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I came across a question (Q-5b) that asks:

Isocitrate Dehydrogenase in the [human] TCA cycle is associated with NAD+.

Why does it make good metabolic sense that it should use NADP+? Explain and show why this is so using appropriate structures and reactions.

This interesting paper argues the evolution of NADP-dependent IDH in prokaryotes as an adaptation to the need for growth in acetate. In the case of glucose growth, NADH can be obtained from the oxidative branch of the pentose phosphate pathway; in contrast, for acetate growth, PPP cannot run efficiently and IDH provides the predominant share of NADH. However, this ought to be a really irrelevant reason concerning IDH enzyme in humans since we do not have enzymes like isocitrate lyase etc. to entertain acetate growth!

Standard textbooks in biochemistry (Voet&Voet, Lehninger, et al) do not offer anything relevant except a generic note that NAD+ and NADP+ are respectively favored for oxidative and reductive metabolism. I am unsure about reasoning using this bit of trivia since TCA is an oxidative pathway! Fwiw, a question had been asked in Biology StackE about NADH vs NADPH where the accepted answer restates this.

To conclude, what is the metabolic advantage? Does there exist a way to arrive at the advantage using the fundamentals of biochemistry?

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    $\begingroup$ I find the question most ambiguous. The context is presumably human, given the preamble in the exam paper. The first sentence says that ICDH "is associated with" (presumably he means "is specific for") NAD+. The second sentence talks about it making metabolic sense to use NADP+. But it doesn't — only in the cytoplasmic form mutated in tumours, which is not involved in the TCA cycle. I can give an answer to a question on the use of NAD v. NADP in mitochondrion and cytoplasm, but I can't answer a question that appears self-contradictory. How do you understand it? Seems like a typo to me. $\endgroup$
    – David
    Nov 26, 2022 at 13:07
  • $\begingroup$ Mitochondria also contain an NADP-specific isocitrate dehydrogenase which probably plays no role in the TCA cycle (but not everyone agrees!). See here, for example, one of several seminal papers on this enzyme from the Roberta F Colman group $\endgroup$
    – user338907
    Nov 28, 2022 at 18:38
  • $\begingroup$ And, of course, there is also a cytoplasmic NADP-linked isocitrate dehydrogenase. See here, for example $\endgroup$
    – user338907
    Nov 28, 2022 at 20:02
  • $\begingroup$ For an interesting take on why there are two pyridine nucleotide cofactors (ie NAD and NADP), see Why NADP? by BT Kaufman, who postulates that " blocking the 2'-position of NAD with a phosphate group, thus yielding NADP, shields a potential pool of pyridine nucleotide cofactor from the drastic effects of ribosylation reactions" $\endgroup$
    – user338907
    Nov 28, 2022 at 22:01

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