hydride ion (two electrons and one proton) at the C4 position of its nicotinamide ring to become NADH, a clean two-electron carrier suited to dehydrogenase reactions (Nelson & Cox, 2021). Flavin coenzymes (FAD and FMN) can accept one or two electrons, allowing them to mediate between two-electron donors and one-electron acceptors and to handle oxygen chemistry; they are usually held as tightly bound prosthetic groups in flavoproteins (Macheroux et al., 2011). In catabolism, NADH and FADH2 carry electrons to the respiratory chain, where complex I oxidises NADH and passes electrons toward ubiquinone, coupling oxidation to proton pumping (Brandt, 2006). NADPH, generated for example by the pentose phosphate pathway, supplies reducing power for biosynthesis and antioxidant defence. Beyond redox, NAD+ is consumed as a substrate by enzymes such as sirtuins and is continuously resynthesised through de novo and salvage routes (Verdin, 2015; Cantó et al., 2015; Belenky et al., 2007).

Clinical relevance

NAD+ metabolism intersects with energy homeostasis, ageing biology, and the function of NAD+-consuming signalling enzymes, which is why it is studied intensively in metabolism research (Verdin, 2015; Cantó et al., 2015). This entry explains the coenzymes' biochemistry; it describes mechanisms and is not a basis for individual diagnosis, supplementation, or treatment decisions.

History

The pyridine and flavin nucleotide coenzymes were identified through early-twentieth-century studies of fermentation and 'yellow enzymes', linking them to the vitamins niacin and riboflavin. Later structural and mechanistic work clarified hydride transfer by NAD+, the versatile one- and two-electron chemistry of flavins, and the role of these carriers in the respiratory chain, while modern work re-examined NAD+ as both a redox coenzyme and a consumed signalling metabolite (Brandt, 2006; Macheroux et al., 2011; Verdin, 2015).

Seminal works

• verdin-2015
• canto-2015
• brandt-2006
• macheroux-2011

Frequently asked questions

What is the difference between NAD+ and NADP+?

They differ by a single phosphate group, but the cell keeps them as separate pools with different jobs: NAD+/NADH mainly drives catabolic, energy-yielding oxidations, while NADP+/NADPH supplies reducing power for biosynthesis and antioxidant defence.

Why can flavins do chemistry that NAD+ cannot?

Flavins can accept and donate one electron at a time as well as two, so they can bridge two-electron donors with one-electron acceptors and participate in oxygen and radical chemistry, which the strictly two-electron NAD+/NADH pair cannot.