Nucleoside-diphosphate kinase
Nucleoside-diphosphate kinase | |||||||||
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ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
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Nucleoside-diphosphate kinases (NDPKs, also NDP kinase, (poly)nucleotide kinases and nucleoside diphosphokinases) are
Structure
NDPK are homohexameric proteins made up of monomers approximately 152 amino acids long with a theoretical weight of 17.17KDa.
Function
NDPK are found in all cells, displaying not much specificity towards the types of
Behind this apparently simple reaction is a multistep mechanism. The key steps of transphosphorylation are as follows:
- NDPK binds to a NTP1
- A phosphoryl group from NTP1 is transferred to His in active site of NDPK
- Phosphoenzyme intermediate is formed
- Initially bound NDP1 is released from NDPK bringing in new NDP2
- Phosphoryl group is transferred from NDPK-His to NDP2 or dNDP2, creating a bound NTP2
- NDPK releases the new NTP2
Each step is part of a reversible process, such that the multistep equilibrium is of the following form.
- NDPK + NTP ↔ NDPK~NTP ↔ NDPK-P~NDP ↔ NDPK-P + NDP
NDPK's roles in these NTPs differ; generally, kinases bring in NTPs for nucleic acid synthesis. CTP is provided for
Regulation
Inhibition by AMPK
NDPK usually consumes ATP, the most abundant cellular nucleotide, and stores the nucleotides. However, consumption of ATP would definitely influence the cellular energy balance, which brings upon the regulation of AMP-activated protein kinase (AMPK).[8] AMPK acts as the energy sensor and regulates ATP pathways by turning the generating pathways or not. Because of such activity, AMPK could directly inhibit NDPK through phosphorylation. To be more specific, NDPK supports the production of nucleotides in high-energy and low-stress cellular states. However, this can only happen when AMPK is inactivated because low-stress cellular states of ATP triggers the activation of AMPK, which eventually decreases NDPK activity by phosphorylating serine residues.
Prokaryotic systems
In most prokaryotes, the NDPK enzyme is
(p)ppGpp metabolism
In the (p)ppGpp biosynthesis cycle, NDPK serves an important role. When there is an absence of a charged tRNA in the A site of a ribosome, the ribosome will stall and trigger the synthesis of the guanosine pentaphosphate ((p)ppGpp) molecule. (p)ppGpp biosynthesis is a part of the purine metabolism pathway and coordinates a series of cellular activities in response to nutritional abundances.[11] Synthesis of (p)ppGpp is triggered by carbon starvation, or the lack of carbon in the cell's environment, and causes the protein SpoT to activate. SpoT works in conjunction with NDPK and both serve as essential enzymes in the (p)ppGpp biosynthesis cycle. NDPK synthesizes the formation of GDP from GTP via dephosphorylation.[12]
Nm23 gene function
While the biomolecular mechanism by which the Nm23 gene works in cells is currently unknown, like in most prokaryotes, nucleoside diphosphate kinase (NDPK) expression levels determine cell growth and differentiation.
Eukaryotic systems
There are at least four enzymatically active isoforms of NDPK in humans: NDPK-A, NDPK-B, NDPK-C and NDPK-D. All four isoforms have very similar structures and can combine in any form to become functional NDPK hexamers. NDPK is suggested to participate in transmembrane signaling in eukaryotic cells.[14]
In humans
In Eukaryotic systems, the role of the NDK is to synthesize nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP beta phosphate via a ping-pong mechanism, using a phosphorylated active-site intermediate, and synthesize products such as UTP. NDK possesses nucleoside-diphosphate kinase, serine/threonine-specific protein kinase, geranyl and farnesyl pyrophosphate kinase, histidine protein kinase, and 3'-5' exonuclease activities. Its processes are involved with cell proliferation, differentiation and development, and gene expression in human cells. It is also part of the neural development process, which includes neural patterning and cell fate determination. Furthermore, NDPK is involved with the signal transduction processes and G protein-coupled receptor endocytosis as it transfers a phosphate group onto the G β-subunits and convert GDP to GTP. This increase in GTP concentration near G protein α-subunits causes activation of G protein α-subunits for G-protein signaling.[15] In addition to signaling, NDPK is involved in controlling K+ channels, cell secretion, and cellular energy production.
In plants
The biochemical reactions catalyzed by NDP kinase in plants are analogous to activities described in humans as autophosphorylation activity takes place from ATP and GTP. In addition to this, plants have four types of NDPK isoforms. Cytosolic type I NDPK is involved in metabolism, growth, and stress responses in plants.[16] Type II NDPK is concentrated in the chloroplast and it is believed to be involved in the photosynthesis process and the oxidative stress management, but its function is not yet known clearly.[16] Type III NDPK targets both mitochondria and chloroplast, and it is mainly involved in energy metabolism.[16] The localization and exact function of the type IV NDPK is not yet well known and needs further investigations.[16] In addition, NDPK is associated with H2O2-mediated mitogen-activated protein kinase signaling in plants.[17]
Ten
Cardiovascular disease
Nme2, one of the NDPK genes, has been associated with
Nme1 and Nme2 as a suppressor of metastasis
There was a lot of debate on whether NM23 gene is responsible for suppressing or activating metastasis. The two contradicting sides on this subject remained ambiguous and undefined throughout the course of NDPK studies. However, recent experiments began to show evidence for NM23 being a suppressor of metastasis. Nme2 was tagged as an anti-metastasis gene, using the tissue chip technology and immunohistochemistry. When Nme2 gene products were over-produced in gastric cancer cells, there was a decrease in proliferation, migration, and invasion of such cancer cells. The cell cultures revealed that Nme2 impacts gastric cancer cells, but the question still remains about what regulates Nme2 activities among various cancer types.[20] Nme1 was found in great number in poorly metastatic sublines of melanoma cells. Also, the transfection of Nme1 into a highly metastatic melanoma line significantly reduced metastasis. This theory has been tested with mice as well; the Nme1-deficient mice formed greater lung metastases than wild type mice, showing that this gene has suppressing activity. Invasion of cancer occurs due to changes in cell adhesion and it is caused by gene expression changes in the epithelial-mesenchymal transition (EMT). Surprisingly, there are many adhesion molecules, motility factors, signaling pathways, proteolytic events, EMT hallmarks, and other transcriptional programs that have been linked to the Nme1 proteins. These proteins go about interrupting metastasis by binding metastasis-promoting proteins. The Nme1 proteins bind to viral proteins, oncogenes, and other metastasis-promoting factors. The binding may be indirect by using the signaling complex.[20]
See also
- Nucleoside
- Nucleotide
- Nucleoside monophosphate
- Nucleoside triphosphate
- Thymidine kinase
- Thymidylate kinase
- Thymidine kinase in clinical chemistry
- Thymidylate synthase
References
- ISBN 978-0-7167-4684-3.
- ^ "PDB 1jxv structure summary ‹ Protein Data Bank in Europe (PDBe) ‹ EMBL-EBI". www.ebi.ac.uk. Retrieved 2 November 2015.
- ^ a b c "Nucleoside diphosphate kinase (IPR001564)". InterPro. Retrieved 15 October 2015.
- PMID 1324167.
- ^ "NME1 - Nucleoside diphosphate kinase A - Homo sapiens (Human) - NME1 gene & protein". www.uniprot.org. Retrieved 17 November 2015.
- ISBN 9781119277781.
- PMID 11121795.
- PMID 22114351.
- ISBN 9781483217321.
- S2CID 18115068.
- ^ "spoT - Bifunctional (p)ppGpp synthase/hydrolase SpoT - Escherichia coli (strain K12) - spoT gene & protein". www.uniprot.org. Retrieved 17 November 2015.
- ISBN 9781444313307.
- S2CID 29304629.
- S2CID 24708684.
- PMID 17463326.
- ^ S2CID 1227825.
- PMID 12506203.
- PMID 25585611.
- PMID 19415463.
- ^ PMID 25700270.
External links
- Nucleoside-Diphosphate+Kinase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- EC 2.7.4.6