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PubMed2004

Side-chain conformational thermodynamics of aspartic acid residue in the peptides and achatin-I in aqueous solution.

Sequence-position dependence of the side-chain conformational equilibrium of aspartic acid (Asp) residue is investigated for both model Asp peptides (di- to tetra-) and neuropeptide achatin-I (Gly--Phe-Ala-Asp) in aqueous solution. The trans-to-gauche conformational changes on the dihedral angle of C-C(alpha)-C(beta)-C are analyzed in terms of the standard free energy DeltaG(0), enthalpy DeltaH(0), and entropy -TDeltaS(0). The thermodynamic quantities are obtained by measuring the dihedral-angle-dependent vicinal (1)H-(1)H coupling constants in nuclear magnetic resonance over a wide temperature range. When the carboxyl groups of Asp are ionized, DeltaG(0) in the aqueous phase depends by approximately 1-2 kJ mol(-1) on the sequence position, whereas the energy change in the gas phase (absence of solvent) depends by tens of kJ mol(-1). Therefore, the weak position dependence of DeltaG(0) is a result of the compensation for the intramolecular effect by the hydration (= DeltaG(0)-). The DeltaH(0) and -TDeltaS(0) components, on the other hand, exhibit a notable trend at the C-terminus. The C-terminal DeltaH(0) is larger than the N- and nonterminal DeltaH(0) values due to the intramolecular repulsion between alpha- and beta-. The C-terminal -TDeltaS(0) is negative and larger in magnitude than the others, and an attractive solute-solvent interaction at the C-terminus serves as a structure breaker of the water solvent.

Amino Acid Sequence↗
PubMed1995

An essential aspartic acid at each of two allosteric cGMP-binding sites of a cGMP-specific phosphodiesterase.

The amino acid sequences of all known cGMP-binding phosphodiesterases (PDEs) contain internally homologous repeats (a and b) that are 80-90 residues in length and are arranged in tandem within the putative cGMP-binding domains. In the bovine lung cGMP-binding, cGMP-specific PDE (cGB-PDE or PDE5A), these repeats span residues 228-311 (a) and 410-500 (b). An aspartic acid (residue 289 or 478) that is invariant in repeats a and b of all known cGMP-binding PDEs was changed to alanine by site-directed mutagenesis of cGB-PDE, and wild type (WT) and mutant cGB-PDEs were expressed in COS-7 cells. Purified bovine lung cGB-PDE (native) and WT cGB-PDE displayed identical cGMP-binding kinetics, with approximately 1.8 microM cGMP required for half-maximal saturation. The D289A mutant showed decreased affinity for cGMP (Kd > 10 microM) and the D478A mutant showed increased affinity for cGMP (Kd approximately 0.5 microM) as compared to WT and native cGB-PDE. WT and native cGB-PDE displayed an identical curvilinear profile of cGMP dissociation which was consistent with the presence of distinct slowly dissociating (koff = 0.26 h-1) and rapidly dissociating (koff = 1.00 h-1) sites of cGMP binding. In contrast, the D289A mutant displayed a single koff = 1.24 h-1, which was similar to the calculated koff for the fast site of WT and native cGB-PDE, and the D478A mutant displayed a single koff = 0.29 h-1, which was similar to that calculated for the slow site of WT and native cGB-PDE. These results were consistent with the loss of a slow cGMP-binding site in repeat a of the D289A mutant cGB-PDE, and the loss of a fast site in repeat b of the D478A mutant, suggesting that cGB-PDE possesses two distinct cGMP-binding sites located at repeats a and b, with the invariant aspartic acid being crucial for interaction with cGMP at each site.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1983

Influence of the ionic environment on the conformation of aspartic acid and possible relevance to its neurotransmitter action.

The conformational changes of aspartic acid, a possible neurotransmitter, induced by increasing ionic strength were investigated by means of NMR spectroscopy. The effects of Li, Na, K, and Cs chlorides in basic and neutral conditions were characterized. The effects of the presence of both Ca2+ and Na+ or K+ were also examined. The results always showed a relative stabilization of the two conformers with gauche carboxylates at the expense of the anticonformer. The significant quantitative difference found between Na+ and K+ in basic solutions, as well as between calcium-free and calcium-containing solutions, may bear some relevance for the role of aspartate as a CNS neurotransmitter.

Aspartic Acid↗
PubMed2000

Practical synthesis of (R)-4-mercaptopyrrolidine-2-thione from L-aspartic acid. Preparation of a novel orally active 1-beta-methylcarbapenem, TA-949.

A facile and economical synthesis of a novel orally active 1-beta-methylcarbapenem, TA-949 (1), is described. The key process involves an efficient synthesis of the C-2 side chain (R)-4-mercaptopyrrolidine-2-thione 2 from L-aspartic acid and the construction of the 1-beta-methylcarbapenem skeleton. The mercapto group of 2 with an R-configuration was formed via deaminative bromination of the amino group of L-aspartic acid beta-methyl ester hydrochloride 12 followed by a complete S(N)2-type substitution with potassium benzenemethanethiolate. High-yield amination and cyclization of the chloride 15 to the pyrrolidin-2-one 16 was accomplished by a simple treatment with ammonia. Thiation of 16 and the Birch reduction of the resultant thiolactam 18 provided the C-2 side chain 2 in high yield with the asymmetric center retained as such. The side chain 2 was installed into the 1-beta-methylcarbapenem skeleton either by coupling with the vinyl phosphate 5 or by the use of the counterattack strategy involving the Dieckmann-type cyclization of the thioester 8. Removal of the protective groups of the coupling product 6 followed by esterification provided TA-949 (1) in high yield.

Administration, Oral↗
PubMed2001

Antidepressant activity of aspartic acid derivatives.

Antidepressant activity of N-phenyl(benzyl)amino derivatives of aspartic acid was studied on various experimental models of depression. IEM-1770 (30 mg/kg) and IEM-1944 (20 mg/kg) exhibited antidepressant activity after single injection in the forced swimming and tail suspension tests. Antidepressant effect of 14-day administration of these compounds and reference drugs maprotiline (10 mg/kg) and citalopram (10 mg/kg) was confirmed on the model of learned helplessness.

Animals↗
PubMed1994

Estimation of dental age using HPLC-technique to determine the degree of aspartic acid racemization.

Age determinations of adult individuals are of great importance within the forensic sciences. Presently, age changes in the teeth provide good means for this. The best method up to now has been "Gustafson's method" with modifications. Over the last 10 years a new chemical method, based on the racemization of aspartic acid in enamel and dentine, has been developed. Enamel and dentine belong to the very few tissues that do not have metabolic turn-over after formation. Both reliability and validity have been shown to be high, and this method therefore seems to be the best choice for the future. However, most studies to date have been using expensive and special instruments (gas chromatographs or amino acid analyzers) for these determinations. This study was performed to explore if the same determinations can be carried out with ordinary HPLC technique. It was shown that there is a good correlation between the ratio of D- and L-forms of the aspartic acid and age of the tooth. The correlation coefficient was 0.97, which is close to those presented with the other techniques, where r has been 0.95 - 0.99. The prediction of an individual age can be made with a 95% confidence interval of about +/- 12 years.

Adolescent↗
PubMed1991

Anti-tumoral activity of L and D isomers of aspartic acid beta-hydroxamate on L5178Y leukemia.

D and L isomers of aspartic acid beta-hydroxamate (respectively DAH and LAH) were compared for their in vitro and in vivo activity against the murine leukemia L5178Y and their tolerance in vivo in DBA/2 mice. DAH and LAH displayed comparable cytotoxic activity against L5178Y leukemia in vitro. Death of leukemia cells was observed at concentrations above 1.2 mM for both DAH and LAH. High concentrations of L-asparagine partially reversed the growth-inhibitory effects of DAH and LAH on L5178Y cells for concentrations of DAH and LAH lower than 0.6 mM. Intraperitoneal administration of DAH and LAH to mice showed that the LD10, LD50 and LD90 of DAH was 3- to 4-fold greater for DAH than for LAH. DAH was able to eradicate L5178Y tumors in mice without inducing toxic deaths, whereas LAH at comparable doses killed all the animals treated.

Animals↗
PubMed1995

Age estimation using a modified HPLC determination of ratio of aspartic acid in dentin.

Diastereomeric dipeptides were derived from the amino acid enantiomers in dentin by O-phthalaldehyde-N-acetyl-L-cysteine. The products were separated using high performance liquid chromatography (HPLC) and detected by fluorescence detector. A short analysis time (total analysis time was 15 min, including retention time, sample derivatization time and column regeneration time) was used. The sensitivity of detection was 1 pmol and high resolution (Rs = 1.5) was reached. We determined the D/L ratio of aspartic acid in dentin of 28 first premolars. The correlation value between the D/L ratio of aspartic acid and actual age was 0.9887; errors of +/- 1 year accounted for 46.4%, and no error exceeded 5 years.

Adolescent↗
PubMed1990

High frequency of aspartic acid at position 57 of HLA-DQ beta-chain in Japanese IDDM patients and nondiabetic subjects.

The HLA-DQ beta-chain (DQB1) genes of 72 Japanese patients with insulin-dependent diabetes mellitus (IDDM) and 85 control subjects were studied with polymerase chain-reaction (PCR) amplification and allele-specific oligonucleotide hybridization. DQW4 (DQBBlank) and DQw9 (DQB3.3) were increased in IDDM patients compared with the control subjects, and DQB1.2, DQB1.9, and DQw7 (DQB3.1) were decreased. Thirty-five (48.6%) IDDM patients had both alleles carrying an aspartic acid at position 57 of the DQ beta-chain (Asp 57), 35 (48.6%) were Asp 57/non-Asp 57 heterozygous, and 2 (2.8%) had non-Asp 57 alleles only. Of 85 control subjects, the respective values for these three genotypes were 49 (57.6%), 29 (34.1%), and 7 (8.2%), respectively. The high frequency of Asp 57 alleles in both IDDM and control subjects contrasts with data for Whites. Therefore, the Asp 57 hypothesis that the presence of an aspartic acid at position 57 of DQ beta-chain provides protection against developing IDDM is not tenable for Japanese IDDM patients. The DRB1 gene, particularly position 57 of the DR beta-chain, may contribute to IDDM susceptibility in Japanese.

Adolescent↗
PubMed1993

Identification of a phosphorylation site and functional analysis of conserved aspartic acid residues of OmpR, a transcriptional activator for ompF and ompC in Escherichia coli.

In Escherichia coli the OmpR and EnvZ proteins regulate the expression of the outer membrane porin proteins OmpC and OmpF. EnvZ and OmpR belong to a family of sensor/effector protein pairs that control adaptation to a variety of environmental conditions. EnvZ acts as the sensor protein that phosphorylates OmpR, which in turn regulates porin gene expression. The level of phosphorylated OmpR appears to be a determining factor for ompC and ompF regulation. Phosphorylation of OmpR is considered to occur at one or more aspartic acid residues (Asp-11, Asp-12 and/or Asp-55) that are highly conserved among the effector proteins. In this report we biochemically characterized the aspartic acid residue(s) in OmpR that were phosphorylated by EnvZ. Reduction of aspartyl phosphate residues in the amino-terminal domain of OmpR with [3H]-NaBH4 indicated that Asp-55 was a primary site of modification. We further studied the role of the highly conserved aspartate residues by creating OmpR mutants having aspartate to alanine substitutions at positions 11 (D11A), 12 (D12A) and 55 (D55A). Studies of ompF and ompC expression as well as in vivo and in vitro phosphorylation experiments also demonstrated that while Asp-55 is the primary phosphate acceptor site in OmpR, Asp-11 may also serve as a phosphorylation site, particularly in the absence of Asp-55.

Amino Acid Sequence↗
PubMed1994

A glycine to aspartic acid change in the MoCo domain of nitrate reductase reduces both activity and phosphorylation levels in Arabidopsis.

Nitrate reductase (NR), the first enzyme in the nitrate assimilation pathway, is regulated post-transcriptionally in response to light and CO2. In spinach, it has been shown that phosphorylation is one mechanism that mediates this regulation. In this paper, the phosphorylation of NR in Arabidopsis is described in both wild-type and NR- mutant plants. A 110-kDa protein radiolabeled in vivo with 32PO4 was immunoprecipitated with anti-NR antibody from extracts of wild-type plants but not of mutant plants in which the NR gene NIA2 had been deleted. Phosphoamino acid and phosphopeptide analysis showed that, as for spinach, NR from Arabidopsis is phosphorylated on serine and produces multiple phosphopeptides upon digestion with CNBr or trypsin. Analysis of three mutants with lesions in the NIA2 NR structural gene showed that one mutant, chl3-1, has a reduced phosphorylation phenotype that is not complemented by a NR deletion mutant. Comparison of the sequences of the wild-type and chl3-1 NIA2 genes revealed a single base mutation changing a glycine codon to an aspartic acid codon. This glycine, at position 308 in the MoCo domain of NR, is completely conserved in all known eukaryotic NR sequences. Thus, glycine 308 is required for normal activity and phosphorylation of NR, and substitution of this residue with aspartic acid disrupts both processes, most likely by altering the conformation of the NR MoCo domain.

Amino Acid Sequence↗
PubMed2002

Conserved aspartic acids are essential for the enzymic activity of the WecA protein initiating the biosynthesis of O-specific lipopolysaccharide and enterobacterial common antigen in Escherichia coli.

The integral membrane protein WecA mediates the transfer of N-acetylglucosamine (GlcNAc) 1-phosphate to undecaprenyl phosphate (Und-P) with the formation of a phosphodiester bond. Bacteria employ this reaction during the biosynthesis of enterobacterial common antigen as well as of many O-specific lipopolysaccharides (LPSs). Alignment of a number of prokaryotic and eukaryotic WecA-homologous sequences identified a number of conserved aspartic acid (D) residues in putative cytoplasmic loops II and III of the inner-membrane protein. Site-directed mutagenesis was used to study the role of the conserved residues D90, D91 (loop II), D156 and D159 (loop III). As controls, D35, D94 and D276 were also mutagenized. The resulting WecA derivatives were assessed for function by complementation analysis of O-antigen biosynthesis, by the ability to incorporate radiolabelled precursor to a biosynthetic intermediate, by detection of the terminal GlcNAc residue in LPS and by a tunicamycin competition assay. It was concluded from these analyses that the conserved aspartic acid residues are functionally important, but also that they participate differently in the transfer reaction. Based on these results it is proposed that D90 and D91 are important in forwarding the reaction product to the next biosynthetic step, while D156 and D159 are a part of the catalytic site of the enzyme.

Amino Acid Sequence↗
PubMed1989

High-performance liquid chromatographic monitoring of transpeptidation reactions in analogues of gonadotropin releasing hormone containing aspartic acid derivatives in position six.

High-performance liquid chromatographic systems were used for monitoring the hydrolysis of five potent agonistic gonadotropin releasing hormone analogues containing aspartic acid derivatives in position six. To separate the closely related nonapeptides formed during the hydrolysis, columns with reversed-phase packings were used under isocratic conditions. The mobile phases were methanol containing ammonium acetate or triethylammonium phosphate buffers. Good separations of the hydrolysis products from the investigated peptides allowed the reaction rate constants for the transformations examined to be calculated.

Amino Acid Sequence↗
PubMedDate not supplied

[Changes in the reactive properties of the body under anesthesia against a background of aspartic acid premedication].

It was shown in acute experiments on mice and dogs that aspartic acid and its sodium salt administered 15-30 minutes prior to ether and hexenal anesthesia prolong the animals' life span by 42.2-99.9% compared to control given an isotonic solution of sodium chloride. The stabilizing action of the aspartate is accounted for by its effect on the reactive properties of the central nervous system, particularly on the new cortex, old cortex, archicortex and circulation. This effect is also associated with the increased oxygen tension in brain tissues, with increased heart contractions and slowing down of their rhythm.

Anesthesia↗
PubMed2006

Reversible B/Z-DNA transition under the low salt condition and non-B-form polydApolydT selectivity by a cubane-like europium-L-aspartic acid complex.

We report here that a cubane-like europium-L-aspartic acid complex at physiological pH can discriminate between DNA structures as judged by the comparison of thermal denaturation, binding stoichiometry, temperature-dependent fluorescence enhancement, and circular dichroism and gel electrophoresis studies. This complex can selectively stabilize non-B-form DNA polydApolydT but destabilize polydGdCpolydGdC and polydAdTpolydAdT. Further studies show that this complex can convert B-form polydGdCpolydGdC to Z-form under the low salt condition at physiological temperature 37 degrees C, and the transition is reversible, similar to RNA polymerase, which turns unwound DNA into Z-DNA and converts it back to B-DNA after transcription. The potential uses of a left-handed helix-selective probe in biology are obvious. Z-DNA is a transient structure and does not exist as a stable feature of the double helix. Therefore, probing this transient structure with a metal-amino acid complex under the low salt condition at physiological temperature would provide insights into their transitions in vivo and are of great interest.

Aspartic Acid↗
PubMed2000

Extracytoplasmic proteins of Mycobacterium tuberculosis - mature secreted proteins often start with aspartic acid and proline.

A surrogate expression system, based on fusions to the phoA bacterial reporter gene, was used to identify Mycobacterium tuberculosis genes that encode exported proteins and the promoter regions required for their expression in the heterologous host Mycobacterium smegmatis. To assess these results in the context of the complete M. tuberculosis genome sequence, the corresponding genes were identified and computational algorithms were employed to identify signal peptide (SP), transmembrane domain and membrane lipoprotein attachment motifs. This information was used to predict the subset of M. tuberculosis genes that encode exported proteins. Of the 34 genes identified by the phoA method, 22 were classified to encode potential soluble secreted proteins. Among these, 14 genes may encode novel secreted proteins. Six of the remaining 12 genes were predicted to encode membrane lipoproteins and an additional six to encode integral membrane proteins. Published observations of proteins proven to be secreted into M. tuberculosis culture filtrates were reviewed to further characterize the mycobacterial SP motif. It was concluded that mycobacterial SPs are comparable in size to Gram-positive SPs, but certain features are different. In particular, arginine was the predominant N-terminally positively charged amino acid in contrast to lysine in the Gram-positives. The hydrophobic transmembrane segment of the SP was dominated by alanine, in contrast to leucine. At the C-terminal end of the SPs, the (-3, -1) rule (AXA motif) holds, with alanine as the dominant amino acid in both positions, being most dominant in the (-1) position. A high proportion of mature sequences start with aspartic acid in the (+1) position and proline in the (+2) position - the DP motif. The authors propose that the DP sequence serves as a sorting signal, following translocation and cleavage by signal peptidase I. Alternatively, the DP motif may be part of the recognition site for the signal peptidase.

Alkaline Phosphatase↗
PubMed2005

Evolutionary and experimental analyses of inorganic phosphate transporter PiT family reveals two related signature sequences harboring highly conserved aspartic acids critical for sodium-dependent phosphate transport function of human PiT2.

The mammalian members of the inorganic phosphate (P(i)) transporter (PiT) family, the type III sodium-dependent phosphate (NaP(i)) transporters PiT1 and PiT2, have been assigned housekeeping P(i) transport functions and are suggested to be involved in chondroblastic and osteoblastic mineralization and ectopic calcification. The PiT family members are conserved throughout all kingdoms and use either sodium (Na+) or proton (H+) gradients to transport P(i). Sequence logo analyses revealed that independent of their cation dependency these proteins harbor conserved signature sequences in their N- and C-terminal ends with the common core consensus sequence GANDVANA. With the exception of 10 proteins from extremophiles all 109 proteins analyzed carry an aspartic acid in one or both of the signature sequences. We changed either of the highly conserved aspartates, Asp28 and Asp506, in the N- and C-terminal signature sequences, respectively, of human PiT2 to asparagine and analyzed P(i) uptake function in Xenopus laevis oocytes. Both mutant proteins were expressed at the cell surface of the oocytes but exhibited knocked out NaP(i) transport function. Human PiT2 is also a retroviral receptor and we have previously shown that this function can be exploited as a control for proper processing and folding of mutant proteins. Both mutant transporters displayed wild-type receptor functions implying that their overall architecture is undisturbed. Thus the presence of an aspartic acid in either of the PiT family signature sequences is critical for the Na+-dependent P(i) transport function of human PiT2. The conservation of the aspartates among proteins using either Na+- or H+-gradients for P(i) transport suggests that they are involved in H+-dependent P(i) transport as well. Current results favor a membrane topology model in which the N- and C-terminal PiT family signature sequences are positioned in intra- and extracellular loops, respectively, suggesting that they are involved in related functions on either side of the membrane. The present data are in agreement with a possible role of the signature sequences in translocation of cations.

Amino Acid Sequence↗
PubMed2004

Analysis of children with type 1 diabetes in Korea: high prevalence of specific anti-islet autoantibodies, immunogenetic similarities to Western populations with "unique" haplotypes, and lack of discrimination by aspartic acid at position 57 of DQB.

This study analyzed the expression of anti-islet autoantibodies and HLA-DR and -DQ genotypes in Korean children with type 1 diabetes mellitus (T1DM). The positivity of the anti-ICA512, anti-GAD65, and anti-insulin autoantibodies in the newly onset T1DM patients (n = 15) was 66.7%, 86.7%, and 46.7%, respectively, and all of them had one or more of the autoantibodies. HLA analysis showed higher frequencies of HLA-DRB1*0301, *0405, *09012 and -DQB1*0201, *0401, *03032 alleles in T1DM patients compared to controls (P(c) < 0.05). Because HLA-DQB1*0401, *03032 alleles carry aspartic acid at position 57 of DQB, susceptibility to T1DM in Korean children was not related to the presence of aspartic acid at position 57 of DQB1 locus. We suggest this unique HLA-DR, -DQ allele distribution might be an important factor for the low incidence of T1DM in Korea, and the combined anti-islet autoantibody assays could be valuable screening markers for the early detection of T1DM in Korea.

Adolescent↗