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PubMed1992

Muscarinic binding sites on bovine pulmonary arterial endothelial cells in culture.

We have investigated the presence and nature of muscarinic binding sites on membranes from cultured bovine pulmonary arterial endothelial cells (BPAE). BPAE were harvested and subcultured nonenzymatically; experiments were performed 3-5 days postconfluence and between 10 and 25 passage numbers. Utilizing radioligand binding techniques with the muscarinic receptor antagonists [3H]3-quinuclidinyl benzilate ([3H]QNB) and [3H]N-methylscopolamine ([3H]MS) as probes, we identified a small population of atropine-sensitive muscarinic sites (1,800-2,000 sites/cell or 7-8 fmol/mg protein). Muscarinic binding sites on BPAE membranes resembled classical muscarinic receptors in that (a) the binding of 2 nM [3H]QNB was inhibited by muscarinic agonists and antagonists, (b) [3H]QNB binding was 30 times more sensitive to R(-)- than to S(+)-QNB, (c) binding of the muscarinic receptor agonist carbamylcholine involved high and low affinity components, (d) the stable GTP analog, Gpp(NH)p (100 microM) shifted agonist binding curves to the right by a factor of three, and (e) the high affinity binding of the agonist [3H]oxotremorine-M to muscarinic receptors was depressed by Gpp(NH)p. On the other hand, gallamine, which allosterically regulates muscarinic receptor binding in other tissues, did not affect the rates of dissociation of [3H]QNB, [3H]MS or [3H]oxotremorine-M from BPAE binding sites. We concluded that BPAE in culture exhibit muscarinic binding sites which possess many but not all of the properties associated with classical muscarinic receptors.

Allosteric Site↗
PubMed1999

Interactive binding to the two principal ligand binding sites of human serum albumin: effect of the neutral-to-base transition.

The relationship between the two principal ligand binding sites, sites I and II, on human serum albumin (HSA) was quantitatively and qualitatively examined by equilibrium dialysis and fluorescence spectroscopy. Among the three subsite markers to site I, only the binding of dansyl-L-asparagine (DNSA), which is a subsite Ib marker (K. Yamasaki et al., Biochim. Biophys. Acta 1295 (1996) 147), was inhibited by the simultaneous binding of a site II ligand, such as ibuprofen and diazepam. This indicates that, in contrast to subsite Ib, subsites Ia and Ic do not strongly interact with site II. The thermodynamic characteristics for the coupling reaction between DNSA and ibuprofen and between DNSA and diazepam, which gave positive coupling free energies and negative values for both coupling enthalpy and entropy, indicated that the reaction process was entropically driven. Increase of pH from 6.5 to 8.2 caused an increase in coupling constant and entropy for the mutual antagonism between DNSA and the site II ligands on binding to HSA. The site II ligand-induced red-shift of lambda(max) and solvent accessibility of DNSA in subsite Ib were decreased when the albumin molecule was isomerized from the neutral (N) to the base (B) conformation in the physiological pH region. Based on these findings, we conclude that a 'competitive' like strong allosteric regulation exists for the binding of these two ligands to the N conformer, whereas for the B conformer this interaction can be classified as nearly 'independent'. Since the distance between Trp-214, which resides within the site I subdomain, and Tyr-411, which is involved in site II, is increased by 6 A during the N-B transition (N.G. Hagag et al., Fed. Proc. 41 (1982) 1189), we propose a mechanism for the pH-dependent antagonistic binding between subsite Ib and site II, which involves the transmission of ligand-induced allosteric effects from one site to another site, modified by changes in the spatial relationship of sites I and II caused by the N-B transition.

Acrylamide↗
PubMed1991

Leucine modulates peptide transport system-1 across the blood-brain barrier at the stereospecific site within the central nervous system.

Previous results have shown that leucine injected into a cerebral ventricle (i.c.v.) can act as an allosteric regulator of peptide transport system-1 (PTS-1), the system that transports Tyr-Pro-Leu-Gly-NH2 (Tyr-MIF-1) and the enkephalins out of the central nervous system (CNS). D-Leucine appeared more potent than L-leucine. In the current study, dose-response curves were constructed for each compound after both intravenous (i.v.) and i.c.v. injection. Based on ED50 values after i.c.v. injection, D-leucine was about 200 times more potent than L-leucine in its inhibition of PTS-1, thereby confirming stereospecificity of the allosteric site. D- and L-Leucine were also more potent when given i.c.v. than when given i.v., suggesting that the site is located on the CNS side of the blood-brain barrier (BBB). The finding that D-leucine was less potent than L-leucine when given i.v. is also consistent with a CNS site of action because the L-isomer of leucine has been shown to be preferentially transported into the brain. These findings agree with the previous suggestion that some of the neurotoxic effects of leucine may be mediated through PTS-1 and could help explain how D-amino acids can exert opiate-related effects on the CNS.

Animals↗
PubMed1998

The crystal structure of Pyrococcus furiosus ornithine carbamoyltransferase reveals a key role for oligomerization in enzyme stability at extremely high temperatures.

The Pyrococcus furiosus (PF) ornithine carbamoyltransferase (OTCase; EC 2.1.3.3) is an extremely heat-stable enzyme that maintains about 50% of its activity after heat treatment for 60 min at 100 degrees C. To understand the molecular basis of thermostability of this enzyme, we have determined its three-dimensional structure at a resolution of 2.7 A and compared it with the previously reported structures of OTCases isolated from mesophilic bacteria. Most OTCases investigated up to now are homotrimeric and devoid of allosteric properties. A striking exception is the catabolic OTCase from Pseudomonas aeruginosa, which is allosterically regulated and built up of four trimers disposed in a tetrahedral manner, an architecture that actually underlies the allostery of the enzyme. We now report that the thermostable PF OTCase (420 kDa) presents the same 23-point group symmetry. The enzyme displays Michaelis-Menten kinetics. A detailed comparison of the two enzymes suggests that, in OTCases, not only allostery but also thermophily was achieved through oligomerization of a trimer as a common catalytic motif. Thermal stabilization of the PF OTCase dodecamer is mainly the result of hydrophobic interfaces between trimers, at positions where allosteric binding sites have been identified in the allosteric enzyme. The present crystallographic analysis of PF OTCase provides a structural illustration that oligomerization can play a major role in extreme thermal stabilization.

Allosteric Site↗
PubMed2002

A peptide template as an allosteric supramolecular catalyst for the cleavage of phosphate esters.

The heptapeptide H-Iva-Api-Iva-ATANP-Iva-Api-Iva-NHCH(3) (P1a), where Iva is (S)-isovaline, Api is 4-amino-4-carboxypiperidine, and ATANP is (S)-2-amino-3-[1-(1,4,7-triazacyclononane)]propanoic acid, has been synthesized. Its conformation in aqueous solution is essentially that of a 3(10)-helix. By connecting three copies of P1a to a functionalized Tris(2-aminoethyl)amine (Tren) platform a new peptide template, [T(P1)(3)], was obtained. This molecule is able to bind up to four metal ions (Cu(II) or Zn(II)): one in the Tren subsite and three in the azacyclononane subunits. The binding of the metals to the Tren platform induces a change from an open to a closed conformation in which the three short, helical peptides are aligned in a parallel manner with the azacyclonane units pointing inward within the pseudocavity they define. T(P1)(3) shows a peculiar behavior in the transphosphorylation of phosphate esters; the tetrazinc complex is a catalyst of the cleavage of 2-hydroxypropyl-p-nitrophenyl phosphate (HPNP), whereas the free ligand is a catalyst of the cleavage of an oligomeric RNA sequence with selectivity for pyrimidine bases. In the case of HPNP, Zn(II) acts as a positive allosteric effector by enhancing the catalytic efficiency of the system. In the case of the polyanionic RNA substrate, Zn(II) switches off the activity, thus behaving as a negative allosteric regulator. It is suggested that the opposite behavior of the catalyst induced by Zn(II) is associated with the change of conformation of the Tren platform, and consequently of the relative spatial disposition of the three linked peptides, that occurs after binding of the metal ion.

Allosteric Site↗
PubMed2004

A glycine-dependent riboswitch that uses cooperative binding to control gene expression.

We identified a previously unknown riboswitch class in bacteria that is selectively triggered by glycine. A representative of these glycine-sensing RNAs from Bacillus subtilis operates as a rare genetic on switch for the gcvT operon, which codes for proteins that form the glycine cleavage system. Most glycine riboswitches integrate two ligand-binding domains that function cooperatively to more closely approximate a two-state genetic switch. This advanced form of riboswitch may have evolved to ensure that excess glycine is efficiently used to provide carbon flux through the citric acid cycle and maintain adequate amounts of the amino acid for protein synthesis. Thus, riboswitches perform key regulatory roles and exhibit complex performance characteristics that previously had been observed only with protein factors.

5' Untranslated Regions↗
PubMed2007

Reversible oxidation of the membrane distal domain of receptor PTPalpha is mediated by a cyclic sulfenamide.

Protein tyrosine phosphatases (PTPs) are fundamental to the regulation of cellular signalling cascades triggered by protein tyrosine kinases. Most receptor-like PTPs (RPTPs) comprise two tandem PTP domains, with only the membrane proximal domains (D1) having significant phosphatase activity; the membrane distal domains (D2) display little to no catalytic activity. Intriguingly, however, many RPTP D2s share the catalytically essential Cys and Arg residues of D1s. D2 of RPTPalpha may function as a redox sensor that mediates regulation of D1 via reactive oxygen species. Oxidation of Cys723 of RPTPalpha D2 (equivalent to PTP catalytic Cys residues) stabilizes RPTPalpha dimers, induces rotational coupling, and is required for inactivation of D1 phosphatase activity. Here, we investigated the structural consequences of RPTPalpha D2 oxidation. Exposure of RPTPalpha D2 to oxidants promotes formation of a cyclic sulfenamide species, a reversibly oxidized state of Cys723, accompanied by conformational changes of the D2 catalytic site. The cyclic sulfenamide is highly resistant to terminal oxidation to sulfinic and sulfonic acids. Conformational changes associated with RPTPalpha D2 oxidation have implications for RPTPalpha quaternary structure and allosteric regulation of D1 phosphatase activity.

Amides↗
PubMed2004

Long-range allosteric transitions in carbamoyl phosphate synthetase.

Carbamoyl phosphate synthetase plays a key role in both pyrimidine and arginine biosynthesis by catalyzing the production of carbamoyl phosphate from one molecule of bicarbonate, two molecules of MgATP, and one molecule of glutamine. The enzyme from Escherichia coli consists of two polypeptide chains referred to as the small and large subunits, which contain a total of three separate active sites that are connected by an intramolecular tunnel. The small subunit harbors one of these active sites and is responsible for the hydrolysis of glutamine to glutamate and ammonia. The large subunit binds the two required molecules of MgATP and is involved in assembling the final product. Compounds such as L-ornithine, UMP, and IMP allosterically regulate the enzyme. Here, we report the three-dimensional structure of a site-directed mutant protein of carbamoyl phosphate synthetase from E. coli, where Cys 248 in the small subunit was changed to an aspartate. This residue was targeted for a structural investigation because previous studies demonstrated that the partial glutaminase activity of the C248D mutant protein was increased 40-fold relative to the wild-type enzyme, whereas the formation of carbamoyl phosphate using glutamine as a nitrogen source was completely abolished. Remarkably, although Cys 248 in the small subunit is located at approximately 100 A from the allosteric binding pocket in the large subunit, the electron density map clearly revealed the presence of UMP, although this ligand was never included in the purification or crystallization schemes. The manner in which UMP binds to carbamoyl phosphate synthetase is described.

Adenosine Diphosphate↗
PubMed1997

Putrescine export in Xenopus laevis oocytes occurs against a concentration gradient: evidence for a non-diffusional export process.

Putrescine export was found to occur by a non-diffusional highly regulated process using Xenopus oocytes as a model system of polyamine transport. Untreated oocytes were observed to possess high endogenous intracellular putrescine and spermidine levels with no detectable polyamine interconversion or biosynthesis over the assay intervals. The putrescine uptake process demonstrated a rapid saturation within a 5 min interval. Spermidine demonstrated a relatively larger uptake capacity with only a minimal ability to export. A kinetic analysis of the concentration-dependence of the putrescine and spermidine uptake processes indicated that the putrescine uptake process may possess two concurrent uptake components while spermidine uptake may possess a two-component process with an allosteric regulation. Elevated intracellular putrescine levels were observed to decrease against a 10-fold higher extracellular concentration gradient in a rapid and specific manner. No noticeable changes in the intracellular levels of other polyamines were observed over the same time interval. The uptake and export rates of putrescine transport also showed a concurrent, rapid and cyclical regulation. These findings support a non-diffusional putrescine export process which is highly regulated.

Animals↗
PubMed2005

Crystallization and preliminary X-ray crystallographic analysis of yeast NAD+-specific isocitrate dehydrogenase.

NAD+-specific isocitrate dehydrogenase (IDH; EC 1.1.1.41) is a complex allosterically regulated enzyme in the tricarboxylic acid cycle. Yeast IDH is believed to be an octamer containing four catalytic IDH2 and four regulatory IDH1 subunits. Crystals of yeast IDH have been obtained and optimized using sodium citrate, a competitive inhibitor of the enzyme, as the precipitating agent. The crystals belong to space group R3, with unit-cell parameters a = 302.0, c = 112.1 A. Diffraction data were collected to 2.9 A from a native crystal and to 4.0 A using multiwavelength anomalous diffraction (MAD) methods from an osmium derivative. Initial electron-density maps reveal large solvent channels and the molecular boundaries of the allosteric IDH multimer.

Allosteric Site↗
PubMed2005

Regulation of human methylenetetrahydrofolate reductase by phosphorylation.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of methylenetetrahydrofolate to methyltetrahydrofolate, the methyl donor for the conversion of homocysteine to methionine. Regulation of MTHFR activity is crucial for maintaining cellular concentrations of methionine and S-adenosylmethionine (AdoMet). Purified recombinant human MTHFR expressed in insect cells is multiply phosphorylated on an N-terminal extension of the protein that contains a highly conserved serine-rich region. Treatment by alkaline phosphatase removes seven phosphoryl groups from the enzyme. Thr-34 was identified as one of the seven phosphorylation sites by using a monoclonal antibody directed toward pThr-Pro. Mutation of Thr-34 to Ala completely blocks modification as judged by mass spectrometric analysis, suggesting that Thr-34 is the priming phosphorylation site. The Thr34Ala mutant was expressed in baculovirus-infected insect cells, and its enzymic properties were compared with wild-type enzyme. The mutant enzyme and alkaline phosphatase-treated wild-type enzyme are more active than untreated wild-type enzyme and less sensitive to inhibition by saturating AdoMet, indicating that phosphorylation at Thr-34 is critical for allosteric regulation of human MTHFR activity by AdoMet. The absence of methionine and the presence of adenosine in the cell culture medium, which lead to a low intracellular AdoMet/S-adenosylhomocysteine ratio, are associated with faster electrophoretic mobility of MTHFR, presumably because of less or no phosphorylation. Because the faster-mobility MTHFR is associated with the more active form of MTHFR, this response is likely to increase methionine production. Those observations suggest that AdoMet functions not only as an allosteric inhibitor but also to control phosphorylation of human MTHFR.

Alkaline Phosphatase↗
PubMed1995

Divergent N-terminal regions in AMP deaminase and isoform-specific catalytic properties of the enzyme.

AMP deaminase (AMPD) catalyzes the hydrolytic deamination of AMP to IMP and NH3. This activity is represented throughout mammalian tissues and cells by at least three isoforms. Human AMPD cDNAs have been cloned and sequenced, leading to predictions that each isoform contains distinct amino-ends (N-terminal regions) in contrast to their highly conserved carboxyl-ends (C-terminal regions). Wild type, truncated, and chimeric human AMPD1 (isoform M) and AMPD2 (isoform L) cDNAs were expressed and the resultant activities partially characterized as a means to examine the role of divergent N-terminal regions in these polypeptides (residues 1-262 and 1-258 of isoforms M and L, respectively) on isoform-specific catalytic properties. Similar to activities purified from human tissues, in the presence of monovalent cation, wild type isoform M displayed hyperbolic kinetics in the presence and absence of ATP, whereas wild type isoform L exhibited allosteric activation in the presence of this nucleotide effector. Expression of both a chimeric M (5'-AMPD1)/L (3'-AMPD2) construct and one in which the N-terminal region of isoform L was deleted produced activities that were also allosterically regulated by ATP. However, no AMPD activity was detectable following expression of either a chimeric L (5'-AMPD2)/M (3'-AMPD1) construct or one in which the N-terminal region of isoform M had been deleted. The N-terminal region also affected the relative ability of each recombinant AMPD activity to deaminate substrate analogs modified in either the sugar or the phosphate, but not in the purine base, moieties of AMP. These combined data show (i) that isoform M, but not isoform L, absolutely requires its N-terminal region for proper function, (ii) that the C-terminal region of isoform L is responsible for allosteric activation by ATP, (iii) an effect of the N-terminal region on substrate-enzyme interaction, a contention that is discussed in context with available information regarding the related purine catabolic activity, adenosine deaminase.

AMP Deaminase↗
PubMed2000

Site-directed mutagenesis studies of human A(2A) adenosine receptors: involvement of glu(13) and his(278) in ligand binding and sodium modulation.

To provide insights into interactions between ligands and A(2A) adenosine receptors, site-directed mutagenesis was used to test the roles of a glutamic acid residue in the first transmembrane domain (Glu13) and a histidine residue in the seventh transmembrane domain (His278). The two residues, which have been suggested to be closely linked in molecular modeling studies, were mutated to glutamine (E13Q) and tyrosine (H278Y), respectively. Saturation experiments revealed that [(3)H]ZM241385 (4-2-[7-amino-2-(2-furyl)-1,2, 4-triazolo[1,5-a][1,3,5]triazin-5-yl-amino]ethylphenol) bound wild-type and mutant receptors in membranes from COS-7 cells expressing human A(2A) adenosine receptors with high affinity and low non-specific binding. It was found from the competition experiments that the affinity of the A(2A) adenosine receptor agonists for the mutant receptors was 3- to 200-fold lower than for the wild-type receptor. Among antagonist competitors of binding at E13Q and H278Y mutant receptors, there was variation in the affinity depending on their different structures, although changes were relatively minor (<3-fold) except in the case of theophylline, whose affinity was decreased approximately 20 times on the H278Y mutant. The possible involvement of the two residues in sodium ion regulation was also tested. The agonist competition curves for [(3)H]ZM241385 were shifted to the right in both wild-type and mutant receptors in the presence of 1 M sodium ions, but the extent of shift (2- to 27-fold) in wild-type receptor was generally larger than for the mutant receptors. Sodium ions also decreased [(3)H]ZM241385 dissociation from both wild-type and mutant receptors, being more influential on the former than the latter. The results suggest that the two closely linked residues Glu13 and His278 in A(2A) adenosine receptor are most important for agonist recognition and are partly responsible for the allosteric regulation by sodium ions.

Animals↗
PubMed2004

Dynamic devices. Shape switching and substrate binding in ion-controlled nanomechanical molecular tweezers.

As examples of supramolecular devices performing chemical (ionic, molecular) control of binding events and models of related natural systems, two molecular conformational switches are described, which display cation-controlled nanomechanical motion coupled to substrate binding and release. The substrate binding relies on donor/acceptor interactions, provided by intercalation between planar sites located at the extremities of the switching units, whereas cation complexation is responsible for conformational regulation. The terpyridine py-py-py-based receptor is activated toward substrate binding upon complexation of a zinc(II) cation and operates in a two-state process. The replacement of the central pyridine by a 4,6-disubstituted pyridimine as in py-pym-py induces a state reversal and yields a new receptor which binds a substrate in the absence of cation, and releases it when copper(I) is introduced, following a three-step process. These systems represent effector-triggered supramolecular switching devices leading toward multistate nanomechanical chemical systems. These two systems illustrate the use of simple conformational switches in the binding site and allosteric regulation of substrate affinity.

Journal Article↗
PubMed1977

Role of orthophosphate and other factors in the regulation of starch formation in leaves and isolated chloroplasts.

Starch synthesis in leaves was increased by phosphate starvation or by treatments which decreased cytoplasmic orthophosphate levels (such as mannose feeding). Usually less than 30% of the total carbon fixed during CO(2) assimilation was incorporated into starch in spinach (Spinacia oleracea L.), spinach beet (Beta vulgaris), and tobacco (Nicotiana tabacum) leaves.In isolated spinach chloroplasts, formation of starch from CO(2) was usually less than in leaves. In the absence of significant levels of 3-phosphoglycerate, concentrations of phosphate as low as 1 mm (in the medium) or 10 mm (in the stroma) almost completely inhibited starch synthesis. The inhibitory action of phosphate could be overcome by 3-phosphoglycerate. The controlling factor of starch synthesis appeared to be the ratio of phosphoglycerate to orthophosphate rather than the stromal hexose monophosphate concentration, and it is suggested that this control is exerted via the phosphate translocator and the known allosteric regulation of ADP-glucose pyrophosphorylase. Starch synthesis was also favored by the presence of dihydroxyacetone phosphate and by high light and high temperature. Oxygen was inhibitory, probably owing to carbon drain into glycolate. Starch formation by intact chloroplasts could not be promoted by added glucose or glucose 6-phosphate.Starch mobilization in the dark was promoted by orthophosphate and phosphate-dependent mobilization was inhibited by phosphoglycerate. The principal products of starch breakdown in the presence of phosphate were the transport metabolites dihydroxyacetone phosphate and 3-phosphoglycerate. Formation of these compounds from starch was stimulated by ATP or oxaloacetate. In a phosphate-independent reaction, starch was also converted to neutral products such as maltose and glucose. The rates of phosphate-dependent starch degradation phosphorolysis were very much higher than those of starch hydrolysis for which there was no phosphate requirement.

Journal Article↗
PubMed1993

Regulation of inositol 1,4,5-trisphosphate receptors.

Inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] is a soluble second messenger responsible for the generation of highly organized Ca2+ signals in a variety of cell types. These Ca2+ signals control many cellular responses, including cell growth, fertilization, smooth muscle contraction and secretion. Ins(1,4,5)P3 is produced at the plasma membrane following receptor activation, but rapidly diffuses into the cytosol, where it binds to specific receptors through which it mobilizes intracellular Ca2+ stores. The actions of Ins(1,4,5)P3 within cells are tightly controlled: enzymes control the rapid generation and metabolism of Ins(1,4,5)P3 following receptor activation; multiple Ins(1,4,5)P3 receptor subtypes and splice variants exist, some of which are differentially expressed between cell types and at different stages of development; and Ins(1,4,5)P3 receptors are the targets for a number of allosteric regulators, including protein kinases, ATP and divalent cations. Understanding how cells control the Ca(2+)-mobilizing activity of Ins(1,4,5)P3 will be important if we are to unravel the mechanisms that underlie the complex arrangements of Ca2+ signals.

Animals↗
PubMed2005

Genes, enzymes and regulation of arginine biosynthesis in plants.

Arabidopsis genes encoding enzymes for each of the eight steps in L-arginine (Arg) synthesis were identified, based upon sequence homologies with orthologs from other organisms. Except for N-acetylglutamate synthase (NAGS; EC 2.3.1.1), which is encoded by two genes, all remaining enzymes are encoded by single genes. Targeting predictions for these enzymes, based upon their deduced sequences, and subcellular fractionation studies, suggest that most enzymes of Arg synthesis reside within the plastid. Synthesis of the L-ornthine (Orn) intermediate in this pathway from L-glutamate occurs as a series of acetylated intermediates, as in most other organisms. An N-acetylornithine:glutamate acetyltransferase (NAOGAcT; EC 2.3.1.35) facilitates recycling of the acetyl moiety during Orn formation (cyclic pathway). A putative N-acetylornithine deacetylase (NAOD; EC 3.5.1.16), which participates in the "linear" pathway for Orn synthesis in some organisms, was also identified. Previous biochemical studies have indicated that allosteric regulation of the first and, especially, the second steps in Orn synthesis (NAGS; N-acetylglutamate kinase (NAGK), EC 2.7.2.8) by the Arg end-product are the major sites of metabolic control of the pathway in organisms using the cyclic pathway. Gene expression profiling for pathway enzymes further suggests that NAGS, NAGK, NAOGAcT and NAOD are coordinately regulated in response to changes in Arg demand during plant growth and development. Synthesis of Arg from Orn is further coordinated with pyrimidine nucleotide synthesis, at the level of allocation of the common carbamoyl-P intermediate.

Amino Acid Sequence↗