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Insights into the inhibitory mechanisms of NADH on the αγ heterodimer of human NAD-dependent isocitrate dehydrogenase.

Liu Y, Hu L, Ma T, Yang J, Ding J
Sci Rep 8 3146 (2018)
Cited: 14 times
EuropePMC logo PMID: 29453450

Abstract

Human NAD-dependent isocitrate dehydrogenase (NAD-IDH) catalyzes the oxidative decarboxylation of isocitrate in the citric acid cycle. In the α2βγ heterotetramer of NAD-IDH, the γ subunit plays the regulatory role and the β subunit the structural role. Previous biochemical data have shown that mammalian NAD-IDHs can be inhibited by NADH; however, the molecular mechanism is unclear. In this work, we show that the αβ, αγ and α2βγ enzymes of human NAD-IDH can be inhibited by NADH, and further determine the crystal structure of the αγ heterodimer bound with an Mg2+ and an NADH at the active site and an NADH at the allosteric site, which resembles that of the inactive αMgγ heterodimer. The NADH at the active site occupies the binding site for NAD+ and prevents the binding of the cofactor. The NADH at the allosteric site occupies the binding sites for ADP and citrate and blocks the binding of the activators. The biochemical data confirm that the NADH binding competes with the binding of NAD+ and the binding of citrate and ADP, and the two effects together contribute to the NADH inhibition on the activity. These findings provide insights into the inhibitory mechanisms of the αγ heterodimer by NADH.

Articles - 5yvt mentioned but not cited (2)

  1. Insights into the inhibitory mechanisms of NADH on the αγ heterodimer of human NAD-dependent isocitrate dehydrogenase. Liu Y, Hu L, Ma T, Yang J, Ding J. Sci Rep 8 3146 (2018)
  2. CoRNeA: A Pipeline to Decrypt the Inter-Protein Interfaces from Amino Acid Sequence Information. Chopra K, Burdak B, Sharma K, Kembhavi A, Mande SC, Chauhan R. Biomolecules 10 E938 (2020)


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  3. Over-Reduced State of Mitochondria as a Trigger of "β-Oxidation Shuttle" in Cancer Cells. Zhelev Z, Sumiyoshi A, Aoki I, Lazarova D, Vlaykova T, Higashi T, Bakalova R. Cancers (Basel) 14 871 (2022)

Articles citing this publication (9)

  1. Structure and allosteric regulation of human NAD-dependent isocitrate dehydrogenase. Sun P, Liu Y, Ma T, Ding J. Cell Discov 6 94 (2020)
  2. Chemical Proteomics Approach for Profiling the NAD Interactome. Šileikytė J, Sundalam S, David LL, Cohen MS. J Am Chem Soc 143 6787-6791 (2021)
  3. Methylene Blue Administration During and After Life-Threatening Intoxication by Hydrogen Sulfide: Efficacy Studies in Adult Sheep and Mechanisms of Action. Haouzi P, Tubbs N, Cheung J, Judenherc-Haouzi A. Toxicol Sci 168 443-459 (2019)
  4. Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics. Stokes J, Freed A, Bornstein R, Su KN, Snell J, Pan A, Sun GX, Park KY, Jung S, Worstman H, Johnson BM, Morgan PG, Sedensky MM, Johnson SC. Elife 10 e65400 (2021)
  5. Molecular basis for the function of the αβ heterodimer of human NAD-dependent isocitrate dehydrogenase. Sun P, Ma T, Zhang T, Zhu H, Zhang J, Liu Y, Ding J. J Biol Chem 294 16214-16227 (2019)
  6. Antidotal Effects of the Phenothiazine Chromophore Methylene Blue Following Cyanide Intoxication. Haouzi P, McCann M, Tubbs N, Judenherc-Haouzi A, Cheung J, Bouillaud F. Toxicol Sci 170 82-94 (2019)
  7. Antidotal effects of methylene blue against cyanide neurological toxicity: in vivo and in vitro studies. Haouzi P, McCann M, Wang J, Zhang XQ, Song J, Sariyer I, Langford D, Santerre M, Tubbs N, Haouzi-Judenherc A, Cheung JY. Ann N Y Acad Sci 1479 108-121 (2020)
  8. Structures of a constitutively active mutant of human IDH3 reveal new insights into the mechanisms of allosteric activation and the catalytic reaction. Chen X, Sun P, Liu Y, Shen S, Ma T, Ding J. J Biol Chem 298 102695 (2022)
  9. Two Different Isocitrate Dehydrogenases from Pseudomonas aeruginosa: Enzymology and Coenzyme-Evolutionary Implications. Chen X, Wei W, Xiong W, Wu S, Wu Q, Wang P, Zhu G. Int J Mol Sci 24 14985 (2023)


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