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Query: UNIPROT:P06889 (Mol)
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The complete nucleotide sequence of a 1,513 bp fragment of Mycobacterium bovis BCG containing the secY gene homolog and partial adk gene that encodes an adenylate kinase has been determined. The secY gene of BCG has an open reading frame of 441 amino acids with homology to the SecY protein family. Comparative analyses of the deduced amino acid sequence of additional partial ORF revealed strong similarity to the known adenylate kinases.
Biochem Mol Biol Int 1997 Oct
PMID:Cloning and sequencing of the secY gene homolog from Mycobacterium bovis BCG. 935 Mar 47

In Lactobacillus acidophilus R-26, the synthesis of DNA precursor deoxynucleotides occurs exclusively by salvage of deoxynucleosides, beginning with phosphorylation by four deoxynucleoside kinases. Subunits bearing three of these activities are uniquely organized into two heterodimers, deoxyadenosine/deoxycytidine kinase (dAK/dCK) and deoxyadenosine/deoxyguanosine kinase (dAK/dGK), which, along with a distinct deoxythymidine kinase (TK), catalyze the parallel first committed steps of dNTP biosynthesis. Whereas TK is common to most prokaryotes (and eukaryotes), the other three activities that are the emphasis of this review are quite unusual in bacteria. Each activity is regulated in cis by its homologous end-product (dNTP) which is understood to act as a multisubstrate inhibitor capable of binding to both nucleoside and phosphate subsites. Conversely, the inactive dAK subunit is progressively activated by 1) association with a dGK or dCK subunit and 2) the conformationally driven heterotropic affect of dGuo or dCyd bound to the opposing subunit. Limited proteolysis has proven to be a powerful probe of conformational states. Further indication of conformational or structural differences between dAK and dGK (or dCK) is that the former follows an ordered kinetic path, while dGK or dCK exhibits rapid-equilibrium random kinetics. The multi-substrate behavior of end-product binding provides a convenient new diagnostic tool for distinguishing kinetic mechanisms. Tandem dak-dgk genes have been cloned from Lactobacillus DNA and expressed in Escherichia coli as dAK/dGK, utilizing the associated promoter. Sequence alignments reveal 65% identity in their DNA and 61% in their derived amino acid sequences. Encoded N-terminal sequences are identical for the first 18 residues, and both subunits share conserved sequences in common with adenylate kinase and viral TK. A more unusual conserved element, which appears to play a role in the activation of dAK, resembles the G2 loop of p21 ras. Remarkably, no homologous gene(s) for the dAK/dCK pair could be found. Comparisons of amino acid sequences, isoelectric pHs and subunit masses strongly indicated that native dCK and dGK are identical in sequence, except at their extreme N-termini (M-IVL for dCK and -TVIVL for dGK), suggesting that processing of a common precursor occurs in Lactobacillus. Accordingly, deletion of codons 2 and 3 from dgk resulted in the expression of dAK/dCK in the E. coli host; its kinetic properties are indistinguishable from those of native dAK/dCK. Subcloning the dgk or engineered dck gene resulted in expression of active dGK or dCK homodimers, each with a virtually unchanged Km toward its primary deoxynucleoside. However, in common with human dCK, dCK (or dGK) homodimer exhibits secondary activities with much larger Kms towards dAdo and dGuo (or dCyd). dCTP (or dGTP) is the best inhibitor of all three activities of the respective homodimer. Fully active heterodimers can be reconstituted simply by mixing a homodimer with independently expressed (inactive) dAK.
Prog Nucleic Acid Res Mol Biol 1998
PMID:Life on the salvage path: the deoxynucleoside kinase of Lactobacillus acidophilus R-26. 942 44

The three-dimensional structure of shikimate kinase from Erwinia chrysanthemi has been determined by multiple isomorphous replacement. Two models are presented: a high resolution 1.9 A model and a 2.6 A model which contains bound Mg-ADP. The enzyme is an alpha/beta protein consisting of a central sheet of five parallel beta-strands flanked by alpha-helices with overall topology similar to adenylate kinase. Evidence is presented that shikimate kinase undergoes major conformational changes on ligand binding. It resembles adenylate kinase in having a P-loop containing core structure and two flexible domains which undergo induced fit movement on substrate binding. The binding of Mg2+ in the active site of shikimate kinase involves direct interaction with two protein side-chains which is different from the situation found in adenylate kinase. Shikimate kinase has a readily identifiable Walker A-motif and a recognisable but modified Walker B-motif. Comparison of shikimate kinase to adenylate kinase has led to the identification of an adenine-binding motif (I/VDAXQ/NXP). Difference Fourier calculations have revealed the shikimate binding site which corresponds to the location of the AMP-binding site in adenylate kinase. A model for shikimate-binding is presented.
J Mol Biol 1998 May 22
PMID:The three-dimensional structure of shikimate kinase. 960 Aug 56

GTP:AMP phosphotransferase (adenylate kinase isozyme 3, AK3) mutants were obtained by using the ability of AK3 to complement a temperature-sensitive mutation of Escherichia coli adenylate kinase (AKe). Five mutants, P16L, G19S, G91D, G91S, and P93L, had mutation sites located at two loops that are involved in substrate binding of the enzyme. P16L and G19S bearing changes at the first loop showed reduced affinity for both GTP and AMP, the extent of reduction being slightly higher for GTP than AMP. In contrast, G91S and P93L having alterations at the second loop had lower affinities for AMP. Only the alterations at the second loop strongly influenced the Vmax value of the enzyme. Another mutant, D163N, had a substitution at the site forming a salt bridge in adenylate kinase isozyme 1 (AK1), which influenced the Vmax as well as the Km values for both substrates. The kinetic characteristics of these mutants were comparable to those of the corresponding AK1 or AKe mutants. Furthermore, from the results of mutations T201P and T201A that had alterations in all the kinetic parameters of AK3 and from a comparison with the structure and the kinetic parameters of AKe, we expect that a residue(s) around Thr201 is involved in recognition of the base of nucleoside triphosphate.
J Mol Biol 1998 Jul 17
PMID:Isolation and characterization of mutated mitochondrial GTP:AMP phosphotransferase. 966 56

Ischaemic myocardium undergoes calcium-independent contracture at millimolar tissue ATP, though in actomyosin solutions ATP must be reduced to micromolar before rigor complexes form. This contracture is associated with myosin ATPase activity that may contribute to tissue de-energization. Here we used isolated rat cardiomyocytes permeabilized with digitonin to analyse in parallel how rigor and myosin ATPase activity are modulated by metabolic conditions that develop during ischaemia. At pH 7.1 and 37 degrees C rigor and myosin ATPase showed co-ordinated bell-shaped dependence on ATP concentration over 3-1000 microM. Rigor, but not myosin ATPase, was inhibited by acidosis (pH 6.2), indicating reduced efficiency of cross-bridge cycling, while both parameters were stimulated by ADP (< or = 1 mM) and unaffected by inorganic phosphate (Pi, 30 mM), AMP, Mg2+, lactate or inhibition of adenylate kinase with diadenosine pentaphosphate. Combined acidosis and high ADP inhibited rigor, while Pi attenuated the enhancement of rigor by ADP. Thus, rigor complex formation activates myosin ATPase in the intact myofilament array, modulated by ADP, Pi and acidosis in the ranges that occur in ischaemia. There was no evidence that adenylate kinase might attenuate falling ATP/ADP ratio at the myofilaments. In combination these effects are sufficient to resolve the apparent discrepancy between ATP concentrations triggering rigor in actomyosin and onset of contracture in ischaemic myocardium. Since rigor contracture activates myosin ATPase it is likely to exacerbate ATP depletion and thereby limit vital cell functions. This positive feedback is consistent with the abrupt depletion of ATP observed in individual cardiomyocytes undergoing deenergization contracture.
J Mol Cell Cardiol 1998 Jul
PMID:Modulation of rigor and myosin ATPase activity in rat cardiomyocytes. 971 Aug 3

The adenylate kinase from the hyperthermophilic archaean species Sulfolobus acidocaldarius has been cloned, expressed in Escherichia coli, purified and crystallized. The crystal structure was elucidated by multiple isomorphous replacement and non-crystallographic density averaging. The structure was refined at 2.6 A (1 A=0.1 nm) resolution. The enzyme is trimeric, in contrast to previous solution measurements that suggested a dimeric structure, and in contrast to the vast majority of adenylate kinases, which are monomeric. In large parts of each subunit the chain fold resembles the known enzyme structure from eubacteria and eukaryotes although the sequence homology is negligible. Since the asymmetric unit contains two trimers with and without bound AMP at the AMP sites and with an ADP at one of the six ATP sites, the analysis shows the enzyme in several states. The conformational differences between these states resemble those of other adenylate kinases. Because of sequence homology, the structure presented provides a good model for the methanococcal adenylate kinases.
J Mol Biol 1998 Sep 11
PMID:The structure of a trimeric archaeal adenylate kinase. 973 48

Monitoring the kinetic behavior of adenylate kinase (AK) and creatine kinase (CK) in intact cells by 18O-phosphoryl oxygen exchange analysis has provided new perspectives from which to more fully define the involvement of these phosphotransferases in cellular bioenergetics. A primary function attributable to both AK and CK is their apparent capability to couple ATP utilization with its generation by glycolytic and/or oxidative processes depending on cell metabolic status. This is evidenced by the observation that the sum of the net AK- plus CK-catalyzed phosphoryl transfer is equivalent to about 95% of the total ATP metabolic flux in non-contracting rat diaphragm; under basal conditions almost every newly generated ATP molecule appears to be processed by one or the other of these phosphotransferases prior to its utilization. Although CK accounts for the transfer of a majority of the ATP molecules generated/consumed in the basal state there is a progressive, apparently compensatory, shift in phosphotransfer catalysis from the CK to the AK system with increasing muscle contraction or graded chemical inhibition of CK activity. AK and CK appear therefore to provide similar and interrelated functions. Evidence that high energy phosphoryl transfer in some cell types or metabolic states can also be provided by specific nucleoside mono- and diphosphate kinases and by the phosphotransfer capability inherent to the glycolytic system has been obtained. Measurements by 18O-exchange analyses of net AK- and CK-catalyzed phosphoryl transfer in conjunction with 31P NMR analyses of total unidirectional phosphoryl flux show that each new energy-bearing molecule CK or AK generates subsequently undergoes about 50 or more unidirectional CK-or AK-catalyzed phosphotransfers en route to an ATP consumption site in intact muscle. This evidence of multiple enzyme catalyzed exchanges coincides with the mechanism of vectorial ligand conduction suggested for accomplishing intracellular high energy phosphoryl transfer by the AK and CK systems. AK-catalyzed phosphotransfer also appears to be integral to the transduction of metabolic signals influencing the operation of ion channels regulated by adenine nucleotides such as ATP-inhibitable K+ channels in insulin secreting cells; transition from the ATP to ADP liganded states closely coincides with the rate AK-catalyzes phosphotransfer transforming ATP (+AMP) to (2)ADP.
Mol Cell Biochem 1998 Jul
PMID:Adenylate kinase: kinetic behavior in intact cells indicates it is integral to multiple cellular processes. 974 20

Some historical aspects of development of the concepts of functional coupling, metabolic channelling, compartmentation and energy transfer networks are reviewed. Different quantitative approaches, including kinetic and mathematical modeling of energy metabolism, intracellular energy transfer and metabolic regulation of energy production and fluxes in the cells in vivo are analyzed. As an example of the system with metabolic channelling, thermodynamic aspects of the functioning the mitochondrial creatine kinase functionally coupled to the oxidative phosphorylation are considered. The internal thermodynamics of the mitochondrial creatine kinase reaction is similar to that for other isoenzymes of creatine kinase, and the oxidative phosphorylation process specifically influences steps of association and dissociation of MgATP with the enzyme due to channelling of ATP from adenine nucleotide translocase. A new paradigm of muscle bioenergetics-the paradigm of energy transfer and feedback signaling networks based on analysis of compartmentation phenomena and structural and functional interactions in the cell is described. Analysis of the results of mathematical modeling of the compartmentalized energy transfer leads to conclusion that both calcium and ADP, which concentration changes synchronously in contraction cycle, may simultaneously activate oxidative phosphorylation in the muscle cells in vivo. The importance of the phosphocreatine circuit among other pathways of intracellular energy transfer network is discussed on the basis of the recent data published in the literature, with some experimental demonstration. The results of studies of perfused rat hearts with completely inhibited creatine kinase show significantly decreased work capacity and respectively, energy fluxes, in these hearts in spite of significant activation of adenylate kinase system (Dzeja et al. this volume). These results, combined with those of mathematical analysis of the energy metabolism of hearts of transgenic mice with switched off creatine kinase isoenzymes confirm the importance of phosphocreatine pathway for energy transfer for cell function and energetics in mature heart and many other types of cells, as one of major parts of intracellular energy transfer network and metabolic regulation.
Mol Cell Biochem 1998 Jul
PMID:Quantitative studies of enzyme-substrate compartmentation, functional coupling and metabolic channelling in muscle cells. 974 26

The accumulation of ATP by preparations of plasma membranes enriched particles (PMEP) isolated from rat hepatocytes, murine splenocytes and human T-lymphocytes has been investigated after the binding of human and murine tumour necrosis factors (TNF alpha) to their specific receptors. The TNF alpha-induced expression of the nuclear oncogene c-myc in intact hepatocytes has been also studied. TNF alpha induced the marked biosynthesis of ATP on PMEP of hepatocytes and splenocytes within the first minute of incubation. The biosynthesis of ATP was independent of the activity of adenylate kinase and only occurred in the presence of all the components of aerobic phosphorylation and the electron acceptor, cytochrome C or diferric transferrin. The level of ATP on PM correlated with the degree of expression of the nuclear oncogene c-myc in the same target cells. Adriamycin totally suppressed the biosynthesis of ATP on PM and simultaneously inhibited the expression of c-myc. The ATP synthesized on PM is suggested to be involved in transduction of the proliferative or growth signal to the cell nucleus.
Biochem Mol Biol Int 1998 Sep
PMID:TNF alpha-induced aerobic synthesis of ATP on plasma membranes of target cells. The relation to the expression of the nuclear oncogene c-myc. 976 16

We identify a novel subtype of adenylate kinase, which is the 4th adenylate kinase (AK4), in the vertebrate. AK4 mRNA is expressed in the mammalian central nervous system in a region-specific manner from the middle stage of embryogenesis to the adulthood in the rodent. The presence of three isozymes of adenylate kinase (AK1, AK2 and AK3) that maintains the homeostasis of adenine and guanine nucleotide composition has been reported in the vertebrate. Obtained mouse AK4 cDNA is 3667 bp in size. The predicted open reading frame consists of 223 amino acid residues. Rat AK4 cDNA is also obtained, and the predicted open reading frame is the same length as that of the mouse. The predicted rat AK4 molecule shows 97.8% homology with mouse AK4. Rat AK4 protein is distinct from rat AK3, 53.8% homologous with rat AK3, although the adenylate kinase signature and the mitochondrial energy transfer protein signature are found in both sequences. Interestingly, rat AK4 is 89.2% homologous with the human AK3 over 223 amino acid residues and rat AK3 is 53.7% homologous with the human AK3 indicating that the reported human AK3 actually belongs to the AK4 group (therefore, it should be referred to as human AK4). Although the sequence of AK4 is most similar to that of AK3 among the AK isozymes, its in vivo expression is completely different from AK3; AK4 mRNA is expressed in the pyramidal cells in the hippocampus (mainly in the subfield CA3), the granular cells in the cerebellum, nasal neuroepithelium and the liver while AK3 mRNA is expressed ubiquitously in the body. It is probable that AK4 acts on the specific mechanism of energy metabolism rather than control of the homeostasis of the ADP pool ubiquitously.
Brain Res Mol Brain Res 1998 Nov 20
PMID:Identification of a novel adenylate kinase system in the brain: cloning of the fourth adenylate kinase. 981 19


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