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PubMed2006

Structural characterization of Spo0E-like protein-aspartic acid phosphatases that regulate sporulation in bacilli.

Spore formation is an extreme response of many bacterial species to starvation. In the case of pathogenic species of Bacillus and Clostridium, it is also a component of disease transmission. Entry into the pathway of sporulation in Bacillus subtilis and its relatives is controlled by an expanded two-component system in which starvation signals lead to the activation of sensor kinases and phosphorylation of the master sporulation response regulator Spo0A. Accumulation of threshold concentrations of Spo0A approximately P heralds the commitment to sporulation. Countering the activities of the sensor kinases are phosphatases such as Spo0E, which dephosphorylate Spo0A approximately P and inhibit sporulation. Spo0E-like protein-aspartic acid-phosphate phosphatases, consisting of 50-90 residues, are conserved in sporeforming bacteria and unrelated in sequence to proteins of known structure. Here we determined the structures of the Spo0A approximately P phosphatases BA1655 and BA5174 from Bacillus anthracis using nuclear magnetic resonance spectroscopy. Each is composed of two anti-parallel alpha-helices flanked by flexible regions at the termini. The signature SQELD motif (SRDLD in BA1655) is situated in the middle of helix alpha2 with its polar residues projecting outward. BA5174 is a monomer, whereas BA1655 is a dimer. The four-helix bundle structure in the dimer is reminiscent of the phosphotransferase Spo0B and the chemotaxis phosphatase CheZ, although in contrast to these systems, the subunits in BA1655 are in head-to-tail rather than head-to-head apposition. The implications of the structures for interactions between the phosphatases and their substrate Spo0A approximately P are discussed.

Amino Acid Motifs↗
PubMed2002

Age-related changes in the D-aspartic acid content of the cranial bones in senescence-accelerated mice (SAM).

We measured the age-related changes in the D/L-aspartic acid ratio (D/L ratio) of cranial bones in two different sublines of senescence-accelerated mice (SAM/Iw): SAMP2/Iw (SAM, prone 2/Iwate) and SAMR1/Iw (SAM, resistant 1/Iwate). In SAM/Iw under 9 months of age, the D/L ratio in SAMP2/Iw was higher than that in SAMR1/Iw (p<0.001). However, in all 12-month old SAM/Iw, whether SAMP2/Iw or SAMR1/Iw, the D/L ratio was higher in males than in females. There were minor differences in the age-related changes in the D/L ratios between different types of cranial bone. In 1-month old SAM/Iw the rectal temperature was similar in both males and females. However from the age of 2 months, there was a divergence, with the rectal temperature measurement in SAMP2/Iw reaching a peak 2 months of age, whereas SAMR1/Iw had the highest temperature readings at 6 months of age. In both SAMP2/Iw older than 2 months, and SAMR1/Iw older than 6 months, the temperature readings tended to gradually decrease with age in both males and females. These results suggest that the differences in D/L-aspartic acid ratios were dependent on the age, gender, and strain of SAM/Iw, but were not dependant on the type of cranial bone studied. It seems likely that these differences may be related mainly to changes in body temperature.

Age Factors↗
PubMed1995

Substitution of aspartic acid for glycine at position 310 in type II collagen produces achondrogenesis II, and substitution of serine at position 805 produces hypochondrogenesis: analysis of genotype-phenotype relationships.

Two different mutations were found in two unrelated probands with lethal chondrodysplasias, one with achondrogenesis type II and the other with the less severe phenotype of hypochondrogenesis. The mutations in the COL2A1 gene were identified by denaturing gradient gel electrophoresis analysis of genomic DNA followed by dideoxynucleotide sequencing and restriction site analysis. The proband with achondrogenesis type II had a heterozygous single-base mutation that substituted aspartate for glycine at position 310 of the alpha 1(II) chain of type II procollagen. The proband with hypochondrogenesis had a heterozygous single-base mutation that substituted serine for glycine at position 805. Type II collagen extracted from cartilage from the probands demonstrated the presence of type I collagen and a delayed electrophoretic mobility, indicating post-translational overmodifications. Analysis of CNBr peptides showed that, in proband 1, the entire peptides were overmodified. Examination of chondrocytes cultured in agarose or alginate indicated that there was a delayed secretion of type II procollagen. In addition, type II collagen synthesized by cartilage fragments from the probands demonstrated a decreased thermal stability. The melting temperature of the type II collagen containing the aspartate-for-glycine substitution was reduced by 4 degrees C, and that of the collagen containing the serine-for-glycine substitution was reduced by 2 degrees C. Electron microscopy of the extracellular matrix from the chondrocyte cultures showed a decreased density of matrix and the presence of unusually short and thin fibrils. Our results indicate that glycine substitutions in the N-terminal region of the type II collagen molecule can produce more severe phenotypes than mutations in the C-terminal region. The aspartate-for-glycine substitution at position 310, which was associated with defective secretion and a probable increased degradation of collagen, is the most destabilizing mutation yet reported in type II procollagen.

Amino Acid Sequence↗
PubMed1986

[Contrasting effect of piracetam and proline on the release of 3H-D-aspartic acid from the cerebral cortical synaptosomes of rats].

Piracetam (at concentrations of 10(-6) and 10(-5), but not 10(-4) and 5 X 10(-4) M) decreased K+-stimulated 3H-D-aspartate release. Proline enhanced K+-stimulated D-aspartate release, and its effect was antagonized by piracetam at a concentration that had no effect on K+-stimulated release. Quisqualic acid attenuated K+-stimulated D-aspartate release, with the effect antagonized by GDEE. GDEE also blocked the effect of piracetam, but not proline. The data are discussed in terms of the role of excitatory amino acid neurotransmission in the mechanisms of amnestic and antihypoxic piracetam action.

Animals↗
PubMed2006

Complete resolution of the microscopic protonation equilibria of N-methyl-D-aspartic acid and related compounds.

Protonation equilibria of N-methyl-D-aspartate (NMDA, a specific glutamate receptor agonist) and its derivatives are characterized at the macroscopic and microscopic levels. (1)H NMR-pH and pH-potentiometric titrations were carried out to determine the macroconstants. Microconstants were obtained by appropriate combination of acidity and NMR parameters of the parent compound and its three synthetic derivatives. These derivatives were close models of the NMDA minor microspecies, allowing the calculation of all the 12 microconstants, the 8 microspecies concentrations and 3 site interactivity parameters. Reliability of the microconstants was assessed by three independent test methods. It was found that protonation of the secondary amino site decreases the beta- and alpha-carboxylate basicities almost exactly by one and two orders of magnitude, respectively, whereas protonation of one of the carboxylates lessens the basicity of the other one by a factor of 3. NMR-pH profiles, macro- and microscopic protonation schemes and species-specific distribution diagrams are presented.

Amides↗
PubMed1991

Application of ligand-exchange chromatography to the assay of L-alanine from DL-aspartic acid by Pseudomonas dacunhae.

A direct chiral ligand-exchange chromatographic method was developed to monitor L-alanine production by fermentation. A mobile phase containing aqueous 0.25 mM Zn2+ solution is utilized to separate amino acids in the fermentation medium. The detection limit for L-alanine is 0.5 ppm and the analysis time for one sample is about 8 min. As sample preparation is simple and the matrix effects are minimal, the assay is fast and convenient. The results indicate that the method has potential for the analysis of complicated fermentation media.

Alanine↗
PubMed1993

Release of endogenous glutamic and aspartic acids from cerebrocortex synaptosomes and its modulation through activation of a gamma-aminobutyric acidB (GABAB) receptor subtype.

The depolarization-evoked release of endogenous glutamate (GLU) and -aspartate (ASP) and its modulation mediated by gamma-aminobutyric acid (GABA) heteroreceptors was investigated in superfused rat cerebrocortical synaptosomes. Exposure to 12 mM K+ enhanced the release of GLU and ASP. The K(+)-evoked overflow of both amino acids was largely Ca(2+)-dependent. Exogenous GABA inhibited the K(+)-evoked overflow of GLU (EC50 2.8 microM) and ASP (EC50 2.7 microM). The effect of GABA was mimicked by the GABAB receptor agonist (-)-baclofen (EC50 2.0 microM for GLU and 1.3 microM for ASP release) but not by the GABAA receptor agonist muscimol, up to 100 microM. Accordingly, the GABA-induced inhibition of GLU and ASP release was not affected by the GABAA receptor antagonists, bicuculline or picrotoxin, but was antagonized by the GABAB receptor antagonist, 3-amino-propyl(diethoxymethyl)phosphinic acid (CGP 35348). The GABA effect was, however, insensitive to another GABAB receptor antagonist, phaclofen, up to 1,000 microM. It can be concluded that GABA heteroreceptors of the GABAB type regulating the depolarization-evoked release of GLU and ASP are present on cortical GLU/ASP-releasing nerve terminals. These receptors may be classified as a phaclofen-insensitive GABAB receptor subtype.

Animals↗
PubMed2000

Kinetic and thermodynamic control of the relative yield of the deamidation of asparagine and isomerization of aspartic acid residues.

Selective deamidation of Asn67 of RNase A to beta-Asp67 and Asp67 residues at neutral pH initially produces greater amounts of the beta-Asp derivative. As the reaction proceeds the relative concentration of [Asp67]-RNase A increases and, at equilibrium, becomes predominant. Such a discrepancy between the kinetic and thermodynamic control on reaction products is discussed in light of information from X-ray three-dimensional analysis and the lower thermodynamic stability of the beta-Asp derivative relative to the parent enzyme.

Animals↗
PubMed1990

Substitution of aspartic acid-217 of Citrobacter freundii cephalosporinase and properties of the mutant enzymes.

On the assumption that Asp-217 of a Citrobacter freundii cephalosporinase forms a salt-bridge with the conserved Lys-67, Asp-217 was changed to glutamic acid, threonine or lysine. The mutant enzymes retained about the same level of activity as that of the wild-type enzyme, and the participation of Asp-217 in the salt-bridge was ruled out. However, the mutations resulted in an increase in hydrolytic activity toward oxyimino-cephalosporins such as cefuroxime, cefmenoxime and ceftazidime, suggesting a possible mechanism of the bacterial resistance to the novel beta-lactams by a single mutation in cephalosporinases.

Aspartic Acid↗
PubMed2006

Aspartic acid 214 in Citrobacter freundii tyrosine phenol-lyase ensures sufficient C--H-acidity of the external aldimine intermediate and proper orientation of the cofactor at the active site.

In the X-ray structure of tyrosine phenol-lyase (TPL) Asp214 is located at H-bonding distance from the N1 atom of the cofactor. This residue has been replaced with Ala and Asn and the properties of the mutant enzymes have been studied. The substitutions result in a decrease in the cofactor affinity of about four orders of magnitude. D214A and D214N TPLs do not catalyze the decomposition of l-Tyr and 3-fluoro-l-Tyr. They decompose substrates, containing better leaving groups with rates reduced by one or two orders of magnitude. Lognormal resolution of the spectra of the mutant enzymes revealed that the N1 atom of the cofactor is deprotonated. Spectral characteristics of internal and external aldimines of the mutant TPLs and the data on their interaction with quasisubstrates demonstrate that replacements of Asp214 lead to alteration of active site conformations. The mutant enzymes do not form noticeable amounts of a quinonoid upon interaction with inhibitors, but catalyze isotope exchange of C-alpha-proton of a number of amino acids for deuterium in (2)H(2)O. The k(ex) values for the isotope exchange of l-phenylalanine and 3-fluoro-l-tyrosine are close to the k(cat) values for reacting substrates. Thus, for the mutant TPLs the stage of C-alpha-proton abstraction may be considered as a rate-limiting for the whole reaction.

Alanine↗
PubMed1993

Fourier transform infrared difference spectroscopy of rhodopsin mutants: light activation of rhodopsin causes hydrogen-bonding change in residue aspartic acid-83 during meta II formation.

Fourier transform infrared (FTIR) difference spectroscopy and site-directed mutagenesis have been used to investigate structural changes which occur during rhodopsin photoactivation at the level of individual amino acid residues. The rhodopsin-->bathorhodopsin FTIR difference spectra of the mutants Asp-83-->Asn (D83N) and Glu-134-->Asp (E134D) incorporated into membranes are similar to that of native rhodopsin in the photoreceptor membrane, demonstrating that the retinal chromophores of these mutants undergo a normal 11-cis to all-trans photoisomerization. Two bands assigned to the C = O stretching mode of Asp and/or Glu carboxylic acid groups are absent in the D83N rhodopsin-->metarhodopsin II FTIR difference spectrum. Corresponding changes are not observed in the carboxylate C = O stretching region. The most straightforward explanation is that the carboxylic acid group of Asp-83 remains protonated in rhodopsin and its bleaching intermediates but undergoes an increase in its hydrogen bonding during the metarhodopsin I-->metarhodopsin II transition. The mutant E134D produced a normal rhodopsin-->bathorhodopsin and rhodopsin-->metarhodopsin II difference spectrum, but a fraction of misfolded protein was observed, supporting earlier evidence that Glu-134 plays a role in proper protein insertion and/or folding in the membrane.

Animals↗
PubMed1994

N-acetylaspartylglutamate selectively inhibits neuronal responses to N-methyl-D-aspartic acid in vitro.

Canavan's disease is an autosomal recessive disorder characterized by a deficiency of aspartoacylase and accumulation of N-acetylaspartic acid (NAA), leading to a severe leukodystrophy and spongy degeneration of the brain. N-Acetylaspartylglutamate (NAAG), the presumed product of NAA, also accumulates in this disease. The endogenous dipeptide NAAG has been suggested to have low potency at NMDA receptors. Here we have tested the actions of NAAG and NAA on NMDA-evoked responses in cultured cerebellar granule cells. In differentiating granule cells grown in low-K+ medium, NAAG negated the survival-promoting effects of NMDA but not K+ depolarization. Neither NAAG nor NAA alone promoted cell survival in low-K+ medium. The modest trophic action of 50 microM kainic acid in low-K+ medium was reinforced by the NMDA receptor antagonist dizocilpine maleate and by NAAG. In K(+)-differentiated granule cells, NAAG raised the threshold of NMDA neurotoxicity but not that of kainate. The observed activities of NAAG were overcome by excess NMDA and were not mimicked by NAA. These data raise the possibility that disruption of NMDA receptor processes by NAAG may be of pathophysiological relevance.

Animals↗
PubMed1986

Pyruvoyl-dependent histidine decarboxylase from Lactobacillus 30a. Covalent modifications of aspartic acid 191, lysine 155, and the pyruvoyl group.

The pyruvoyl-dependent histidine decarboxylase from Lactobacillus 30a is rapidly inactivated by incubation with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and glycine ethyl ester. On 90% of inactivation, 1.3 residues of [14C]glycine ethyl ester are incorporated per alpha subunit; nearly 60% of this is linked to the beta-carboxyl group of Asp-191. Histamine, a competitive inhibitor, protects against this inactivation. The KM value of the modified enzyme for histidine (6.2 mM) is much higher than that of the unmodified enzyme (KM = 0.4 mM); catalytic activity is reduced but not eliminated. Thus, Asp-191 is the most reactive accessible carboxyl group under these conditions and is close to the substrate-binding site, but apparently is not essential for catalysis. At pH 8.0, fluorodinitrobenzene inactivates histidine decarboxylase completely with the incorporation of two dinitrophenyl residues/alpha subunit; the modified residues are Lys-155 and Cys-228. Urocanic acid, a competitive inhibitor, protects against inactivation. Treatment with mercaptoethanol restores the free -SH of Cys-228 but does not restore activity. Conversion of Cys-228 to its cyano derivative slows but does not prevent dinitrophenylation of Lys-155; the resulting derivative is catalytically inactive. Thus, Lys-155 is located within the active site and may play an essential role in catalysis. Finally, histidine methyl ester was shown to inhibit this decarboxylase by forming a Schiff's base with the essential pyruvoyl group.

Aspartic Acid↗
PubMed1993

Structural and biologic properties of a human aspartic acid-126 interleukin-2 analog.

Point mutations at position 141 in the murine interleukin-2 (IL-2) sequence have been reported to generate proteins with full antagonist activity on some IL-2-dependent cell lines. To evaluate the potential therapeutic utility of this observation, we have prepared recombinant human IL-2 with a point mutation at the corresponding position (Asp for Gln 126) and examined its structural and biologic properties. This mutation apparently induces minor changes in tertiary conformation accompanied by an increased sensitivity to changes in pH. The biologic activity of this analog is greatly reduced, primarily as a result of decreased affinity to the beta/gamma IL-2 receptor complex; however, it is only weakly antagonistic to the IL-2 response of normal peripheral blood lymphocytes.

Animals↗
PubMedDate not supplied

[Uptake and K+-evoked release of 3H-norepinephrine in the mesodiencephalic synaptosomes of albino rats during aging. Role of N-acetyl-L-aspartic acid].

The uptake and K(+)-evoked (40 mM) release of 3H-norepinephrine (3H-NE) in mesodiencephalic synaptosomes of adult and senescent rats and the effect of N-acetylaspartic acid (NAA) on these processes have been studied. It has been shown that the uptake of 3H-NE by old rats is reduced considerably. The K(+)-evoked release of 3H-NE from rats synaptosomes is significantly decreased in aged rats. In the presence of 10(-4)-3.10(-3) M NAA the uptake of 3H-NE by adult and senescent rats synaptosomes remains unchanged. In these concentrations NAA inhibits the K(+)-evoked release of 3H-NE from synaptosomes of adult rats, but it exerts no effect on this process in senescent rats.

Aging↗
PubMed1999

Mutation of aspartic acid residues in the fructosyltransferase of Streptococcus salivarius ATCC 25975.

The site-directed mutated fructosyltransferases (Ftfs) of Streptococcus salivarius ATCC 25975, D312E, D312S, D312N and D312K were all active at 37 degrees C, indicating that Asp-312 present in the 'sucrose box' was not the nucleophilic Asp residue responsible for the formation of a covalent fructosyl-enzyme intermediate required for enzyme activity. Analysis of the kinetic constants of the purified mutated forms of the enzyme showed that Asp-312 was most likely an essential amino acid involved in determining acceptor recognition and/or stabilizing a beta-turn in the protein. In contrast, when the Asp-397 of the Ftf present in the conserved triplet RDP motif of all 60 bacterial and plant family-32 glycosylhydrolases was mutated to a Ser residue, both sucrose hydrolysis and polymerization ceased. Tryptophan emission spectra confirmed that this mutation did not alter protein structure. Comparison of published data from other site-directed mutated enzymes implicated the Asp residue in the RDP motif as the one that may form a transient covalent fructosyl intermediate during the catalysis of sucrose by the Ftf of S. salivarius.

Aspartic Acid↗
PubMedDate not supplied

Growth inhibitory effect of N-(phosphonacetyl)-L-aspartic acid on human myeloid leukemia-derived cell lines and modulation by dipyridamole.

Dipyridamole (DIP) inhibited the uptake of tritiated thymidine (TdR), deoxyuridine (UdR) and uridine (UR) in myeloid leukemia-derived cell lines, PL-21 and KCL-22. DIP also inhibited the growth of PL-21 (50% inhibitory concentrations, IC50, 15 microM) and KCL-22 (IC50, 3.0 microM). PALA inhibited the growth of PL-21 (IC50, 68 microM) and KCL-22 (IC50, 62 microM). The growth inhibition by PALA was significantly enhanced by the addition of 1 microM (PL-21) and 0.1 microM (KCL-22) of DIP. The inhibitory effect of PALA or PALA with DIP was completely abolished by the addition of 50 microM of UR in both cell cultures. Clinical evaluation of PALA in combination with DIP is warranted for the treatment of myeloid leukemia.

Antineoplastic Agents↗
PubMed1992

Asp85 is the only internal aspartic acid that gets protonated in the M intermediate and the purple-to-blue transition of bacteriorhodopsin. A solid-state 13C CP-MAS NMR investigation.

High-resolution solid-state 13C NMR spectra of the ground state and M intermediate of the bacteriorhodopsin mutant D96N with the isotope label at [4-13C]Asp and [11-13C]Trp were recorded. The NMR spectra show that Asp85 is protonated in the M intermediate. The environment of Asp85 is quite hydrophobic. On the other hand, Asp212 remains deprotonated and a slight shift to lower field indicates a more hydrophilic environment. Asp85 also protonates in the purple-to-blue transition of bacteriorhodopsin in the deionized membrane, where it experiences a similar environment to M. The shift of Trp resonances in M reflect a conformational change of the protein in forming the M intermediate.

Aspartic Acid↗