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MetaCyc Enzyme: nucleoside diphosphate kinase

Species: Homo sapiens

Subunit composition of nucleoside diphosphate kinase = [NME1]3[NME2]3
         nucleoside diphosphate kinase A = NME1 (summary available)
         nucleoside diphosphate kinase B = NME2 (summary available)

Summary:
The eukaryotic nucleoside diphosphate kinase is a hexamer composed of any combination of nucleoside diphosphate kinase A and nucleoside diphosphate kinase B subunits (most prokaryotes have a tetrameric enzyme). The subunits are encoded by the NME1 and NME2 genes, respectively, both of which are located on chromosome 17 [Stahl91, Kelsell93, Chandrasekharap93, Dooley94]. The enzyme is expressed ubiquitously [Okamoto02].

The enzyme is multifunctional, and catalyzes the following biochemical reactions [Postel02]:

(1) Phosphotransferring activity from mainly ATP to cognate NDPs generating nucleoside triphosphates (NTPs).

(2) Autophosphorylation activity from ATP and GTP.

(3) Protein kinase (phosphotransferring) activity phosphorylating proteins such as myelin basic protein.

Both subunits have been cloned, expressed in Escherichia coli, and purified to homogeneity [Schaertl98]. nucleoside diphosphate kinase A has been crystallized [Min02].

While NDP kinase can function to provide NTPs as a housekeeping enzyme, it also has some other functions. NDK-A and -B were shown to be identical to the tumor suppressor proteins nm23-H1 and nm23-H2, respectively. The proteins have been demonstrated to be powerful metastasis suppressors [Rosengard89, Wang93f, Freije98, Zhang99b, Tomita01, Ouatas02]. In addition, the proteins may play a role in signal transduction [Hasunuma03, Narayanan03].

The enzyme has been found as a key molecule in breast tumor angiogenesis [Youn08]. Mutations in the genes were linked to several types of tumors [Leone91, Godfried02, Ji02, Galani02, Roymans02, Wu02b].

Locations: cytosol, nuclear lumen

Gene-Reaction Schematic: ?

Instance reactions of [a nucleoside diphosphate + ATP → a nucleoside triphosphate + ADP] (2.7.4.6):
i1: dCDP + ATP → dCTP + ADP (2.7.4.6)

i2: dUDP + ATP → dUTP + ADP (2.7.4.6)

i3: dTDP + ATP → dTTP + ADP (2.7.4.6)

i4: ATP + dIDP = ADP + dITP (2.7.4.6)

i5: dADP + ATP → dATP + ADP (2.7.4.6)

i6: UDP + ATP → UTP + ADP (2.7.4.6)

i7: CDP + ATP → CTP + ADP (2.7.4.6)

i8: dGDP + ATP → dGTP + ADP (2.7.4.6)

i9: GDP + ATP → GTP + ADP (2.7.4.6)

i10: ATP + IDP = ITP + ADP (2.7.4.6)

GO Terms:

Cellular Component: GO:0005829 - cytosol
GO:0031981 - nuclear lumen

Credits:
Created 06-Jan-2009 by Caspi R , SRI International


Enzymatic reaction of: nucleoside diphosphate kinase

EC Number: 2.7.4.6

a nucleoside diphosphate + ATP <=> a nucleoside triphosphate + ADP

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: guanosine ribonucleotides de novo biosynthesis , superpathway of guanosine nucleotides de novo biosynthesis I , guanosine deoxyribonucleotides de novo biosynthesis I , CMP phosphorylation , superpathway of pyrimidine ribonucleotides de novo biosynthesis , UTP and CTP de novo biosynthesis , superpathway of purine nucleotide salvage , superpathway of adenosine nucleotides de novo biosynthesis I , superpathway of purine nucleotides de novo biosynthesis I , purine deoxyribonucleosides salvage , adenosine deoxyribonucleotides de novo biosynthesis , superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis , superpathway of pyrimidine deoxyribonucleoside salvage , pyrimidine deoxyribonucleotides de novo biosynthesis I , pyrimidine deoxyribonucleotide phosphorylation , pyrimidine deoxyribonucleotides biosynthesis from CTP


Enzymatic reaction of: UDP kinase (nucleoside diphosphate kinase)

EC Number: 2.7.4.6

UDP + ATP <=> UTP + ADP

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis , superpathway of pyrimidine ribonucleotides de novo biosynthesis , UTP and CTP de novo biosynthesis


Enzymatic reaction of: GDP kinase (nucleoside diphosphate kinase)

EC Number: 2.7.4.6

GDP + ATP <=> GTP + ADP

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: superpathway of guanosine nucleotides de novo biosynthesis I , superpathway of purine nucleotides de novo biosynthesis I , superpathway of purine nucleotide salvage , guanosine ribonucleotides de novo biosynthesis


Enzymatic reaction of: dTDP kinase (nucleoside diphosphate kinase)

EC Number: 2.7.4.6

dTDP + ATP <=> dTTP + ADP

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis , superpathway of pyrimidine deoxyribonucleoside salvage , pyrimidine deoxyribonucleotides de novo biosynthesis I , pyrimidine deoxyribonucleotide phosphorylation , pyrimidine deoxyribonucleotides biosynthesis from CTP


Enzymatic reaction of: dUDP kinase (nucleoside diphosphate kinase)

EC Number: 2.7.4.6

dUDP + ATP <=> dUTP + ADP

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis , pyrimidine deoxyribonucleotides de novo biosynthesis I


Enzymatic reaction of: CDP kinase (nucleoside diphosphate kinase)

EC Number: 2.7.4.6

CDP + ATP <=> CTP + ADP

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: CMP phosphorylation


Enzymatic reaction of: dGDP kinase (nucleoside diphosphate kinase)

EC Number: 2.7.4.6

dGDP + ATP <=> dGTP + ADP

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: superpathway of guanosine nucleotides de novo biosynthesis I , superpathway of purine nucleotides de novo biosynthesis I , purine deoxyribonucleosides salvage , guanosine deoxyribonucleotides de novo biosynthesis I


Enzymatic reaction of: dADP kinase (nucleoside diphosphate kinase)

EC Number: 2.7.4.6

dADP + ATP <=> dATP + ADP

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: superpathway of purine nucleotide salvage , superpathway of adenosine nucleotides de novo biosynthesis I , superpathway of purine nucleotides de novo biosynthesis I , purine deoxyribonucleosides salvage , adenosine deoxyribonucleotides de novo biosynthesis


Enzymatic reaction of: dCDP kinase (nucleoside diphosphate kinase)

EC Number: 2.7.4.6

dCDP + ATP <=> dCTP + ADP

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis , superpathway of pyrimidine deoxyribonucleoside salvage , pyrimidine deoxyribonucleotides de novo biosynthesis I , pyrimidine deoxyribonucleotide phosphorylation , pyrimidine deoxyribonucleotides biosynthesis from CTP


Subunit of nucleoside diphosphate kinase: nucleoside diphosphate kinase A

Synonyms: NDK A, NDP kinase A, tumor metastatic process-associated protein, metastasis inhibition factor nm23, NM23-H1, non-metastatic cells 1 protein

Gene: NME1 Accession Number: HS00300 (MetaCyc)

Molecular Weight: 17.149 kD (from nucleotide sequence)

Unification Links: DIP:DIP-39164N , Mint:MINT-221462 , PhosphoSite:P15531 , Pride:P15531 , Protein Model Portal:P15531 , SMR:P15531 , String:9606.ENSP00000013034 , UniProt:P15531

Relationship Links: InterPro:IN-FAMILY:IPR001564 , InterPro:IN-FAMILY:IPR023005 , Panther:IN-FAMILY:PTHR11349 , PDB:Structure:1JXV , PDB:Structure:1UCN , PDB:Structure:2HVD , PDB:Structure:2HVE , PDB:Structure:3L7U , PDB:Structure:4ENO , Pfam:IN-FAMILY:PF00334 , Prints:IN-FAMILY:PR01243 , Prosite:IN-FAMILY:PS00469 , Smart:IN-FAMILY:SM00562

Summary:
Three isoforms of this protein, formed by alternative splicing, are known.

Mutations in NME1 have been identified in aggressive neuroblastomas.


Subunit of nucleoside diphosphate kinase: nucleoside diphosphate kinase B

Synonyms: NDK B, NM23-H2

Gene: NME2 Accession Number: HS04463 (MetaCyc)

Molecular Weight: 17.298 kD (from nucleotide sequence)

Unification Links: Mint:MINT-1429922 , PhosphoSite:P22392 , PhylomeDB:P22392 , Pride:P22392 , Protein Model Portal:P22392 , SMR:P22392 , String:9606.ENSP00000376886 , UniProt:P22392

Relationship Links: InterPro:IN-FAMILY:IPR001564 , InterPro:IN-FAMILY:IPR023005 , Panther:IN-FAMILY:PTHR11349 , PDB:Structure:1NSK , PDB:Structure:1NUE , PDB:Structure:3BBB , PDB:Structure:3BBC , PDB:Structure:3BBF , Pfam:IN-FAMILY:PF00334 , Prints:IN-FAMILY:PR01243 , Prosite:IN-FAMILY:PS00469 , Smart:IN-FAMILY:SM00562

Summary:
Three isoforms of this protein, formed by alternative splicing, are known.


References

Chandrasekharap93: Chandrasekharappa SC, Gross LA, King SE, Collins FS (1993). "The human NME2 gene lies within 18kb of NME1 in chromosome 17." Genes Chromosomes Cancer 6(4);245-8. PMID: 7685630

Dooley94: Dooley S, Seib T, Engel M, Theisinger B, Janz H, Piontek K, Zang KD, Welter C (1994). "Isolation and characterization of the human genomic locus coding for the putative metastasis control gene nm23-H1." Hum Genet 93(1);63-6. PMID: 8270257

Freije98: Freije JM, MacDonald NJ, Steeg PS (1998). "Nm23 and tumour metastasis: basic and translational advances." Biochem Soc Symp 63;261-71. PMID: 9513729

Galani02: Galani E, Sgouros J, Petropoulou C, Janinis J, Aravantinos G, Dionysiou-Asteriou D, Skarlos D, Gonos E (2002). "Correlation of MDR-1, nm23-H1 and H Sema E gene expression with histopathological findings and clinical outcome in ovarian and breast cancer patients." Anticancer Res 22(4);2275-80. PMID: 12174914

Godfried02: Godfried MB, Veenstra M, v Sluis P, Boon K, v Asperen R, Hermus MC, v Schaik BD, Voute TP, Schwab M, Versteeg R, Caron HN (2002). "The N-myc and c-myc downstream pathways include the chromosome 17q genes nm23-H1 and nm23-H2." Oncogene 21(13);2097-101. PMID: 11960382

Hasunuma03: Hasunuma K, Yabe N, Yoshida Y, Ogura Y, Hamada T (2003). "Putative functions of nucleoside diphosphate kinase in plants and fungi." J Bioenerg Biomembr 35(1);57-65. PMID: 12848342

Ji02: Ji SQ, Hua YW, Zhuang J, Gao Y, Kong Y, Han SL, Shao YF (2002). "[Significance of COX-2, p53, proliferating cell nuclear antigen and nm23 expressions in gastric cancer and its behavior]." Ai Zheng 21(6);619-24. PMID: 12452062

Kelsell93: Kelsell DP, Black DM, Solomon E, Spurr NK (1993). "Localization of a second NM23 gene, NME2, to chromosome 17q21-q22." Genomics 17(2);522-4. PMID: 8406509

Leone91: Leone A, McBride OW, Weston A, Wang MG, Anglard P, Cropp CS, Goepel JR, Lidereau R, Callahan R, Linehan WM (1991). "Somatic allelic deletion of nm23 in human cancer." Cancer Res 51(9);2490-3. PMID: 2015608

Min02: Min K, Song HK, Chang C, Kim SY, Lee KJ, Suh SW (2002). "Crystal structure of human nucleoside diphosphate kinase A, a metastasis suppressor." Proteins 46(3);340-2. PMID: 11835509

Narayanan03: Narayanan R, Ramaswami M (2003). "Regulation of dynamin by nucleoside diphosphate kinase." J Bioenerg Biomembr 35(1);49-55. PMID: 12848341

Okamoto02: Okamoto T, Iwase K, Niu R (2002). "Expression and localization of nm23-H1 in the human placenta." Arch Gynecol Obstet 266(1);1-4. PMID: 11998956

Ouatas02: Ouatas T, Clare SE, Hartsough MT, De La Rosa A, Steeg PS (2002). "MMTV-associated transcription factor binding sites increase nm23-H1 metastasis suppressor gene expression in human breast carcinoma cell lines." Clin Exp Metastasis 19(1);35-42. PMID: 11918081

Postel02: Postel EH, Abramczyk BA, Gursky SK, Xu Y (2002). "Structure-based mutational and functional analysis identify human NM23-H2 as a multifunctional enzyme." Biochemistry 41(20);6330-7. PMID: 12009894

Postel98: Postel EH (1998). "NM23-NDP kinase." Int J Biochem Cell Biol 30(12);1291-5. PMID: 9924799

Rosengard89: Rosengard AM, Krutzsch HC, Shearn A, Biggs JR, Barker E, Margulies IM, King CR, Liotta LA, Steeg PS (1989). "Reduced Nm23/Awd protein in tumour metastasis and aberrant Drosophila development." Nature 342(6246);177-80. PMID: 2509941

Roymans02: Roymans D, Willems R, Van Blockstaele DR, Slegers H (2002). "Nucleoside diphosphate kinase (NDPK/NM23) and the waltz with multiple partners: possible consequences in tumor metastasis." Clin Exp Metastasis 19(6);465-76. PMID: 12405283

Schaertl98: Schaertl S, Konrad M, Geeves MA (1998). "Substrate specificity of human nucleoside-diphosphate kinase revealed by transient kinetic analysis." J Biol Chem 273(10);5662-9. PMID: 9488696

Stahl91: Stahl JA, Leone A, Rosengard AM, Porter L, King CR, Steeg PS (1991). "Identification of a second human nm23 gene, nm23-H2." Cancer Res 51(1);445-9. PMID: 1988104

Tomita01: Tomita M, Ayabe T, Matsuzaki Y, Edagawa M, Maeda M, Shimizu T, Hara M, Onitsuka T (2001). "Expression of nm23-H1 gene product in esophageal squamous cell carcinoma and its association with vessel invasion and survival." BMC Cancer 1;3. PMID: 11319942

Wang93f: Wang L, Patel U, Ghosh L, Chen HC, Banerjee S (1993). "Mutation in the nm23 gene is associated with metastasis in colorectal cancer." Cancer Res 53(4);717-20. PMID: 7916650

Wu02b: Wu S, Zhao C (2002). "[Expression of NM23-H(1) mRNA in acute leukemia]." Zhonghua Nei Ke Za Zhi 41(6);367-9. PMID: 12137595

Youn08: Youn B, Kim HD, Kim J (2008). "Nm23-H1/nucleoside diphosphate kinase as a key molecule in breast tumor angiogenesis." Expert Opin Ther Targets 12(11);1419-30. PMID: 18851697

Zhang99b: Zhang T, Lai Q, Du D (1999). "[Expression of metastasis suppressor gene nm23-H1 in oral squamous cell carcinoma and its relation to tumor prognosis]." Zhonghua Kou Qiang Yi Xue Za Zhi 34(5);292-4. PMID: 11776896


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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Fri Nov 28, 2014, BIOCYC13B.