Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 5-hydroxytryptamine1A (5-HT1A) receptor can bind certain beta-adrenergic receptor antagonists, such as pindolol, with high affinity. Such pharmacological cross-reactivity suggests a structural similarity in the ligand binding site between the two receptors. To identify this structural entity, we mutated Asn385 in the seventh transmembrane domain of the human 5-HT1A receptor, based on the observation that this residue is conserved in all 5-HT1A and beta-adrenergic receptors of different species but is absent in all other cloned guanine nucleotide-binding protein-coupled receptors. This single point mutation (Asn385 to valine) causes a highly selective decrease in the affinity of pindolol and other aryloxyalkylamines for the mutant receptor (about 100-fold), while producing only minor changes in the binding of other 5-HT agonists and antagonists. The results provide direct evidence that Asn385 is responsible for the high affinity interaction between 5-HT1A receptors and aryloxyalkylamine beta-adrenergic antagonists but is not required for the binding of other chemical classes of ligands.
Mol Pharmacol 1992 Apr
PMID:Identification of a single amino acid residue responsible for the binding of a class of beta-adrenergic receptor antagonists to 5-hydroxytryptamine1A receptors. 134 54

A 2,256-bp sequence of the mitochondrial genome of a lepidopteran (Spodoptera frugiperda) contains tRNAs for valine and leucine, the 16S rRNA, and three-quarters of the ND-1 presumptive protein-coding gene. A 64-bp stretch of unknown function was located between the rRNA and leucine tRNA. Sequence divergence in the 16S rRNA obtained from alignment with published insect sequences is consistent with phylogenetic hypotheses, in that Diptera and Lepidoptera are more closely related to each other (24% sequence divergence) than either is to Hymenoptera (31%). Within the ND-1 gene, sequences for four additional Lepidoptera were generated for a 314-bp region and contrasted with published sequences for the locust and Drosophila. Sequence divergence in this region was consistent with accepted phylogenetic relationships, but results of parsimony analyses were not. Cladograms consistently recovered accepted higher level relationships (monophyly of Lepidoptera), despite high homoplasy, but were unable to resolve superfamily and family relationships within Lepidoptera, regardless of the outgroup or character subset analyzed. Character analysis indicated that homoplasy was decreased at higher levels when first- and second-codon sites were used exclusively. At the lowest level (families), resolution was enhanced by inclusion of third-codon sites. Inability of molecular data to recover a well-established phylogeny may be rectified by additional characters or taxa, but it is clear that homoplasy is sufficiently high to caution against the acceptance of relationships generated with this molecular region that are not extremely robust.
Mol Biol Evol 1992 Nov
PMID:Sequence evolution in mitochondrial ribosomal and ND-1 genes in lepidoptera: implications for phylogenetic analyses. 143 34

Nephrotoxic lesions were induced in Fischer 344 rats using HgCl2, a proximal tubular toxin, and 2-bromoethanamine (BEA), a medullary toxin. Biochemical effects of these toxins on urinary composition were observed by high resolution 1H NMR spectroscopy over 9 days after dosing. The onset of, progression of, and recovery from the induced toxic lesions were also followed histopathologically and related to the perturbed urinary biochemistry. Urinary concentrations of 20 endogenous substances were measured simultaneously by NMR at eight time points, to provide a time-related 20-dimensional description of the urinary biochemistry for each rat. Principal components analysis and nonlinear mapping were used to reduce the biochemical parameter spaces for each rat to two or three dimensions for display and classification purposes. An investigation of alternative data-presentation methods was made, and taking interanimal means of the map coordinates at each time point yielded a novel type of metabolic trajectory diagram with which the biochemical abnormalities associated with the HgCl2 and BEA lesions could be related to the progression and recovery phases of the toxic lesions. The time-course trajectories showed characteristically different paths for each toxin. These trajectories allowed the time points at which there were maximum metabolic differences to be determined and provided the visualization of net movements of the treatment group populations in time in relation to interanimal variation. Control animal urine samples subjected to this analysis showed simple clustering, with no evidence of metabolic trajectory. The trajectory for BEA showed different routes for onset of and recovery from toxicity, whereas for HgCl2 the outward trajectory (onset) mapped a space similar to the inward trajectory (recovery phase). This suggests that the NMR-detectable biochemical abnormalities after mercury toxicity mainly reflect the proportions of functional cells lining the nephron, whereas the biochemical abnormalities associated with renal medullary insult probably relate to functional integrity. An examination has been made for those metabolites that are most responsible for defining the trajectories, i.e., the discrimination of renal cortical and medullary toxicity from each other and from controls. These discriminatory metabolites (using paired t test, p < 0.001) included valine, taurine, trimethylamine N-oxide, and glucose for HgCl2 and acetate, methylamine, dimethylamine, lactate, and creatine for BEA, whereas citrate, succinate, N-acetyl resonances from as yet unidentified metabolites, hippurate, alanine, and 2-oxoglutarate played an important role in defining the biochemically perturbed trajectory of both toxins.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1992 Nov
PMID:Nuclear magnetic resonance spectroscopy and pattern recognition analysis of the biochemical processes associated with the progression of and recovery from nephrotoxic lesions in the rat induced by mercury(II) chloride and 2-bromoethanamine. 143 56

Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D) (or familial cerebral amyloid angiopathy) and familial Alzheimer's disease (FAD) share several properties. Both are autosomal dominant forms of cerebral amyloidosis characterized by beta-amyloid (A beta) deposition. In HCHWA-D the A beta is predominantly found in blood vessels and in early parenchymal plaques, whereas in AD parenchymal A beta deposits in the form of senile plaques and neurofibrillary tangles are a more prominent finding. Point mutations in the amyloid precursor protein (APP) have recently been described, in both conditions. A G to C transversion at codon 618 (extracellular portion of APP695), producing a single amino acid substitution of glutamine instead of glutamine acid, occurs in HCHWA-D; whereas mutations at codon 642 in the intramembrane region of APP695 (phenylalanine, isoleucine, or glycine instead of valine) are associated with early onset FAD. This suggests that the site of particular mutations in the APP gene and the type of amino acid substitution in the APP holoprotein are more important in determining clinicopathological phenotype and age at which A beta is deposited. Thus FAD and HCHWA-D can be regarded as two sides of the same coin.
Mol Neurobiol 1992
PMID:Molecular biology of Alzheimer's amyloid--Dutch variant. 146 89

We have previously shown that resistance to the beta-lactam mecillinam in Escherichia coli can be brought about by a high ppGpp pool, as observed under conditions of partial amino acid starvation and RelA-dependent induction of the stringent response. We show here that our E. coli wild-type strain, which is sensitive to mecillinam on minimal glucose plates, becomes resistant in the presence of L-leucine or L-serine (or cysteine, which inactivates the antibiotic). The resistance, which is not a transient effect and does not depend on the physiological state of the cells when plated, is specific for mecillinam and is reversed by the presence of isoleucine and valine in the medium. At least in the case of serine, the resistance is RelA-dependent. We conclude that the presence of leucine and serine in the growth medium cause partial starvation for isoleucine/valine, leading to induction of the stringent response and concomitant resistance to mecillinam.
Mol Gen Genet 1992 Nov
PMID:Leucine and serine induce mecillinam resistance in Escherichia coli. 146 98

In the normal C57BL/6J male mouse a specific subset of the kidney glycosphingolipids which is associated with multilamellar bodies of lysosomal origin and represents about 10% of the total kidney glycolipids, is excreted into the urine each day. This excretion is blocked and glycosphingolipids accumulate in the kidney of bgJ/bgJ mutants of this strain. To examine this process in vitro, glycosphingolipid metabolism and excretion were studied in beige mouse kidney cell cultures. Primary kidney cell cultures from male C57BL/6J control and bgJ/bgJ beige mutants were grown in D-valine medium and glycosphingolipids labeled with [3H]palmitate. As we have shown previously, the giant lysosomes of altered morphology were maintained in cultures of the beige kidney cells. Beige-J and control cells synthesized the same types of glycosphingolipids, but the mutant cells had quantitatively higher levels of these compounds than control cells, as determined by high performance liquid chromatography. Beige-J cells incorporated more [3H]palmitate into glycosphingholipids than control cells on a cpm/mg protein basis and the specific activity (cpm/pmole glycosphingolipid) was lower in beige cells. Medium from beige-J cells accumulated more glycosphingolipids than that from control cells in a 24 h period. The glycosphingolipids released into the medium as determined by HPLC were primarily non-lysosomal types and both control and mutant cells retained the glycosphingolipids associated with lysosomal multilamellar bodies excreted in vivo. The elevated levels of lysosomal glycosphingolipids and the dysmorphic lysosomes in primary cultures of beige cells, then, are not caused by a mutant block in secretion of lysosomes.
Mol Cell Biochem 1992 Dec 02
PMID:The accumulation and metabolism of glycosphingolipids in primary kidney cell cultures from beige mice. 148 56

Plasmids carrying different regions of the wild-type dnaA gene were used for marker rescue analysis of the temperature sensitivity of twelve strains carrying dnaA mutations. The different dnaA(Ts) mutations could be unambiguously located within specific regions of the dnaA gene. The mutant dnaA genes were cloned on pBR322-derived plasmids and on nucleotide sequencing by dideoxy chain termination the respective mutations were determined using M13 clones carrying the relevant parts of the mutant dnaA gene. Several of the mutant dnaA genes were found to have two mutations. The dnaA5, dnaA46, dnaA601, dnaA602, dnaA604, and dnaA606 genes all had identical mutations corresponding to an amino acid change from alanine to valine at amino acid 184 in the DnaA protein, close to the proposed ATP binding site, but all carried one further mutation giving rise to an amino acid substitution. The dnaA508 gene also had two mutations, whereas dnaA167, dnaA203, dnaA204, dnaA205, and dnaA211 each had only one. The pairs dnaA601/602, dnaA604/606, and dnaA203/204 were each found to have identical mutations. Plasmids carrying the different dnaA mutant genes intact were introduced into the respective dnaA mutant strains. Surprisingly, these homopolyploid mutant strains were found to be temperature resistant in most cases, indicating that a high intracellular concentration of the mutant DnaA protein can compensate for the decreased activity of the protein.
Mol Gen Genet 1992 Jul
PMID:Cloning and nucleotide sequence determination of twelve mutant dnaA genes of Escherichia coli. 149 77

The entire nucleotide sequence of the Bacillus brevis grsB gene encoding the gramicidin S synthetase 2, which activates and condenses the four amino acids proline, valine, ornithine and leucine has been determined. The gene contains an open reading frame of 13,359 bp which encodes a protein of 4453 amino acids with a predicted Mr of 510,287. The gene is located within the gramicidin S biosynthetic operon, also containing the genes grsT and grsA, whose nucleotide sequences have been determined previously. Within the GrsB amino acid sequence four conserved and repeated domains of about 600 amino acids (45-50% identity) have been identified. The four domains are separated by non-homologous sequences of about 500 amino acids. The domains also share a high degree of similarity (20-70%) with eight peptide synthetases of bacterial and fungal origin as well as with conserved sequences of nine other adenylate-forming enzymes of diverse origin. On the basis of sequence homology and functional similarities, we infer that those enzymes share a common evolutionary origin and present a phylogenetic tree for this superfamily of domain-bearing enzymes.
Mol Microbiol 1992 Feb
PMID:Four homologous domains in the primary structure of GrsB are related to domains in a superfamily of adenylate-forming enzymes. 144 81

Barnase is described anatomically in terms of its substructures and their mode of packing. The surface area of hydrophobic residues buried on formation and packing of the structural elements has been calculated. Changes in stability have been measured for 64 mutations, 41 constructed in this study, strategically located over the protein. The purpose is to provide: (1) information on the magnitudes of changes in stabilization energy for mutations of residues that are important in maintaining the structure; and (2) probes for the folding pathway to be used in subsequent studies. The majority of mutations delete functional moieties of side-chains or make isosteric changes. The energetics of the interactions are variable and context-dependent. The following general conclusions may be drawn, however, from this study about the classes of interactions that stabilize the protein. (1) Truncation of buried hydrophobic side-chains has, in general, the greatest effect on stability. For fully buried residues, this averages at 1.5 kcal mol-1 per methylene group with a standard deviation of +/- 0.6 kcal mol-1. Truncation of partly exposed leucine, isoleucine or valine residues that are in the range of 50 to 80 A2 of solvent-accessible area (30 to 50% of the total solvent-accessible area on a Gly-X-Gly tripeptide, i.e. those packed against the surface) has a smaller, but relatively constant effect on stability, at 0.81 kcal mol-1 per methylene group with a statistical standard deviation of +/- 0.18 kcal mol-1. (2) There is a very poor correlation between hydrophobic surface area buried and the free energy change for an extensive data set of hydrophobic mutants. The best correlation is found to be between the free energy change and the number of methylene groups within a 6 A radius of the hydrophobic groups deleted. (3) Burial of the hydroxyl group of threonine in a pocket that is intended for a gamma-methyl group of valine costs 2.5 kcal mol-1, in the range expected for the loss of two hydrogen bonds.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Biol 1992 Apr 05
PMID:The folding of an enzyme. II. Substructure of barnase and the contribution of different interactions to protein stability. 156 57

The specificity of interaction of amino acids with triplets in the acceptor helix stem of tRNA was investigated by means of a statistical analysis of 1400 tRNA sequences. The imprint of a prototypic genetic code at position 3-5 of the acceptor helix was detected, but only for those major amino acids, glycine, alanine, aspartic acid, and valine, that are formed by spark discharges of simple gases in the laboratory. Although remnants of the code at position 3-5 are typical for tRNAs of archaebacteria, eubacteria, and chloroplasts, eukaryotes do not seem to contain this code, and mitochondria take up an intermediary position. A duplication mechanism for the transposition of the original 3-5 code toward its present position in the anticodon stem of tRNA is proposed. From this viewpoint, the mode of evolution of mRNA and functional ribosomes becomes more understandable.
J Mol Evol 1992 Jun
PMID:Statistical evidence for remnants of the primordial code in the acceptor stem of prokaryotic transfer RNA. 159 40


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