Nucleoside-diphosphate kinase

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Crystal structure of NDPK in human, viewed from front and side, respectively: X-ray diffraction, 2.2 A NDPK structure .jpg
Crystal structure of NDPK in human, viewed from front and side, respectively: X-ray diffraction, 2.2 Å
Nucleoside-diphosphate kinase
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EC no. 2.7.4.6
CAS no. 9026-51-1
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Nucleoside-diphosphate kinases (NDPKs, also NDP kinase, (poly)nucleotide kinases and nucleoside diphosphokinases) are enzymes that catalyze the exchange of terminal phosphate between different nucleoside diphosphates (NDP) and triphosphates (NTP) in a reversible manner to produce nucleotide triphosphates. Many NDP serve as acceptor while NTP are donors of phosphate group. The general reaction via ping-pong mechanism is as follows: XDP + YTP ←→ XTP + YDP (X and Y each represent different nitrogenous base). NDPK activities maintain an equilibrium between the concentrations of different nucleoside triphosphates such as, for example, when guanosine triphosphate (GTP) produced in the citric acid (Krebs) cycle is converted to adenosine triphosphate (ATP). [1] Other activities include cell proliferation, differentiation and development, signal transduction, G protein-coupled receptor, endocytosis, and gene expression.

Contents

Structure

NDPK are homohexameric proteins made up of monomers approximately 152 amino acids long with a theoretical weight of 17.17KDa. [2] The complex is found in mitochondria and in the soluble cytoplasm of cells.

Function

NDPK are found in all cells, displaying not much specificity towards the types of nucleoside bases and are capable of accepting nucleotides and deoxyribonucleotides as substrates or donors. [3] Therefore, NDPK is the source of RNA and DNA precursors, except ATP. [4] 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 a NTP, and NDPK catalyzes such reversible reactions. [5] 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). [6]

Ping-pong mechanism utilized by NDPK Ping-Pong Mechanism.jpg
Ping-pong mechanism utilized by NDPK

Behind this apparently simple reaction is a multistep mechanism. The key steps of transphosphorylation are as follows:

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 lipid synthesis, UTP for polysaccharide synthesis while GTP is used for protein elongation and signal transduction. [3] During cAMP-mediated signal transduction, NDPK is responsible for phosphorylating GDP released from G proteins activated from receptor binding; once ATP donates a phosphate group via activity of NDPK, GTP is consecutively bound. [7] Increased activity of membrane-associated NDPK yields cAMP synthesis. NDPK controls K+ channels, G proteins, cell secretion, cellular energy production, and UTP synthesis.

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 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 . [9] Prokaryotic NDPK forms a functional homotetramer. Nucleoside diphosphate kinase activity involves 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 a reversible histidine phosphorylation as a well-known regulatory signal. [10] However, in most prokaryotes, NDPK expression levels are involved in the cell growth, development and differentiation of the organism, especially bacteria.

NDPK is the enzyme triggering the dephosphorylation of GTP to GDP in the ppGpp cycle. NDPK ppGpp Cycle.png
NDPK is the enzyme triggering the dephosphorylation of GTP to GDP in the ppGpp cycle.

(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. [3] Normally, the Nm23 gene (NME) is involved in metastasis suppression in humans. In prokaryotes, 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. [13]

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 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 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 the biological basis of the Nm23 gene family is necessary to have a firm knowledge of its diverse results.

Cardiovascular disease

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 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. [18] Furthermore, more studies with zebra fish revealed that the NDPK depletion has a detrimental effect on heart functioning. [19]

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

Related Research Articles

<span class="mw-page-title-main">Adenosine triphosphate</span> Energy-carrying molecule in living cells

Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known forms of life, it is often referred to as the "molecular unit of currency" for intracellular energy transfer.

<span class="mw-page-title-main">Nucleotide</span> Biological molecules constituting nucleic acids

Nucleotides are organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver.

<span class="mw-page-title-main">Kinase</span> Enzyme catalyzing transfer of phosphate groups onto specific substrates

In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. As a result, kinase produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.

<span class="mw-page-title-main">Adenosine monophosphate</span> Chemical compound

Adenosine monophosphate (AMP), also known as 5'-adenylic acid, is a nucleotide. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine. It is an ester of phosphoric acid and the nucleoside adenosine. As a substituent it takes the form of the prefix adenylyl-.

<span class="mw-page-title-main">Guanosine triphosphate</span> Chemical compound

Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only difference being that nucleotides like GTP have phosphates on their ribose sugar. GTP has the guanine nucleobase attached to the 1' carbon of the ribose and it has the triphosphate moiety attached to ribose's 5' carbon.

<span class="mw-page-title-main">Guanosine diphosphate</span> Chemical compound

Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of a pyrophosphate group, a pentose sugar ribose, and the nucleobase guanine.

A salvage pathway is a pathway in which a biological product is produced from intermediates in the degradative pathway of its own or a similar substance. The term often refers to nucleotide salvage in particular, in which nucleotides are synthesized from intermediates in their degradative pathway.

A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar, with three phosphate groups bound to the sugar. They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. Nucleoside triphosphates also serve as a source of energy for cellular reactions and are involved in signalling pathways.

<span class="mw-page-title-main">Ribonucleotide reductase</span> Class of enzymes

Ribonucleotide reductase (RNR), also known as ribonucleoside diphosphate reductase, is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. It catalyzes this formation by removing the 2'-hydroxyl group of the ribose ring of nucleoside diphosphates. This reduction produces deoxyribonucleotides. Deoxyribonucleotides in turn are used in the synthesis of DNA. The reaction catalyzed by RNR is strictly conserved in all living organisms. Furthermore, RNR plays a critical role in regulating the total rate of DNA synthesis so that DNA to cell mass is maintained at a constant ratio during cell division and DNA repair. A somewhat unusual feature of the RNR enzyme is that it catalyzes a reaction that proceeds via a free radical mechanism of action. The substrates for RNR are ADP, GDP, CDP and UDP. dTDP is synthesized by another enzyme from dTMP.

<span class="mw-page-title-main">Adenylate kinase</span> Class of enzymes

Adenylate kinase is a phosphotransferase enzyme that catalyzes the interconversion of the various adenosine phosphates. By constantly monitoring phosphate nucleotide levels inside the cell, ADK plays an important role in cellular energy homeostasis.

<span class="mw-page-title-main">Nucleotide exchange factor</span>

Nucleotide exchange factors (NEFs) are proteins that stimulate the exchange (replacement) of nucleoside diphosphates for nucleoside triphosphates bound to other proteins.

The stringent response, also called stringent control, is a stress response of bacteria and plant chloroplasts in reaction to amino-acid starvation, fatty acid limitation, iron limitation, heat shock and other stress conditions and growth processes. The stringent response is signaled by the alarmone (p)ppGpp, and modulates transcription of up to 1/3 of all genes in the cell. This in turn causes the cell to divert resources away from growth and division and toward amino acid synthesis in order to promote survival until nutrient conditions improve.

<span class="mw-page-title-main">Succinyl coenzyme A synthetase</span> Class of enzymes

Succinyl coenzyme A synthetase is an enzyme that catalyzes the reversible reaction of succinyl-CoA to succinate. The enzyme facilitates the coupling of this reaction to the formation of a nucleoside triphosphate molecule from an inorganic phosphate molecule and a nucleoside diphosphate molecule. It plays a key role as one of the catalysts involved in the citric acid cycle, a central pathway in cellular metabolism, and it is located within the mitochondrial matrix of a cell.

<span class="mw-page-title-main">Nucleic acid metabolism</span> Process

Nucleic acid metabolism is a collective term that refers to the variety of chemical reactions by which nucleic acids are either synthesized or degraded. Nucleic acids are polymers made up of a variety of monomers called nucleotides. Nucleotide synthesis is an anabolic mechanism generally involving the chemical reaction of phosphate, pentose sugar, and a nitrogenous base. Degradation of nucleic acids is a catabolic reaction and the resulting parts of the nucleotides or nucleobases can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require multiple enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.

<span class="mw-page-title-main">Deoxycytidine kinase</span> Protein-coding gene in the species Homo sapiens

Deoxycytidine kinase (dCK) is an enzyme which is encoded by the DCK gene in humans. dCK predominantly phosphorylates deoxycytidine (dC) and converts dC into deoxycytidine monophosphate. dCK catalyzes one of the initial steps in the nucleoside salvage pathway and has the potential to phosphorylate other preformed nucleosides, specifically deoxyadenosine (dA) and deoxyguanosine (dG), and convert them into their monophosphate forms. There has been recent biomedical research interest in investigating dCK's potential as a therapeutic target for different types of cancer.

<span class="mw-page-title-main">NME1</span> Protein-coding gene in the species Homo sapiens

Nucleoside diphosphate kinase A is an enzyme that in humans is encoded by the NME1 gene. It is thought to be a metastasis suppressor.

<span class="mw-page-title-main">ATP phosphoribosyltransferase</span> Class of enzymes

In enzymology, an ATP phosphoribosyltransferase is an enzyme that catalyzes the chemical reaction

In enzymology, a nucleoside-triphosphate-aldose-1-phosphate nucleotidyltransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">NME2</span> Protein-coding gene in the species Homo sapiens

Nucleoside diphosphate kinase B is an enzyme that in humans is encoded by the NME2 gene.

<span class="mw-page-title-main">NME4</span> Protein-coding gene in the species Homo sapiens

Non-metastatic cells 4, protein expressed in, also known as NME4, is a protein which in humans is encoded by the NME4 gene.

References

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  2. ↑ "PDB 1jxv structure summary ‹ Protein Data Bank in Europe (PDBe) ‹ EMBL-EBI". www.ebi.ac.uk. Retrieved 2 November 2015.
  3. 1 2 3 "Nucleoside diphosphate kinase (IPR001564)". InterPro. Retrieved 15 October 2015.
  4. ↑ Dumas C, Lascu I, Moréra S, Glaser P, Fourme R, Wallet V, Lacombe ML, Véron M, Janin J (September 1992). "X-ray structure of nucleoside diphosphate kinase". The EMBO Journal. 11 (9): 3203–8. doi:10.1002/j.1460-2075.1992.tb05397.x. PMC   556853 . PMID   1324167.
  5. ↑ "NME1 - Nucleoside diphosphate kinase A - Homo sapiens (Human) - NME1 gene & protein". www.uniprot.org. Retrieved 17 November 2015.
  6. ↑ Salway, J.G (2017). Metabolism at a Glance, 4th edition. UK: Wiley Blackwell. p. 110. ISBN   9781119277781.
  7. ↑ Lutz S, Mura R, Baltus D, Movsesian M, Kübler W, Niroomand F (January 2001). "Increased activity of membrane-associated nucleoside diphosphate kinase and inhibition of cAMP synthesis in failing human myocardium". Cardiovascular Research. 49 (1): 48–55. doi: 10.1016/S0008-6363(00)00222-4 . PMID   11121795.
  8. ↑ Onyenwoke RU, Forsberg LJ, Liu L, Williams T, Alzate O, Brenman JE (January 2012). "AMPK directly inhibits NDPK through a phosphoserine switch to maintain cellular homeostasis". Molecular Biology of the Cell. 23 (2): 381–9. doi:10.1091/mbc.E11-08-0699. PMC   3258181 . PMID   22114351.
  9. ↑ Stadtman ER, Chock PB (2014-06-28). From Metabolite, to Metabolism, to Metabolon: Current Topics in Cellular Regulation. Elsevier. ISBN   9781483217321.
  10. ↑ Attwood PV, Wieland T (February 2015). "Nucleoside diphosphate kinase as protein histidine kinase". Naunyn-Schmiedeberg's Archives of Pharmacology. 388 (2): 153–60. doi:10.1007/s00210-014-1003-3. PMID   24961462. S2CID   18115068.
  11. ↑ "spoT - Bifunctional (p)ppGpp synthase/hydrolase SpoT - Escherichia coli (strain K12) - spoT gene & protein". www.uniprot.org. Retrieved 17 November 2015.
  12. ↑ Lengeler J, Drews G, Schlegel H (10 July 2009). Biology of the Prokaryotes. John Wiley & Sons. ISBN   9781444313307.
  13. ↑ de la Rosa A, Williams RL, Steeg PS (January 1995). "Nm23/nucleoside diphosphate kinase: toward a structural and biochemical understanding of its biological functions". BioEssays. 17 (1): 53–62. doi:10.1002/bies.950170111. PMID   7702594. S2CID   29304629.
  14. ↑ Otero AS (June 2000). "NM23/nucleoside diphosphate kinase and signal transduction". Journal of Bioenergetics and Biomembranes. 32 (3): 269–75. doi:10.1023/A:1005589029959. PMID   11768310. S2CID   24708684.
  15. ↑ Engelhardt S, Rochais F (April 2007). "G proteins: more than transducers of receptor-generated signals?". Circulation Research. 100 (8): 1109–11. doi: 10.1161/01.RES.0000266971.15127.e8 . PMID   17463326.
  16. 1 2 3 4 Dorion S, Rivoal J (February 2015). "Clues to the functions of plant NDPK isoforms". Naunyn-Schmiedeberg's Archives of Pharmacology. 388 (2): 119–32. doi:10.1007/s00210-014-1009-x. PMID   24964975. S2CID   1227825.
  17. ↑ Moon H, Lee B, Choi G, Shin D, Prasad DT, Lee O, Kwak SS, Kim DH, Nam J, Bahk J, Hong JC, Lee SY, Cho MJ, Lim CO, Yun DJ (January 2003). "NDP kinase 2 interacts with two oxidative stress-activated MAPKs to regulate cellular redox state and enhances multiple stress tolerance in transgenic plants" (PDF). Proceedings of the National Academy of Sciences of the United States of America. 100 (1): 358–63. Bibcode:2003PNAS..100..358M. doi: 10.1073/pnas.252641899 . PMC   140977 . PMID   12506203.
  18. ↑ Hsu T, Steeg PS, Zollo M, Wieland T (February 2015). "Progress on Nme (NDP kinase/Nm23/Awd) gene family-related functions derived from animal model systems: studies on development, cardiovascular disease, and cancer metastasis exemplified". Naunyn-Schmiedeberg's Archives of Pharmacology. 388 (2): 109–17. doi: 10.1007/s00210-014-1079-9 . PMC   10153104 . PMID   25585611.
  19. ↑ Mehta A, Orchard S (September 2009). "Nucleoside diphosphate kinase (NDPK, NM23, AWD): recent regulatory advances in endocytosis, metastasis, psoriasis, insulin release, fetal erythroid lineage and heart failure; translational medicine exemplified". Molecular and Cellular Biochemistry. 329 (1–2): 3–15. doi:10.1007/s11010-009-0114-5. PMC   2721137 . PMID   19415463.
  20. 1 2 Liu YF, Yang A, Liu W, Wang C, Wang M, Zhang L, Wang D, Dong JF, Li M (2015-01-01). "NME2 reduces proliferation, migration and invasion of gastric cancer cells to limit metastasis". PLOS ONE. 10 (2): e0115968. Bibcode:2015PLoSO..1015968L. doi: 10.1371/journal.pone.0115968 . PMC   4336288 . PMID   25700270.
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