NAD+ kinase

NAD+ kinase

Ribbon diagram of NAD+ kinase in complex with substrates.[1]
Identifiers
EC number 2.7.1.23
CAS number 9032-66-0
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
NAD kinase
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols NADK ; dJ283E3.1
External IDs OMIM: 611616 MGI: 2183149 HomoloGene: 49724 ChEMBL: 6177 GeneCards: NADK Gene
EC number 2.7.1.23
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 65220 192185
Ensembl ENSG00000008130 ENSMUSG00000029063
UniProt O95544 P58058
RefSeq (mRNA) NM_001198993 NM_001159637
RefSeq (protein) NP_001185922 NP_001153109
Location (UCSC) Chr 1:
1.75 – 1.78 Mb		 Chr 4:
155.56 – 155.59 Mb
PubMed search

NAD+ kinase (EC 2.7.1.23, NADK) is an enzyme that converts nicotinamide adenine dinucleotide (NAD+) into NADP+ through phosphorylating the NAD+ coenzyme.[2] 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.[3] The structure of the NADK from the archaean Archaeoglobus fulgidus has been determined.[1]

In humans, the genes NADK[4] and MNADK[5] encode NAD+ kinases localized in cytosol[4] and mitochondria,[5] respectively. Similarly, yeast have both cytosolic and mitochondrial isoforms, and the yeast mitochondrial isoform accepts both NAD+ and NADH as substrates for phosphorylation.[6][7]

Reaction

ATP + NAD+ \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.[4] NADK also uses magnesium to coordinate the ATP in the active site. However, in vitro studies with other 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.[4] A proposed mechanism involves the 2' alcohol oxygen acting as a nucleophile to attack the gamma-phosphoryl of ATP, releasing ADP.

Proposed mechanism of action for NAD+ phosphorylation by NADK

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.[8][9] 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.[10] NADK is also reportedly stimulated by calcium/calmodulin binding in certain cell types, such as neutrophils.[11] NAD kinases in plants and sea urchin eggs have also been found to bind calmodulin.[12][13]

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.[14][15] Thionicotinamide and other nicotinamide analogs are potential inhibitors of NADK,[16] and studies show that treatment of colon cancer cells with thionicotinamide suppresses the cytosolic NADPH pool to increase oxidative stress and synergizes with chemotherapy.[17]

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.[18]

See also

References

  1. 1 2 PDB: 1SUW​; Liu J, Lou Y, Yokota H, Adams PD, Kim R, Kim SH (Nov 2005). "Crystal structures of an NAD kinase from Archaeoglobus fulgidus in complex with ATP, NAD, or NADP". Journal of Molecular Biology 354 (2): 289–303. doi:10.1016/j.jmb.2005.09.026. PMID 16242716.
  2. ↑ Magni G, Orsomando G, Raffaelli N (Jul 2006). "Structural and functional properties of NAD kinase, a key enzyme in NADP biosynthesis". Mini Reviews in Medicinal Chemistry 6 (7): 739–46. doi:10.2174/138955706777698688. PMID 16842123.
  3. ↑ Pollak N, Dölle C, Ziegler M (Mar 2007). "The power to reduce: pyridine nucleotides--small molecules with a multitude of functions". The Biochemical Journal 402 (2): 205–18. doi:10.1042/BJ20061638. PMC 1798440. PMID 17295611.
  4. 1 2 3 4 Lerner F, Niere M, Ludwig A, Ziegler M (Oct 2001). "Structural and functional characterization of human NAD kinase". Biochemical and Biophysical Research Communications 288 (1): 69–74. doi:10.1006/bbrc.2001.5735. PMID 11594753.
  5. 1 2 Zhang R (Aug 2015). "MNADK, a Long-Awaited Human Mitochondrion-Localized NAD Kinase". Journal of Cellular Physiology 230 (8): 1697–701. doi:10.1002/jcp.24926. PMID 25641397.
  6. ↑ Iwahashi Y, Hitoshio A, Tajima N, Nakamura T (Apr 1989). "Characterization of NADH kinase from Saccharomyces cerevisiae". Journal of Biochemistry 105 (4): 588–93. PMID 2547755.
  7. ↑ Iwahashi Y, Nakamura T (Jun 1989). "Localization of the NADH kinase in the inner membrane of yeast mitochondria". Journal of Biochemistry 105 (6): 916–21. PMID 2549021.
  8. ↑ Burch HB, Bradley ME, Lowry OH (Oct 1967). "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. PMID 4383634.
  9. ↑ Veech RL, Eggleston LV, Krebs HA (Dec 1969). "The redox state of free nicotinamide-adenine dinucleotide phosphate in the cytoplasm of rat liver". The Biochemical Journal 115 (4): 609–19. PMC 1185185. PMID 4391039.
  10. ↑ Grose JH, Joss L, Velick SF, Roth JR (May 2006). "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. doi:10.1073/pnas.0602494103. PMC 1472491. PMID 16682646.
  11. ↑ Williams MB, Jones HP (Feb 1985). "Calmodulin-dependent NAD kinase of human neutrophils". Archives of Biochemistry and Biophysics 237 (1): 80–7. PMID 2982330.
  12. ↑ Lee SH, Seo HY, Kim JC, Heo WD, Chung WS, Lee KJ, Kim MC, Cheong YH, Choi JY, Lim CO, Cho MJ (Apr 1997). "Differential activation of NAD kinase by plant calmodulin isoforms. The critical role of domain I". The Journal of Biological Chemistry 272 (14): 9252–9. PMID 9083059.
  13. ↑ Epel D, Patton C, Wallace RW, Cheung WY (Feb 1981). "Calmodulin activates NAD kinase of sea urchin eggs: an early event of fertilization". Cell 23 (2): 543–9. PMID 6258805.
  14. ↑ Lu J, Holmgren A (Jan 2014). "The thioredoxin antioxidant system". Free Radical Biology & Medicine 66: 75–87. doi:10.1016/j.freeradbiomed.2013.07.036. PMID 23899494.
  15. ↑ Estrela JM, Ortega A, Obrador E (2006-01-01). "Glutathione in cancer biology and therapy". Critical Reviews in Clinical Laboratory Sciences 43 (2): 143–81. doi:10.1080/10408360500523878. PMID 16517421.
  16. ↑ Hsieh YC, Tedeschi P, Adebisi Lawal R, Banerjee D, Scotto K, Kerrigan JE, Lee KC, Johnson-Farley N, Bertino JR, Abali EE (Feb 2013). "Enhanced degradation of dihydrofolate reductase through inhibition of NAD kinase by nicotinamide analogs". Molecular Pharmacology 83 (2): 339–53. doi:10.1124/mol.112.080218. PMC 3558814. PMID 23197646.
  17. ↑ Tedeschi PM, Lin H, Gounder M, Kerrigan JE, Abali EE, Scotto K, Bertino JR (Oct 2015). "Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy". Molecular Pharmacology 88 (4): 720–7. doi:10.1124/mol.114.096727. PMC 4576680. PMID 26219913.
  18. ↑ Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, Superti-Furga G, Stockwell BR (Jul 2015). "Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death". ACS Chemical Biology 10 (7): 1604–9. doi:10.1021/acschembio.5b00245. PMC 4509420. PMID 25965523.

Further reading

  • Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (Apr 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474. 
  • Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA (Apr 1997). "Large-scale concatenation cDNA sequencing". Genome Research 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174. 
  • Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE (Sep 2005). "A human protein-protein interaction network: a resource for annotating the proteome". Cell 122 (6): 957–68. doi:10.1016/j.cell.2005.08.029. PMID 16169070. 
  • Pollak N, Niere M, Ziegler M (Nov 2007). "NAD kinase levels control the NADPH concentration in human cells". The Journal of Biological Chemistry 282 (46): 33562–71. doi:10.1074/jbc.M704442200. PMID 17855339. 

External links


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