Which enzyme in the citric acid (tricarboxylic acid, TCA) cycle is least likely to be affected by a lack of dependence on Nicotinamide adenine dinucleotide (NAD+)?

From the Research

The enzyme in the TCA cycle least likely affected by a lack of NAD+ is succinate dehydrogenase, as it uniquely uses FAD as its electron acceptor rather than NAD+ 1. This enzyme catalyzes the oxidation of succinate to fumarate in the TCA cycle and transfers electrons directly to the electron transport chain through FAD and iron-sulfur clusters.

Key Characteristics of Succinate Dehydrogenase

• Uses FAD as electron acceptor
• Transfers electrons directly to the electron transport chain
• Participates in both the TCA cycle and the electron transport chain (as Complex II) While most other TCA cycle enzymes like isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase depend on NAD+ as their electron acceptor, succinate dehydrogenase's independence from NAD+ means that even when NAD+ levels are depleted, it can continue to function, allowing at least this step of the TCA cycle to proceed 2.

Comparison with Other Enzymes

• Isocitrate dehydrogenase: depends on NAD+
• α-ketoglutarate dehydrogenase: depends on NAD+
• Malate dehydrogenase: depends on NAD+
• Succinyl-CoA synthetase: catalyzes substrate-level phosphorylation, but its activity is not directly dependent on NAD+ 3, 4. However, succinate dehydrogenase is the most direct example of an enzyme that does not rely on NAD+, making it the least likely to be affected by a lack of NAD+.