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73-646: NDK may refer to: Nucleoside-diphosphate kinase , an enzyme National Palace of Culture , a congress centre in Sofia, Bulgaria Nihon Dempa Kogyo Co., Ltd. , a crystal device manufacturer in Tokyo, Japan Nan Desu Kan , an annual anime convention located in Colorado The Android NDK (native development kit), the C/C++ SDK for Android apps . Topics referred to by

146-592: A rate-limiting enzyme involved in the production of heme . Malate dehydrogenase and succinate dehydrogenase also increase, as well as citrate synthase activity, in rats treated with AICAR injections. Conversely, in LKB1 knockout mice, there are decreases in cytochrome c and citrate synthase activity, even if the mice are "trained" by voluntary exercise. AMPK is required for increased peroxisome proliferator-activated receptor γ coactivator-1α ( PGC-1α ) expression in skeletal muscle in response to creatine depletion. PGC-1α

219-460: A NTP, and NDPK catalyzes such reversible reactions. NTP phosphorylates a histidine, which in turn phosphorylates NDP. NDPK are involved in the synthesis of nucleoside triphosphates (NTP), such as guanosine triphosphate (GTP), cytidine triphosphate (CTP) and uridine triphosphate (UTP), thymidine triphosphate (TTP). Behind this apparently simple reaction is a multistep mechanism. The key steps of transphosphorylation are as follows: Each step

292-490: A condition that can occur biochemically, physically via protein aggregates such as proteopathic tau in Alzheimer's disease , crystalline silica causing silicosis , cholesterol crystals causing inflammation via NLRP3 inflammasome and rupture of atherosclerotic lesions, urate crystals associated with gout , or during microbial invasion such as Mycobacterium tuberculosis or coronaviruses causing SARS . Both of

365-449: A correlation with a reduced risk of cancer, compared to other medications. Gene knockout and knockdown studies with mice found that mice without the gene to express AMPK had greater risks of developing lymphomas, though as the gene was knocked out globally instead of just in B cells , it was impossible to conclude that AMP knockout had cell-autonomous effects within tumor progenitor cells. In contrast, some studies have linked AMPK with

438-467: A decrease in PGC-1α, as well as mitochondrial proteins. AMPK and thyroid hormone regulate some similar processes. Knowing these similarities, Winder and Hardie et al. designed an experiment to see if AMPK was influenced by thyroid hormone . They found that all of the subunits of AMPK were increased in skeletal muscle , especially in the soleus and red quadriceps, with thyroid hormone treatment. There

511-631: A direct interaction of these two proteins via their kinase domains. The interaction of CaMKK2 with AMPK only involves the α and β subunits of AMPK (AMPK γ is absent from the CaMKK2 complex), thus rendering regulation of AMPK in this context to changes in calcium levels but not AMP or ADP. AMPK is regulated allosterically mostly by competitive binding to the CBS sites on its γ subunit between ATP (which allows phosphatase access to Thr-172) and AMP or ADP (each of which blocks access to phosphatases). It thus appears that AMPK

584-496: A long-term training regimen, AMPK and other signals will facilitate contracting muscle adaptations by escorting muscle cell activity to a metabolic transition resulting in a fatty-acid oxidation approach to ATP generation as opposed to a glycolytic approach. AMPK accomplishes this transition to the oxidative mode of metabolism by upregulating and activating oxidative enzymes such as hexokinase II , PPAR-α , PPAR-δ , PGC-1 , UCP-3 , cytochrome C and TFAM . Mutations in

657-438: A phosphate group via activity of NDPK, GTP is consecutively bound. Increased activity of membrane-associated NDPK yields cAMP synthesis. NDPK controls K+ channels, G proteins, cell secretion, cellular energy production, and UTP synthesis. 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

730-506: A process named mitohormesis . One of the effects of exercise is an increase in fatty acid metabolism , which provides more energy for the cell. One of the key pathways in AMPK's regulation of fatty acid oxidation is the phosphorylation and inactivation of acetyl-CoA carboxylase . Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl-CoA , an inhibitor of carnitine palmitoyltransferase 1 ( CPT-1 ). CPT-1 transports fatty acids into

803-810: A recent study investigating the response to exercise training in AMPKα2 knockout mice opposes this idea. Their study compared the response to exercise training of several proteins and enzymes in wild type and AMPKα2 knockout mice. And even though the knockout mice had lower basal markers of mitochondrial density (COX-1, CS, and HAD), these markers increased similarly to the wild type mice after exercise training. These findings are supported by another study also showing no difference in mitochondrial adaptations to exercise training between wild type and knockout mice. The C. elegans homologue of AMPK, aak-2, has been shown by Michael Ristow and colleagues to be required for extension of life span in states of glucose restriction mediating

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876-525: A result of both temporary and maintained increases in AMPK activity brought about by increases in the AMP:ATP ratio during single bouts of exercise and long-term training. During a single acute exercise bout, AMPK allows the contracting muscle cells to adapt to the energy challenges by increasing expression of hexokinase II, translocation of GLUT4 to the plasma membrane , for glucose uptake, and by stimulating glycolysis. If bouts of exercise continue through

949-415: A reversible histidine phosphorylation as a well-known regulatory signal. However, in most prokaryotes , NDPK expression levels are involved in the cell growth, development and differentiation of the organism, especially bacteria . 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

1022-479: A role as a tumor promoter by protecting cancer cells from stress. Thus, once cancerous cells have formed in an organism, AMPK may swap from protecting against cancer to protecting the cancer itself. Studies have found that tumor cells with AMPK knockout are more susceptible to death by glucose starvation or extracellular matrix detachment, which may indicate AMPK has a role in preventing these two outcomes. A recent study on pancreatic cancer suggests that AMPKα may play

1095-610: A role in the metastatic cascade and the phenotype of cancer cells. Mechanistically, the authors propose that in the absence of AMPKα, pancreatic cancer cells are more vulnerable to oxidative stress, supporting a tumor-promoting function of AMPKα. A seemingly paradoxical role of AMPK occurs when we take a closer look at the energy-sensing enzyme in relation to exercise and long-term training. Similar to short-term acute training scale, long-term endurance training studies also reveal increases in oxidative metabolic enzymes, GLUT-4, mitochondrial size and quantity, and an increased dependency on

1168-610: A single bout of exercise or an extended duration of training , such as increased mitochondrial biogenesis and capacity, increased muscle glycogen , and an increase in enzymes which specialize in glucose uptake in cells such as GLUT4 and hexokinase II are thought to be mediated in part by AMPK when it is activated. Additionally, recent discoveries can conceivably suggest a direct AMPK role in increasing blood supply to exercised/trained muscle cells by stimulating and stabilizing both vasculogenesis and angiogenesis . Taken together, these adaptations most likely transpire as

1241-484: Is a heterotrimeric protein complex that is formed by α, β, and γ subunits. Each of these three subunits takes on a specific role in both the stability and activity of AMPK. Specifically, the γ subunit includes four particular Cystathionine-β-synthase (CBS) domains , giving AMPK its ability to sensitively detect shifts in the AMP / ATP ratio. AMPK is deactivated upon AMP displacement by ATP at CBS site 3, suggesting CBS3 to be

1314-454: Is a hormone which helps regulate glucose levels in the body. When blood glucose is high, insulin is released from the Islets of Langerhans . Insulin, among other things, will then facilitate the uptake of glucose into cells via increased expression and translocation of glucose transporter GLUT-4 . Under conditions of exercise, however, blood sugar levels are not necessarily high, and insulin

1387-422: Is a sensor of AMP/ATP or ADP/ATP ratios and thus cell energy level. AMPK undergoes a large conformational change upon ATP binding. A region on the α subunit known as the kinase domain (KD) dissociates from its active-state conformation and loosely associates with the γ subunit ~100Å away. The KD also rotates ~180° in the conformational change. Upon KD dissociation, the active loop (AL) of the α subunit which contains

1460-562: Is a transcriptional regulator for genes involved in fatty acid oxidation , gluconeogenesis , and is considered the master regulator for mitochondrial biogenesis . To do this, it enhances the activity of transcription factors like nuclear respiratory factor 1 ( NRF-1 ), myocyte enhancer factor 2 (MEF2), host cell factor (HCF), and others. It also has a positive feedback loop , enhancing its own expression. Both MEF2 and cAMP response element ( CRE ) are essential for contraction-induced PGC-1α promoter activity. LKB1 knockout mice show

1533-507: 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. In addition to signaling, NDPK

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1606-413: Is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 in yeast, and SnRK1 in plants. It consists of three proteins ( subunits ) that together make a functional enzyme, conserved from yeast to humans. It

1679-400: Is associated with H 2 O 2 -mediated mitogen-activated protein kinase signaling in plants. Ten paralogous genes code for the proteins NDPKs, which are separated into two groups. The first group encodes proteins with NDPK functions. The other group genes code for other various proteins that display low or no NDPK activities. In the first group, one of the genes named NM23 was identified as

1752-528: Is blocked if AMP or ADP can block access for and ATP can displace AMP and ADP. That residue is phosphorylated by at least three kinases ( liver kinase B1 (LKB1), which works in a complex with STRAD and MO25 , Calcium/calmodulin-dependent protein kinase kinase II-( CAMKK2 ), and TGFβ-activated kinase 1 (TAK1)) and is dephosphorylated by three phosphatases ( protein phosphatase 2A (PP2A); protein phosphatase 2C (PP2C) and Mg -/Mn -dependent protein phosphatase 1E ( PPM1E )). Regulation of AMPK by CaMKK2 requires

1825-416: 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. Type III NDPK targets both mitochondria and chloroplast, and it is mainly involved in energy metabolism. The localization and exact function of the type IV NDPK is not yet well known and needs further investigations. In addition, NDPK

1898-416: Is different from Wikidata All article disambiguation pages All disambiguation pages Nucleoside-diphosphate kinase NDPK are homohexameric proteins made up of monomers approximately 152 amino acids long with a theoretical weight of 17.17KDa. The complex is found in mitochondria and in the soluble cytoplasm of cells. NDPK are found in all cells, displaying not much specificity towards

1971-628: Is expressed in a number of tissues, including the liver , brain , and skeletal muscle . In response to binding AMP and ADP , the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis , stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis , and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis , and modulation of insulin secretion by pancreatic β-cells . It should not be confused with cyclic AMP -activated protein kinase ( protein kinase A ). AMPK

2044-852: Is inhibited or activated by insulin, leptin, and diacylglycerol by inducing various other phosphorylations. AMPK may be inhibited or activated by various tissue-specific ubiquitinations . It is also regulated by several protein-protein interactions, and may either be activated or inhibited by oxidative factors; the role of oxidation in regulating AMPK was controversial as of 2016. When AMPK phosphorylates acetyl-CoA carboxylase 1 (ACC1) or sterol regulatory element-binding protein 1c (SREBP1c), it inhibits synthesis of fatty acids, cholesterol, and triglycerides, and activates fatty acid uptake and β-oxidation. AMPK stimulates glucose uptake in skeletal muscle by phosphorylating Rab-GTPase-activating protein TBC1D1 , which ultimately induces fusion of GLUT4 vesicles with

2117-424: Is involved in controlling K+ channels, cell secretion, and cellular energy production. 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. Type II NDPK

2190-537: Is likewise thought to be regulated to some extent by AMPK activity. If the AMPK response to exercise is responsible in part for biochemical adaptations to training, how then can these adaptations to training be maintained if the AMPK response to exercise is being attenuated with training? It is hypothesized that these adaptive roles to training are maintained by AMPK activity and that the increases in AMPK activity in response to exercise in trained skeletal muscle have not yet been observed due to biochemical adaptations that

2263-504: Is not necessarily activated, yet muscles are still able to bring in glucose. AMPK seems to be responsible in part for this exercise -induced glucose uptake. Goodyear et al. observed that with exercise, the concentration of GLUT-4 was increased in the plasma membrane , but decreased in the microsomal membranes, suggesting that exercise facilitates the translocation of vesicular GLUT-4 to the plasma membrane . While acute exercise increases GLUT-4 translocation, endurance training will increase

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2336-547: Is part of a reversible process, such that the multistep equilibrium is of the following form. NDPK's roles in these NTPs differ; generally, kinases bring in NTPs for nucleic acid synthesis. CTP is provided for lipid synthesis , UTP for polysaccharide synthesis while GTP is used for protein elongation and signal transduction . During cAMP -mediated signal transduction, NDPK is responsible for phosphorylating GDP released from G proteins activated from receptor binding; once ATP donates

2409-763: Is suggested to participate in transmembrane signaling in eukaryotic cells. 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

2482-452: Is the histidine kinase activity, which is the phosphorylation of the channels to regulate what goes through and the other is a scaffold function of the formation of caveolae . The depletion of Nme2/caveolin interaction exhibited a decreased rate of cardiac contractility. Furthermore, more studies with zebra fish revealed that the NDPK depletion has a detrimental effect on heart functioning. There

2555-672: The AXIN - LKB1 complex, acting in response to glucose limitations functioning independently of AMP sensing, which detects low glucose as absence of fructose-1,6-bisphosphate via a dynamic set of interactions between lysosomally localized V-ATPase - aldolase in contact with the endoplasmic reticulum localized TRPV . A second AMPK-control system localized to lysosomes depends on the Galectin-9 - TAK1 system and ubiquitination responses at controlled by deubiquitinating enzymes such as USP9X leading to AMPK activation in response to lysosomal damage,

2628-735: The cell , and by changing the structure of glucose through phosphorylation, it decreases the concentration of glucose molecules, maintaining a gradient for more glucose to be transported into the cell. Hexokinase II transcription is increased in both red and white skeletal muscle upon treatment with AICAR. With chronic injections of AICAR, total protein content of hexokinase II increases in rat skeletal muscle. Mitochondrial enzymes, such as cytochrome c , succinate dehydrogenase , malate dehydrogenase , α-ketoglutarate dehydrogenase , and citrate synthase , increase in expression and activity in response to exercise. AICAR stimulation of AMPK increases cytochrome c and δ-aminolevulinate synthase ( ALAS ),

2701-513: The liver . It has long been known that hepatic ACC has been regulated in the liver by phosphorylation . AMPK also phosphorylates and inactivates 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key enzyme in cholesterol synthesis . HMGR converts 3-hydroxy-3-methylglutaryl-CoA, which is made from acetyl-CoA, into mevalonic acid , which then travels down several more metabolic steps to become cholesterol . AMPK, therefore, helps regulate fatty acid oxidation and cholesterol synthesis. Insulin

2774-491: The mitochondria for oxidation . Inactivation of ACC, therefore, results in increased fatty acid transport and subsequent oxidation. It is also thought that the decrease in malonyl-CoA occurs as a result of malonyl-CoA decarboxylase (MCD), which may be regulated by AMPK. MCD is an antagonist to ACC, decarboxylating malonyl-CoA to acetyl-CoA, resulting in decreased malonyl-CoA and increased CPT-1 and fatty acid oxidation. AMPK also plays an important role in lipid metabolism in

2847-582: The muscle cell . Two proteins are essential for the regulation of GLUT-4 expression at a transcriptional level – myocyte enhancer factor 2 ( MEF2 ) and GLUT4 enhancer factor (GEF). Mutations in the DNA binding regions for either of these proteins results in ablation of transgene GLUT-4 expression. These results prompted a study in 2005 which showed that AMPK directly phosphorylates GEF, but it doesn't seem to directly activate MEF2. AICAR treatment has been shown, however, to increase transport of both proteins into

2920-497: The nucleus , as well as increase the binding of both to the GLUT-4 promoter region . There is another protein involved in carbohydrate metabolism that is worthy of mention along with GLUT-4. The enzyme hexokinase phosphorylates a six-carbon sugar, most notably glucose , which is the first step in glycolysis . When glucose is transported into the cell it is phosphorylated by hexokinase. This phosphorylation keeps glucose from leaving

2993-468: The (p)ppGpp biosynthesis cycle. NDPK synthesizes the formation of GDP from GTP via dephosphorylation. 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. Normally, the Nm23 gene (NME) is involved in metastasis suppression in humans. In prokaryotes,

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3066-455: The AL is exposed to upstream phosphatases, and AMPK is deactivated. The pharmacological compounds Merck Compound 991 and Abbott A769662 bind to the allosteric drug and metabolism site (ADaM) on the β subunit and have been shown to activate AMPK up to 10-fold. ADaM site binding may have roles in AMPK activation as well as protection against dephosphorylation. There are other mechanisms by which AMPK

3139-545: The AMPK role with respect to biochemical adaptations to exercise and endurance training. This is due in part to the marked increases in the mitochondrial biogenesis , upregulation of GLUT-4 , UCP-3 , Hexokinase II along with other metabolic and mitochondrial enzymes despite decreases in AMPK activity with training. Questions also arise because skeletal muscle cells which express these decreases in AMPK activity in response to endurance training also seem to be maintaining an oxidative dependent approach to metabolism, which

3212-501: The LKB1/MO25/STRAD complex is considered to be the major upstream AMPKK of the 5’-AMP-activated protein kinase phosphorylating the α subunit of AMPK at Thr-172. This fact is puzzling considering that although AMPK protein abundance has been shown to increase in skeletal tissue with endurance training, its level of activity has been shown to decrease with endurance training in both trained and untrained tissue. Currently,

3285-740: The Nm23 gene is involved in normal cell development and differentiation. Highly conserved homologues of the Nm23 gene have been found in prokaryotes, more specifically, Myxococcus xanthus , a gram-negative soil bacteria. Homologues of Nm23 in M. xanthus have been closed and characterized as a nucleoside diphosphate kinase (ndk gene) and seems to be essential for M. xanthus growth. During M. xanthus development, nucleoside diphosphate kinase activity has also been shown to drastically decrease. 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

3358-451: 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. AMP-activated protein kinase 5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase

3431-519: 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

3504-430: The above lysosomally localized systems controlling AMPK activate it in response to metformin , a widely prescribed anti-diabetic drug. Some evidence indicates that AMPK may have a role in tumor suppression. Studies have found that AMPK may exert most, or even all of, the tumor suppressing properties of liver kinase B1 (LKB1). Additionally, studies where the AMPK activator metformin was used to treat diabetes found

3577-419: The activation of AMPK within the hypothalamus , whilst also suppressing the counterregulatory response to hypoglycemia. Pharmacological activation of AMPK by delivery of AMPK activating drug AICAR, directly into the hypothalamus can increase the counterregulatory response to hypoglycaemia. AMPK is recruited to lysosomes and regulated at the lysosomes via several systems of clinical significance. This includes

3650-509: The activation of AMPK, which eventually decreases NDPK activity by phosphorylating serine residues. In most prokaryotes, the NDPK enzyme is tetrameric . It has been reported in a number of pathogens. NDPK function has been studied in Escherichia coli , Bacillus subtilis , Salmonella typhimurium , Micrococcus luteus , and Myxococcus xanthus . Prokaryotic NDPK forms a functional homotetramer . Nucleoside diphosphate kinase activity involves

3723-431: The activity of AMPK immediately following a 2 hour bout of exercise of an endurance trained rat is unclear. It is possible that a direct link exists between the observed decrease in AMPK activity in endurance trained skeletal muscle and the apparent decrease in the AMPK response to exercise with endurance training. Although AMPKα2 activation has been thought to be important for mitochondrial adaptations to exercise training,

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3796-407: The biological basis of the Nm23 gene family is necessary to have a firm knowledge of its diverse results. Nme2, one of the NDPK genes, has been associated with cardiovascular functions. Nme2 gene is known to form a complex with the beta subunit of the heterotrimetric G protein in heart cells and regulates the contractility of heart. There are two functions of Nme2 that allow for such regulation; one

3869-520: The cell, so all of the energy consuming pathways like protein synthesis are inhibited, and pathways that generate energy are activated to restore appropriate energy levels in the cell. AMPK activates autophagy by directly and indirectly activating ULK1 . AMPK also appears to stimulate mitochondrial biogenesis by regulating PGC-1α which in turn promotes gene transcription in mitochondria. AMPK also activates anti-oxidant defenses. Many biochemical adaptations of skeletal muscle that take place during

3942-536: The critical phosphorylated Thr residue is fully exposed to upstream phosphatases. This conformational change represents a plausible mechanism for AMPK modulation. When cellular energy states are low (high AMP/ATP or ADP/ATP levels), AMPK adopts the KD-associated conformation and AMPK is protected from dephosphorylation and remains activated. When cellular energy states are high, AMPK adopts the KD-displaced conformation,

4015-434: The energy-intensive protein biosynthesis process and can also force a switch from cap-dependent translation to cap-independent translation, which requires less energy, by phosphorylation of TSC2 , RPTOR , transcription initiation factor 1A.66, and eEF2K . When TSC2 is activated it inhibits mTORC1. As a result of inhibition of mTORC1 by AMPK, protein synthesis comes to a halt. Activation of AMPK signifies low energy within

4088-486: The first metastasis suppressor protein and its gene Nm23 was less activated in metastatic cells. In a different experiment, human Nm23 was cultured with cancer cells and showed inhibition of metastasis. The level of NM23 protein was inversely proportional to the metastatic potential for human solid tumors. However, other tumor types such as ovarian cancers, neuroblastoma and hematological malignancies displayed upregulated NM23 levels in patient samples. Therefore, understanding

4161-407: The oxidation of fatty acids; however, Winder et al. reported in 2002 that despite observing these increased oxidative biochemical adaptations to long-term endurance training (similar to those mentioned above), the AMPK response (activation of AMPK with the onset of exercise) to acute bouts of exercise decreased in red quadriceps (RQ) with training (3 – see Fig.1). Conversely, the study did not observe

4234-489: The plasma membrane. AMPK stimulates glycolysis by activating phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2/3 and activating phosphorylation of glycogen phosphorylase, and it inhibits glycogen synthesis through inhibitory phosphorylation of glycogen synthase. In the liver, AMPK inhibits gluconeogenesis by inhibiting transcription factors including hepatocyte nuclear factor 4 (HNF4) and CREB regulated transcription coactivator 2 (CRTC2). AMPK inhibits

4307-458: The presence of isoforms of its components, there are 12 versions of AMPK in mammals, each of which can have different tissue localizations, and different functions under different conditions. AMPK is regulated allosterically and by post-translational modification, which work together. If residue Thr-172 of AMPK's α1-subunit (or Thr-174 of AMPK's α2-subunit) is phosphorylated, AMPK is activated around 100-fold; access to that residue by phosphatases

4380-402: The primary allosteric regulatory site. The four CBS domains create two binding sites for AMP commonly referred to as Bateman domains. Binding of one AMP to a Bateman domain cooperatively increases the binding affinity of the second AMP to the other Bateman domain. As AMP binds both Bateman domains the γ subunit undergoes a conformational change which exposes the catalytic domain found on

4453-462: The regulation of AMP-activated protein kinase ( AMPK ). 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

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4526-549: The same results in white quadriceps (WQ) and soleus (SOL) muscles that they did in RQ. The trained rats used for that endurance study ran on treadmills 5 days/wk in two 1-h sessions, morning and afternoon . The rats were also running up to 31m/min (grade 15%). Finally, following training, the rats were sacrificed either at rest or following 10 minutes of exercise. Because the AMPK response to exercise decreases with increased training duration, many questions arise that would challenge

4599-403: The same term [REDACTED] This disambiguation page lists articles associated with the title NDK . If an internal link led you here, you may wish to change the link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=NDK&oldid=1120962416 " Category : Disambiguation pages Hidden categories: Short description

4672-703: The skeletal muscle calcium release channel ( RYR1 ) underlies a life- threatening response to heat in patients with malignant hyperthermia susceptibility (MHS). Upon acute exposure to heat, these mutations cause uncontrolled Ca release from the sarcoplasmic reticulum , leading to sustained muscle contractures, severe hyperthermia, and sudden death. At basal conditions, the temperature-dependent Ca leak also leads to increased energy demand and activation of energy sensing AMP kinase (AMPK) in skeletal muscle. The activated AMPK increases muscle metabolic activity, including glycolysis, which leads to marked elevation of circulating lactate . AMPK activity increases with exercise and

4745-490: 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. 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

4818-431: The total amount of GLUT-4 protein available. It has been shown that both electrical contraction and AICA ribonucleotide (AICAR) treatment increase AMPK activation, glucose uptake, and GLUT-4 translocation in perfused rat hindlimb muscle, linking exercise-induced glucose uptake to AMPK. Chronic AICAR injections, simulating some of the effects of endurance training , also increase the total amount of GLUT-4 protein in

4891-428: The transfer of the γ-phosphate of nucleoside triphosphate (NTP) to nucleoside diphosphate (NDP), where N1 and N2 can be ribo- or deoxyribonucleosides. This is done via a high energy phosphohistidine intermediate. Besides involvement in the synthesis of pyrimidine nucleotides, prokaryotic NDPK is also involved in several metabolism cycles. NDPK has also been discovered to act as a protein histidine kinase , which involves

4964-474: The types of nucleoside bases and are capable of accepting nucleotides and deoxyribonucleotides as substrates or donors. Therefore, NDPK is the source of RNA and DNA precursors, except ATP. NDPK utilize specific enzyme kinetics for multi-substrate reaction, namely ping-pong mechanism . A ping-pong mechanism integrates phosphorylation of a histidine residue by transferring terminal phosphate group (γ-phosphate) from ATP to NDP β-phosphate in order to produce

5037-475: The α subunit can exist as either the α1 or α2 isoform. Although the most common isoforms expressed in most cells are the α1, β1, and γ1 isoforms, it has been demonstrated that the α2, β2, γ2, and γ3 isoforms are also expressed in cardiac and skeletal muscle . The following human genes encode AMPK subunits: The crystal structure of mammalian AMPK regulatory core domain (α C terminal, β C terminal, γ) has been solved in complex with AMP, ADP or ATP. Due to

5110-403: The α subunit. It is in this catalytic domain where AMPK becomes activated when phosphorylation takes place at threonine -172 (on α1 isoform) or Thr-174 (on α2 isoform) by an upstream AMPK kinase ( AMPKK ). The α, β, and γ subunits can also be found in different isoforms: the γ subunit can exist as either the γ1, γ2 or γ3 isoform ; the β subunit can exist as either the β1 or β2 isoform; and

5183-475: 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. 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;

5256-486: 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

5329-453: Was also an increase in phospho-ACC, a marker of AMPK activity. Loss of AMPK has been reported to alter the sensitivity of glucose sensing cells, through poorly defined mechanisms. Loss of the AMPKα2 subunit in pancreatic β-cells and hypothalamic neurons decreases the sensitivity of these cells to changes in extracellular glucose concentration. Moreover, exposure of rats to recurrent bouts of insulin induced hypoglycemia /glucopenia, reduces

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