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PubMed2004

Nitric oxide synthesis in the kidney: isoforms, biosynthesis, and functions in health.

Nitric oxide (NO) is a gaseous free radical that serves cell signaling, cellular energetics, host defense, and inflammatory functions in virtually all cells. In the kidney and vasculature, NO plays fundamental roles in the control of systemic and intrarenal hemodynamics, the tubuloglomerular feedback response, pressure natriuresis, release of sympathetic neurotransmitters and renin, and tubular solute and water transport. NO is synthesized from L-arginine by NO synthases (NOS). Because of its high chemical reactivity and high diffusibility, NO production by each of the 3 major NOS isoforms is regulated tightly at multiple levels from gene transcription to spatial proximity near intended targets to covalent modification and allosteric regulation of the enzyme itself. Many of these regulatory mechanisms have yet to be tested in renal cells. The NOS isoforms are distributed differentially and regulated in the kidney, and there remains some controversy over the specific expression of functional protein for the NOS isoforms in specific renal cell populations. Mice with targeted deletion of each of the NOS isoforms have been generated, and these each have unique phenotypes. Studies of the renal and vascular phenotypes of these mice have yielded important insights into certain vascular diseases, ischemic acute renal failure, the tubuloglomerular feedback response, and some mechanisms of tubular fluid and electrolyte transport, but thus far have been underexploited. This review explores the collective knowledge regarding the structure, regulation, and function of the NOS isoforms gleaned from various tissues, and highlights the progress and gaps in understanding in applying this information to renal and vascular physiology.

Animals↗
PubMed1999

Yeast Sml1, a protein inhibitor of ribonucleotide reductase.

Ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to deoxyribonucleotides; this step is rate-limiting in DNA precursor synthesis. A number of regulatory mechanisms ensure optimal deoxyribonucleotide pools, which are essential for cell viability. The best studied mechanisms are transcriptional regulation of the RNR genes during the cell cycle and in the response to DNA damage, and the allosteric regulation of ribonucleotide reductase by nucleoside triphosphates. Recently, another mode of RNR regulation has been hypothesized in yeast. A novel protein, Sml1, was shown to bind to the Rnr1 protein of the yeast ribonucleotide reductase; this interaction was proposed to inhibit ribonucleotide reductase activity when DNA synthesis is not required (Zhao, X., Muller, E.G.D., and Rothstein, R. (1998) Mol. Cell 2, 329-340). Here, we use highly purified recombinant proteins to directly demonstrate that the Sml1 protein is a strong inhibitor of yeast RNR. The Sml1p specifically binds to the yeast Rnr1p in a 1:1 ratio with a dissociation constant of 0.4 microM. Interestingly, Sml1p also specifically binds to the mouse ribonucleotide reductase R1 protein. However, the inhibition observed in an in vitro mouse ribonucleotide reductase assay is less pronounced than the inhibition in yeast and probably occurs via a different mechanism.

Animals↗
PubMed1999

Allosteric voltage gating of potassium channels I. Mslo ionic currents in the absence of Ca(2+).

Activation of large conductance Ca(2+)-activated K(+) channels is controlled by both cytoplasmic Ca(2+) and membrane potential. To study the mechanism of voltage-dependent gating, we examined mSlo Ca(2+)-activated K(+) currents in excised macropatches from Xenopus oocytes in the virtual absence of Ca(2+) (<1 nM). In response to a voltage step, I(K) activates with an exponential time course, following a brief delay. The delay suggests that rapid transitions precede channel opening. The later exponential time course suggests that activation also involves a slower rate-limiting step. However, the time constant of I(K) relaxation [tau(I(K))] exhibits a complex voltage dependence that is inconsistent with models that contain a single rate limiting step. tau(I(K)) increases weakly with voltage from -500 to -20 mV, with an equivalent charge (z) of only 0.14 e, and displays a stronger voltage dependence from +30 to +140 mV (z = 0.49 e), which then decreases from +180 to +240 mV (z = -0.29 e). Similarly, the steady state G(K)-V relationship exhibits a maximum voltage dependence (z = 2 e) from 0 to +100 mV, and is weakly voltage dependent (z congruent with 0.4 e) at more negative voltages, where P(o) = 10(-5)-10(-6). These results can be understood in terms of a gating scheme where a central transition between a closed and an open conformation is allosterically regulated by the state of four independent and identical voltage sensors. In the absence of Ca(2+), this allosteric mechanism results in a gating scheme with five closed (C) and five open (O) states, where the majority of the channel's voltage dependence results from rapid C-C and O-O transitions, whereas the C-O transitions are rate limiting and weakly voltage dependent. These conclusions not only provide a framework for interpreting studies of large conductance Ca(2+)-activated K(+) channel voltage gating, but also have important implications for understanding the mechanism of Ca(2+) sensitivity.

Algorithms↗
PubMed1983

Hidden overflow pathway to L-phenylalanine in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is representative of a large group of pseudomonad bacteria that possess coexisting alternative pathways to L-phenylalanine (as well as to L-tyrosine). These multiple flow routes to aromatic end products apparently account for the inordinate resistance of P. aeruginosa to end product analogs. Manipulation of carbon source nutrition produced a physiological state of sensitivity to p-fluorophenylalanine and m-fluorophenylalanine, each a specific antimetabolite of L-phenylalanine. Analog-resistant mutants obtained fell into two classes. One type lacked feedback sensitivity of prephenate dehydratase and was the most dramatic excretor of L-phenylalanine. The presence of L-tyrosine curbed phenylalanine excretion to one-third, a finding explained by potent early-pathway regulation of 3-deoxy-D-arabinoheptulosonate 7-phosphate (DAHP) synthase-Tyr (a DAHP synthase subject to allosteric inhibition by L-tyrosine). The second class of regulatory mutants possessed a completely feedback-resistant DAHP synthase-Tyr, the major species (greater than 90%) of two isozymes. Deregulation of DAHP synthase-Tyr resulted in the escape of most chorismate molecules produced into an unregulated overflow route consisting of chorismate mutase (monofunctional), prephenate aminotransferase, and arogenate dehydratase. In the wild type the operation of the overflow pathway is restrained by factors that restrict early-pathway flux. These factors include the highly potent feedback control of DAHP synthase isozymes by end products as well as the strikingly variable abilities of different carbon source nutrients to supply the aromatic pathway with beginning substrates. Even in the wild type, where all allosteric regulation in intact, some phenylalanine overflow was found on glucose-based medium, but not on fructose-based medium. This carbon source-dependent difference was much more exaggerated in each class of regulatory mutants.

3-Deoxy-7-Phosphoheptulonate Synthase↗
PubMed1988

The role of glucose and pyruvate transport in regulating nutrient utilization by preimplantation mouse embryos.

Preimplantation mouse embryos utilize pyruvate preferentially during the early cleavage stages before switching to glucose at around the time of compaction. This switch in substrate preference has been studied using a non-invasive ultramicrofluorometric analytical technique on single mouse embryos. On the basis of transport kinetic studies and inhibition by phloretin, cytochalasin B and sugar analogues, a component of glucose uptake by mouse blastocysts was found to be mediated by facilitated diffusion. The Jmax and Kt of this facilitated component were 3.53 pmol embryo-1 h-1 and 0.14 mM, respectively. At physiological concentrations of glucose, the facilitated component accounts for around 75% of glucose uptake. Glucose uptake by blastocysts was found to be insensitive to insulin, added at a range of concentrations. There was no evidence for glucose active transport. The carrier-mediated component of glucose entry was detectable from the 2-cell stage onwards. Pyruvate uptake was also mediated by a carrier throughout development. In the absence of glucose in the incubation medium, the characteristic decline in pyruvate uptake does not occur. The data are consistent with a role for embryonic cell transport in regulating glucose utilization prior to compaction, but do not exclude the involvement of metabolic factors, such as the allosteric regulation of the enzymes hexokinase and phosphofructokinase.

Animals↗
PubMed1990

Regulation of phosphofructokinase at physiological concentration of enzyme studied by stopped-flow measurements.

Stopped-flow measurements have been carried out to study some basic allosteric properties of muscle and yeast phosphofructokinase at physiological concentration of enzyme. An important increase in the affinity for fructose-6-P accompanied by an intense decrease in the ATP inhibition was observed with the muscle enzyme, which also became insensitive to fructose-2,6-P2 under these conditions. Yeast phosphofructokinase exhibited a significant diminution in the inhibition by ATP, although with no apparent change in the affinity for fructose-6-P. These results provide strong support in favor of the dependence of the allosteric regulation of phosphofructokinase on its concentration in vivo.

Adenosine Triphosphate↗
PubMed2006

A mutation in the S-switch region of the Runt domain alters the dynamics of an allosteric network responsible for CBFbeta regulation.

The Runt domain is the DNA binding domain of the core binding factor (CBF) Runx subunits. The CBFs are transcription factors that play critical roles in hematopoiesis, bone, and neuron development in mammals. A common non-DNA binding CBFbeta subunit heterodimerizes with the Runt domain of the Runx proteins and allosterically regulates its affinity for DNA. Previous NMR dynamics studies suggested a model whereby CBFbeta allosterically regulates DNA binding by quenching conformational exchange in the Runt domain, particularly in the S-switch region and the betaE'-F loop. We sought to test this model, and to this end introduced all possible single amino acid substitutions into the S-switch region and the betaE'-F loop, and screened for mutations that enhanced DNA-binding. We demonstrate that one Runt domain mutant, R164N, binds both DNA and CBFbeta with higher affinity, but it is less sensitive to allosteric regulation by CBFbeta. Analysis of NMR relaxation data shows that the chemical exchange exhibited by the wild-type Runt domain is largely quenched by the R164N substitution. These data support a model in which the dynamic behavior of a network of residues connecting the CBFbeta and DNA binding sites on the Runt domain plays a critical role in the mechanism of allosteric regulation. This study provides an important functional link between dynamic behavior and protein allosteric function, consistent with results on other allosterically regulated proteins.

Allosteric Regulation↗
PubMed1992

Hemoglobin Thionville. An alpha-chain variant with a substitution of a glutamate for valine at NA-1 and having an acetylated methionine NH2 terminus.

In hemoglobin (Hb) Thionville, the substitution of a glutamic acid for the alpha-chain NH2-terminal valine inhibits the cleavage of the initiator methionine which is then acetylated. The elongation of the alpha-chain NH2 terminus modifies the three-dimensional structure of hemoglobin at a region that is known to have an important role in the allosteric regulation of oxygen binding. Relative to Hb A, Hb Thionville has a lower affinity for oxygen, and the heterotropic allosteric effects of protons, chloride, and bezafibrate are reduced. In contrast, the response to 2,3-diphosphoglycerate is normal. Analysis of oxygen equilibrium data within the framework of the two-state allosteric model indicates that the structure of deoxy Hb Thionville is stabilized relative to that of deoxy Hb A. The x-ray crystal structure of deoxy Hb Thionville shows that the glutamate side chain extends away from the alpha 1-alpha 2 interface, whereas the methionine side chain (which has two conformations) extends into the alpha 1-alpha 2 interface, physically displacing chloride and bezafibrate. The increased stability of deoxy Hb Thionville is due to new intrasubunit and intersubunit contacts made by the methionine. These interactions replace the indirect contacts, made through bound chloride ions, that Val-1 alpha normally contributes to the alpha 1-alpha 2 interface.

Acetylation↗
PubMed1991

Monovalent cation and amiloride analog modulation of adrenergic ligand binding to the unglycosylated alpha 2B-adrenergic receptor subtype.

The unglycosylated alpha 2B subtype of the alpha 2-adrenergic receptor found in NG-108-15 cells possesses allosteric regulation of adrenergic ligand binding by monovalent cations and 5-amino-substituted amiloride analogs. These findings demonstrate that allosteric modulation of adrenergic ligand binding is not a property unique to the alpha 2A subtype. The observation that amiloride analogs as well as monovalent cations can modulate adrenergic ligand binding to the nonglycosylated alpha 2B subtype indicates that charge shielding due to carbohydrate moieties does not play a role in this allosteric modulation but, rather, these regulatory effects result from interactions of cations and amiloride analogs with the protein moiety of the receptor. Furthermore, the observation that both alpha 2A and alpha 2B receptor subtypes are modulated by amiloride analogs suggests that structural domains that are conserved between the two are likely to be involved in this allosteric modulation.

Amiloride↗
PubMed1990

Calcium binding to extracellular sites of skeletal muscle calcium channels regulates dihydropyridine binding.

The binding of dihydropyridine (PN200-110) to skeletal muscle microsomes (which were 84% sealed inside-out vesicles) was not influenced by the addition of calcium or magnesium nor by addition of their chelators (EDTA or EGTA) unless the vesicles were pretreated with the calcium-magnesium ionophore A23187 and EDTA to remove entrapped cations. Separation of inside-out vesicles from right-side-out vesicles by wheat germ agglutinin chromatography revealed that only the right-side-out vesicles exhibited a calcium-, magnesium-, and chelator-dependent binding of PN200-110. Dihydropyridine binding to cardiac sarcolemma membranes (which were 46% inside-out) and to solubilized skeletal muscle membranes was inhibited by EDTA and could be fully restored by 10 microM calcium or 1 mM magnesium. Calcium increased PN200-110 binding to partially purified rabbit skeletal muscle calcium channels from 3.9 pmol/mg protein to 25.5 pmol/mg protein with a pK0.5 = 6.57 +/- 0.059 and a Hill coefficient of 0.56 +/- 0.04. Magnesium increased binding from 0.7 pmol/mg protein to 16.8 pmol/mg protein with a pK0.5 = 3.88 +/- 0.085 and a Hill coefficient of 0.68 +/- 0.074. These studies suggest that calcium binding to high affinity sites or magnesium binding to low affinity sites on the extracellular side of skeletal muscle T-tubule calcium channels regulates dihydropyridine binding. Further, similar calcium and magnesium binding sites exist on the cardiac calcium channel and serve to allosterically regulate dihydropyridine binding.

Animals↗
PubMed1985

Alterations in intracellular deoxyribonucleotide levels of mutationally altered ribonucleotide reductases in Escherichia coli.

Four recombinant plasmid clones (pPS305, pPS308, pPS317, and pPS319) coding for Escherichia coli ribonucleotide reductase have been characterized in vivo and in vitro. Each clone carried a different missense mutation affecting the B1 subunit. Measurements were made of deoxyribonucleoside triphosphate pools. Cells carrying the wild-type plasmid, pPS2, overproduced ribonucleotide reductase 10 to 20 times. As a consequence of this elevated enzyme level, the deoxyribonucleotide pools were approximately three times higher. All four mutant clones showed disturbed deoxyribonucleotide pools. The in vitro studies involved chromatography on affinity media, measurements of enzyme activity and allosteric regulation with a variety of substrates and effector molecules, and direct photoaffinity labeling in the presence of dTTP. Clones pPS305 and pPS308 were shown to code for catalytically defective enzymes, whereas clones pPS317 and pPS319 were shown to code for allosterically altered enzymes. The characterized missense mutations can thus be localized to areas involved in regulation of the substrate specificity or to the active site of protein B1. The alteration of the deoxyribonucleotide pools found in cells containing the allosterically defective clones pPS317 and pPS319 clearly demonstrated in vivo significance for the allosteric control of protein B1 in E. coli cells.

Affinity Labels↗
PubMed1999

Regulation of skeletal muscle glycogen phosphorylase and PDH during maximal intermittent exercise.

The time course for the activation of glycogen phosphorylase (Phos) and pyruvate dehydrogenase (PDH) and their allosteric regulators was determined in human skeletal muscle during repeated bouts of maximal exercise. Six subjects completed three 30-s bouts of maximal isokinetic cycling separated by 4-min recovery periods. Muscle biopsies were taken at rest and at 6, 15, and 30 s of exercise during bouts 1 and 3. Phos was rapidly activated within the first 6 s of bout 1 from 12% at rest to 47% at 6 s. The activation of PDH increased from 14% at rest to 48% at 6 s and 95% at 15 s of bout 1. Phos reverted back to basal values at the end of the first bout, whereas PDH remained fully activated. In contrast, in the third bout, PDH was 42% at rest and was activated more rapidly and was nearly completely activated by 6 s, whereas Phos remained at basal levels (range 14-20%). Lactate accumulation was marked in the first bout and increased progressively from 2.7 to 76.1 mmol/kg dry wt with no further increase in bout 3. Glycogen utilization was also marked in the first bout and was negligible in bout 3. The rapid activation of Phos and slower activation of PDH in bout 1 was probably due to Ca(2+) release from the sarcoplasmic reticulum. Lactate accumulation appeared to be due to an imbalance of the relative activities of Phos and PDH. The increase in H(+) concentration may have served to reduce pyruvate production by inhibiting Phos transformation and may have simultaneously activated PDH in the third bout such that there was a better matching between pyruvate production and oxidation and minimal lactate accumulation. As each bout progressed and with successive bouts, there was a decreasing ability to stimulate substrate phosphorylation through phosphocreatine hydrolysis and glycolysis and a shift toward greater reliance on oxidative phosphorylation.

Acetylcarnitine↗
PubMed1998

Cyclic AMP stimulates the cyclic GMP egression pump in human erythrocytes: effects of probenecid, verapamil, progesterone, theophylline, IBMX, forskolin, and cyclic AMP on cyclic GMP uptake and association to inside-out vesicles.

The knowledge about the structure and function of the protein families responsible for cGMP synthesis and metabolic conversion has grown vastly the last years, whereas little is known about proteins that account for the cellular export of cGMP. In the present study, we have employed a model with inside-out vesicles prepared from human erythrocytes to characterize modulation and regulation of cellular cGMP extrusion. The active transport was saturable (Km of 2.4 +/- 0.2 microM, mean +/- SEM, n = 3) and coupled to ATP hydrolysis since no accumulation was detected in the presence of ATP-gamma-S and AMP-PNP. The observation that 100 microM of cAMP caused a minimal inhibition (14.4 +/- 0.3%) of active cGMP transport showed that the extrusion system for cGMP was not shared with cAMP, but a competitive interaction occurred for the ATP-independent association to the inside out vesicles. In contrast, the lowest, but physiological relevant cAMP concentrations (0.1-5 microM) stimulated the active cGMP transport with 30-35%, an observation that suggests cAMP as an allosteric regulator of the cGMP transporter. Several well-known modulators of other energy-requiring membrane transport systems caused a competitive and concentration-dependent inhibition, including verapamil (Ki = 13.0 +/- 2.4 microM), forskolin (Ki = 13.5 +/- 1.4 microM) and probenecid (Ki = 27.0 +/- 1.3 microM). Progesterone, which was the most potent inhibitor (Ki = 2.2 +/- 0.3 microM), interacted with the active cGMP transport in a noncompetitive manner. The highest concentration (100 microM) of IBMX and theophylline reduced the active cGMP uptake with 29.5 +/- 1.9% and 21.6 +/- 2.1%, respectively. None of these substances interfered with the association of cGMP to the vesicles in absence of ATP. The present results show that human erythrocytes possess a cell membrane cGMP transporter which is coupled to an ATPase. Its activity is regulated by cAMP in an apparent allosteric manner and inhibited by substances previously known to interact with other membrane transport systems.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Luciferase of Luciola mingrelica fireflies. Kinetics and regulation mechanism.

Biochemical properties, spectral parameters of bioluminescence and reaction kinetics for Luciola mingrelica firefly luciferase are described and analysed. The kinetic scheme of the enzymatic process is proposed and discussed. Allosteric regulation of luciferase activity by ATP and its analogues is considered and binding Mg2+ to luciferase shown to increase its activity. Regulation mechanism of luciferase activity by phospholipids is analysed and choline-containing phospholipids shown to be specific luciferase activators. Some properties of firefly luciferase and the luciferase synthesized during firefly mRNA translation in frog oocytes are compared.

Allosteric Site↗
PubMed2005

A polymorphic motif in the small subunit of ADP-glucose pyrophosphorylase modulates interactions between the small and large subunits.

The heterotetrameric, allosterically regulated enzyme, adenosine-5'-diphosphoglucose pyrophosphorylase (AGPase) catalyzes the rate-limiting step in starch synthesis. Despite vast differences in allosteric properties and a long evolutionary separation, heterotetramers of potato small subunit and maize large subunit have activity comparable to either parent in an Escherichia coli expression system. In contrast, co-expression of maize small subunit with the potato large subunit produces little activity as judged by in vivo activity stain. To pinpoint the region responsible for differential activity, we expressed chimeric maize/potato small subunits in E. coli. This identified a 55-amino acid motif of the potato small subunit that is critical for glycogen production when expressed with the potato large subunit. Potato and maize small subunit sequences differ at five amino acids in this motif. Replacement experiments revealed that at least four amino acids of maize origin were required to reduce staining. An AGPase composed of a chimeric potato small subunit containing the 55-amino acid maize motif with the potato large subunit exhibited substantially less affinity for the substrates, glucose-1-phosphate and ATP and an increased Ka for the activator, 3-phosphoglyceric acid. Placement of the potato motif into the maize small subunit restored glycogen synthesis with the potato large subunit. Hence, a small polymorphic motif within the small subunit influences both catalytic and allosteric properties by modulating subunit interactions.

Amino Acid Motifs↗
PubMed1981

Modulation of phosphofructokinase behavior by chemical modifications during the immobilization process.

Phosphofructokinase was immobilized within a protein membrane or on soluble protein polymers using glutaraldehyde as cross-linking reagent. The native enzyme was also modified chemically, using the cross-linking reagent alone. A comparative kinetic investigation of these preparations was carried out. The catalytic activity of the chemically modified enzyme and its affinity towards fructose 6-phosphate decreased significantly; the modified enzyme lost its cooperative properties and the allosteric regulation by AMP was affected. When the chemical treatment was performed in the presence of effectors (AMP or ATP) the allosteric transition induced by AMP was restored, suggesting that the cross-linking reagent modified the AMP regulatory sites, albeit no higher-substrate-affinity enzyme conformation was frozen. Molecular data showed that glutaraldehyde produced intramolecular then intermolecular bonds as its concentration increased. When the enzyme was immobilized into protein membranes or on soluble polymers, the enzyme behavior was quite similar: decrease of affinity towards fructose 6-phosphate but no changes in cooperative properties and modifications of allosteric transition induced by AMP. When AMP was present during the immobilisation process, the enzyme immobilized in this way was no longer sensitive to effectors, either AMP or ATP. It showed Michaelian behavior and higher substrate affinity quite similar to that of the native enzyme. The data suggested that a higher-substrate-affinity enzymatic form was most probably stabilized by immobilization.

Adenosine Monophosphate↗
PubMed1996

The Cys292-->Ala substitution in protein R1 of class I ribonucleotide reductase from Escherichia coli has a global effect on nucleotide binding at the specificity-determining allosteric site.

Ribonucleotide reductase from aerobically grown Escherichia coli is allosterically regulated, both with respect to general activity and substrate specificity. Protein R1, the homodimeric enzyme component which harbours binding sites for allosteric effectors (nucleoside triphosphates) as well as substrates (ribonucleoside diphosphates), has been engineered at Cys292 close to the dimer interaction area. This residue was earlier shown to be specifically photoaffinity labelled with the allosteric nucleotide dTTP. In this study the effect of the Cys292-->Ala substitution is shown to be an overall diminished nucleotide binding at the specificity site reflected in Kd values for dTTP, dGTP and dATP higher by more than one order of magnitude with respect to wild type. The mutant protein's interaction with other protein components of the ribonucleotide reductase system was unaffected by the mutation. These results show that Cys292 in protein R1 of class I ribonucleotide reductase from E. coli is located in the allosteric specificity site.

Allosteric Site↗
PubMed1992

Ribonucleotide reductase: regulation, regulation, regulation.

Ribonucleotide reductase (RNR) catalyses the rate limiting step in the production of deoxyribonucleotides needed for DNA synthesis. It is composed of two dissimilar subunits, R1, the large subunit containing the allosteric regulatory sites, and R2, the small subunit containing a binuclear iron center and a tyrosyl free radical. Recent isolation of the mammalian and yeast RNR genes has shown that, in addition to the well documented allosteric regulation, the synthesis of the enzyme is also tightly regulated at the level of transcription. The mRNAs for both subunits are cell-cycle regulated and, in yeast, inducible by DNA damage. Yeast encode a second large subunit gene, RNR3, that is expressed only in the presence of DNA damage. This regulation is thought to provide a metabolic state that facilitates DNA replicational repair processes.

Animals↗