NAD+ kinase explained

NAD+ kinase
Ec Number:2.7.1.23
Cas Number:9032-66-0
Go Code:0003951

NAD+ kinase (EC 2.7.1.23, NADK) is an enzyme that converts nicotinamide adenine dinucleotide (NAD+) into NADP+ through phosphorylating the NAD+ coenzyme.[1] NADP+ is an essential coenzyme that is reduced to NADPH primarily by the pentose phosphate pathway to provide reducing power in biosynthetic processes such as fatty acid biosynthesis and nucleotide synthesis.[2] The structure of the NADK from the archaean Archaeoglobus fulgidus has been determined.

In humans, the genes NADK[3] and MNADK[4] encode NAD+ kinases localized in cytosol[3] and mitochondria,[4] respectively. Similarly, yeast have both cytosolic and mitochondrial isoforms, and the yeast mitochondrial isoform accepts both NAD+ and NADH as substrates for phosphorylation.[5] [6]

Reaction

The reaction catalyzed by NADK is

\rightleftharpoons

ADP + NADP+

Mechanism

NADK phosphorylates NAD+ at the 2’ position of the ribose ring that carries the adenine moiety. It is highly selective for its substrates, NAD and ATP, and does not tolerate modifications either to the phosphoryl acceptor, NAD, or the pyridine moiety of the phosphoryl donor, ATP. NADK also uses metal ions to coordinate the ATP in the active site. In vitro studies with various divalent metal ions have shown that zinc and manganese are preferred over magnesium, while copper and nickel are not accepted by the enzyme at all. A proposed mechanism involves the 2' alcohol oxygen acting as a nucleophile to attack the gamma-phosphoryl of ATP, releasing ADP.

Regulation

NADK is highly regulated by the redox state of the cell. Whereas NAD is predominantly found in its oxidized state NAD+, the phosphorylated NADP is largely present in its reduced form, as NADPH.[7] [8] Thus, NADK can modulate responses to oxidative stress by controlling NADP synthesis. Bacterial NADK is shown to be inhibited allosterically by both NADPH and NADH.[9] NADK is also reportedly stimulated by calcium/calmodulin binding in certain cell types, such as neutrophils.[10] NAD kinases in plants and sea urchin eggs have also been found to bind calmodulin.[11] [12]

Clinical significance

Due to the essential role of NADPH in lipid and DNA biosynthesis and the hyperproliferative nature of most cancers, NADK is an attractive target for cancer therapy. Furthermore, NADPH is required for the antioxidant activities of thioredoxin reductase and glutaredoxin.[13] [14] Thionicotinamide and other nicotinamide analogs are potential inhibitors of NADK,[15] and studies show that treatment of colon cancer cells with thionicotinamide suppresses the cytosolic NADPH pool to increase oxidative stress and synergizes with chemotherapy.[16]

While the role of NADK in increasing the NADPH pool appears to offer protection against apoptosis, there are also cases where NADK activity appears to potentiate cell death. Genetic studies done in human haploid cell lines indicate that knocking out NADK may protect from certain non-apoptotic stimuli.[17]

See also

Further reading

External links

Notes and References

  1. Magni G, Orsomando G, Raffaelli N . Structural and functional properties of NAD kinase, a key enzyme in NADP biosynthesis . Mini Reviews in Medicinal Chemistry . 6 . 7 . 739–46 . Jul 2006 . 16842123 . 10.2174/138955706777698688 .
  2. Pollak N, Dölle C, Ziegler M . The power to reduce: pyridine nucleotides--small molecules with a multitude of functions . The Biochemical Journal . 402 . 2 . 205–18 . Mar 2007 . 17295611 . 1798440 . 10.1042/BJ20061638 .
  3. Lerner F, Niere M, Ludwig A, Ziegler M . Structural and functional characterization of human NAD kinase . Biochemical and Biophysical Research Communications . 288 . 1 . 69–74 . Oct 2001 . 11594753 . 10.1006/bbrc.2001.5735 .
  4. Zhang R . MNADK, a Long-Awaited Human Mitochondrion-Localized NAD Kinase . Journal of Cellular Physiology . 230 . 8 . 1697–701 . Aug 2015 . 25641397 . 10.1002/jcp.24926 . 11539186 .
  5. Iwahashi Y, Hitoshio A, Tajima N, Nakamura T . Characterization of NADH kinase from Saccharomyces cerevisiae . Journal of Biochemistry . 105 . 4 . 588–93 . Apr 1989 . 2547755 . 10.1093/oxfordjournals.jbchem.a122709 .
  6. Iwahashi Y, Nakamura T . Localization of the NADH kinase in the inner membrane of yeast mitochondria . Journal of Biochemistry . 105 . 6 . 916–21 . Jun 1989 . 2549021 . 10.1093/oxfordjournals.jbchem.a122779 .
  7. Burch HB, Bradley ME, Lowry OH . The measurement of triphosphopyridine nucleotide and reduced triphosphopyridine nucleotide and the role of hemoglobin in producing erroneous triphosphopyridine nucleotide values . The Journal of Biological Chemistry . 242 . 19 . 4546–54 . Oct 1967 . 10.1016/S0021-9258(18)99573-6 . 4383634 . free .
  8. Veech RL, Eggleston LV, Krebs HA . The redox state of free nicotinamide-adenine dinucleotide phosphate in the cytoplasm of rat liver . The Biochemical Journal . 115 . 4 . 609–19 . Dec 1969 . 4391039 . 1185185 . 10.1042/bj1150609a.
  9. Grose JH, Joss L, Velick SF, Roth JR . Evidence that feedback inhibition of NAD kinase controls responses to oxidative stress . Proceedings of the National Academy of Sciences of the United States of America . 103 . 20 . 7601–6 . May 2006 . 16682646 . 1472491 . 10.1073/pnas.0602494103 . 2006PNAS..103.7601G . free .
  10. Williams MB, Jones HP . Calmodulin-dependent NAD kinase of human neutrophils . Archives of Biochemistry and Biophysics . 237 . 1 . 80–7 . Feb 1985 . 2982330 . 10.1016/0003-9861(85)90256-5.
  11. Lee SH, Seo HY, Kim JC, Heo WD, Chung WS, Lee KJ, Kim MC, Cheong YH, Choi JY, Lim CO, Cho MJ . Differential activation of NAD kinase by plant calmodulin isoforms. The critical role of domain I . The Journal of Biological Chemistry . 272 . 14 . 9252–9 . Apr 1997 . 9083059 . 10.1074/jbc.272.14.9252 . free .
  12. Epel D, Patton C, Wallace RW, Cheung WY . Calmodulin activates NAD kinase of sea urchin eggs: an early event of fertilization . Cell . 23 . 2 . 543–9 . Feb 1981 . 6258805 . 10.1016/0092-8674(81)90150-1. 44821877 .
  13. Lu J, Holmgren A . The thioredoxin antioxidant system . Free Radical Biology & Medicine . 66 . 75–87 . Jan 2014 . 23899494 . 10.1016/j.freeradbiomed.2013.07.036 .
  14. Estrela JM, Ortega A, Obrador E . Glutathione in cancer biology and therapy . Critical Reviews in Clinical Laboratory Sciences . 43 . 2 . 143–81 . 2006-01-01 . 16517421 . 10.1080/10408360500523878 . 8962293 .
  15. Hsieh YC, Tedeschi P, Adebisi Lawal R, Banerjee D, Scotto K, Kerrigan JE, Lee KC, Johnson-Farley N, Bertino JR, Abali EE . Enhanced degradation of dihydrofolate reductase through inhibition of NAD kinase by nicotinamide analogs . Molecular Pharmacology . 83 . 2 . 339–53 . Feb 2013 . 23197646 . 3558814 . 10.1124/mol.112.080218 .
  16. Tedeschi PM, Lin H, Gounder M, Kerrigan JE, Abali EE, Scotto K, Bertino JR . Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy . Molecular Pharmacology . 88 . 4 . 720–7 . Oct 2015 . 26219913 . 4576680 . 10.1124/mol.114.096727 .
  17. Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, Superti-Furga G, Stockwell BR . Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death . ACS Chemical Biology . 10 . 7 . 1604–9 . Jul 2015 . 25965523 . 4509420 . 10.1021/acschembio.5b00245 .

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