Stability Constants of Metal Complexes with Mononucleotides.

Walaas, Eva; Bergström, Kurt; Löw, Henrik; Siekevitz, Philip; Ernster, Lars; Diczfalusy, E.

doi:10.3891/acta.chem.scand.12-0528

Cited by 223 publications

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“…Stability constants and enthalpy changes for metal-nucleotide complexes were obtained by referring to NIST Critically Selected Stability Constants of Metal Complexes: Version 6.0 (http://www.nist.gov/srd/ nist46.htm). For calculation of concentrations of metal-GTP complex and metal-free GTP, we used stability constants and enthalpy changes of metal-ATP or proton-ATP complex as a substitute for those of the metal-GTP complex, because there were no data for stability constants and enthalpy changes of the Mg-, Zn-, Co-or Mn-GTP complexes in K + salt as a background electrolyte; however, stability constants of GTP with respect to Mg 2+ in Na + salt as a background electrolyte and stability constants and enthalpy changes of GTP with respect to H + in K + salt as a background electrolyte were very similar to those of ATP in the database, and apparent stability constants of GTP with respect to Mg 2+ , Mn 2+ and Co 2+ were almost the same as those of ATP given in a previous report [20]. Based on the condition of the incubation mixture for the enzyme activity described as above, parameters used in the calculation program were 37°C, pH 7.5, and 0.110 1 ionic strength.…”

Section: Measurement Of Gch Activitymentioning

confidence: 82%

“…When the concentration of Mg-free GTP was fixed at 10 lM, the concentrations of MgCl 2 in the reaction mixture were 35, 70, 105, 140, 175 and 210 lM at the total GTP concentrations of 15,20,25,30,35 and 40 lM, respectively ( Fig. 3A and B).…”

Section: Gch Recognizes Mg-free Gtpmentioning

confidence: 99%

“…The presence of Zn 2+ during the refolding procedure elicited a To fix the concentration of Mg-free GTP at 10 lM constant, we adjusted the concentrations of MgCl 2 in the reaction mixture to 35, 70, 105, 140, 175, and 210 lM at the total GTP concentrations of 15,20,25,30,35, and 40 lM, respectively. Under these conditions at a constant 10 lM Mg-free GTP (A; s), the concentrations of Mg-GTP complex (A; d) and Mg 2+ (B; n) were plotted.…”

Section: Requirement Of Zn 2+ For the Gch Enzymatic Activitymentioning

confidence: 99%

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GTP cyclohydrolase I utilizes metal‐free GTP as its substrate

Suzuki

Kurita

Ichinose

2003

European Journal of Biochemistry

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GTP cyclohydrolase I (GCH) is the rate-limiting enzyme for the synthesis of tetrahydrobiopterin and its activity is important in the regulation of monoamine neurotransmitters such as dopamine, norepinephrine and serotonin. We have studied the action of divalent cations on the enzyme activity of purified recombinant human GCH expressed in Escherichia coli. First, we showed that the enzyme activity is dependent on the concentration of Mg-free GTP. Inhibition of the enzyme activity by Mg 2+ , as well as by Mn 2+ , Co 2+ or Zn 2+ , was due to the reduction of the availability of metal-free GTP substrate for the enzyme, when a divalent cation was present at a relatively high concentration with respect to GTP. We next examined the requirement of Zn 2+for enzyme activity by the use of a protein refolding assay, because the recombinant enzyme contained approximately one zinc atom per subunit of the decameric protein. Only when Zn 2+ was present was the activity of the denatured enzyme effectively recovered by incubation with a chaperone protein. These are the first data demonstrating that GCH recognizes Mg-free GTP and requires Zn 2+ for its catalytic activity. We suggest that the cellular concentration of divalent cations can modulate GCH activity, and thus tetrahydrobiopterin biosynthesis as well.Keywords: GTP cyclohydrolase I; magnesium; recombinant protein; tetrahydrobiopterin; zinc.Metal ions are essential for many physiological functions of the brain. They may also induce or aggravate numerous neurodegenerative processes. Thus, it is important to understand the roles of metal ions in normal and pathological brain functions.GTP cyclohydrolase I (GCH) is the rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin (BH 4 ), and the cellular BH 4 content is regulated mainly by the activity of this enzyme. BH 4 is an essential cofactor for three aromatic amino-acid monooxygenases ) phenylalanine, tyrosine, and tryptophan hydroxylases -and for nitric oxide synthase [1]. BH 4 deficiency caused not only a decrease in the activity of these enzymes but also a decrease in the protein levels of tyrosine hydroxylase and nitric oxide synthase [2,3]. Therefore, the availability of BH 4 affects the amounts of neurotransmitters such as catecholamines, serotonin, melatonin and nitric oxide. The role of BH 4 in the activity of nitric oxide synthase also makes BH 4 an important factor for the immune system and endothelial cell function.Various hormones and cytokines are known to induce the expression of the GCH gene in neural, lymphocytic and endothelial cells, and in different cell lines, resulting in an increased BH 4 content [4][5][6][7][8]. At the post-transcriptional level, BH 4 was shown to inhibit, and phenylalanine to stimulate, GCH activity through interaction with GFRP, a GTP cyclohydrolase I feedback regulatory protein [9]. GCH, which is a homodecameric protein, shows positive cooperativity against the GTP substrate [10] and phenylalanine changes the substrate velocity curve from sigmoidal to hyperbolic [11].Recent...

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Section: Measurement Of Gch Activitymentioning

confidence: 82%

Section: Gch Recognizes Mg-free Gtpmentioning

confidence: 99%

Section: Requirement Of Zn 2+ For the Gch Enzymatic Activitymentioning

confidence: 99%

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GTP cyclohydrolase I utilizes metal‐free GTP as its substrate

Suzuki

Kurita

Ichinose

2003

European Journal of Biochemistry

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“…Hydrolysis of ATP is strictly dependent on the presence of Ca2+ or M g2+, sug gesting that ATP alone is not (detectably) used as a substrate. Upon addition of Ca2+ or M g2+ to ATPcontaining media, these metal ions will be chelated by ATP (Walaas, 1958;Sapper et al, 1980). Although M g2+ is chelated more strongly than C a2+ by ATP, both interactions have the same modifying effect on the conformation of the adenosine-phosphate-ester and thus allow effective binding of the phosphate group to the active site of enzymes.…”

Section: Characteristics O F the C A2+-activated Atpase Activ Itiesmentioning

confidence: 99%

Ca2+-dependent phosphatase and ATPase activities in eel gill plasma membranes—I. Identification of Ca2+-activated ATPase activities with non-specific phosphatase activities

Flik

Bonga

Fenwick

1983

Comparative Biochemistry and Physiology Part B: Comparative Bio

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Abstract-1. The characteristics of Ca2+-activated ATPase activities previously often postulated as components for the calcium transporting system in fish gills do not fulfil the requirements of a transport Ca:'-ATPase.2. The chelation of Ca;~-or Mg:~-ions is a prerequisite for the adenosinephosphate esters to serve as substrate for gill plasma membrane phosphatases.3. Ca2+-activated ATP hydrolysis results from the activity of a heterogeneous pool of phosphatases located in the plasma membranes of the branchial epithelium, as is concluded from substrate specificity tests and the effects of various inhibitors on these hydrolytic activities.4. In the present study only non-specific phosphatases could be shown.

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“…As in their studies, in the absence of hormones, Mg++ concentration, in excess of that required for maximal Mg-ATP concentrations (Walaas, 1958 ;Burton, 1959), enhanced the basal activity of adenyl cyclase. If, as suggested by Bimbaumer et al (1969), Mg-ATP is the true substrate for adenyl cyclase, free ATP an inhibitor and free Mg+ + an allosteric effector, it is possible that the observed accumulation of cyclic AMP in the presence of adrenaline is an action of the hormone in increasing the affinity of adenyl cyclase for Mg++ at a site distinct from the catalytic site.…”

Section: Discussionmentioning

confidence: 94%

The relation of adenyl cyclase to the activity of other ATP utilizing enzymes and phosphodiesterase in preparations of rat brain; mechanism of stimulation of cyclic AMP accumulation by adrenaline, ouabain and Mn⁺⁺

Katz¹,

Tenenhouse²

1973

British J Pharmacology

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Stability Constants of Metal Complexes with Mononucleotides.

Cited by 223 publications

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GTP cyclohydrolase I utilizes metal‐free GTP as its substrate

GTP cyclohydrolase I utilizes metal‐free GTP as its substrate

Ca2+-dependent phosphatase and ATPase activities in eel gill plasma membranes—I. Identification of Ca2+-activated ATPase activities with non-specific phosphatase activities

The relation of adenyl cyclase to the activity of other ATP utilizing enzymes and phosphodiesterase in preparations of rat brain; mechanism of stimulation of cyclic AMP accumulation by adrenaline, ouabain and Mn⁺⁺

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Stability Constants of Metal Complexes with Mononucleotides.

Cited by 223 publications

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GTP cyclohydrolase I utilizes metal‐free GTP as its substrate

GTP cyclohydrolase I utilizes metal‐free GTP as its substrate

Ca2+-dependent phosphatase and ATPase activities in eel gill plasma membranes—I. Identification of Ca2+-activated ATPase activities with non-specific phosphatase activities

The relation of adenyl cyclase to the activity of other ATP utilizing enzymes and phosphodiesterase in preparations of rat brain; mechanism of stimulation of cyclic AMP accumulation by adrenaline, ouabain and Mn++

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The relation of adenyl cyclase to the activity of other ATP utilizing enzymes and phosphodiesterase in preparations of rat brain; mechanism of stimulation of cyclic AMP accumulation by adrenaline, ouabain and Mn⁺⁺