Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemical binding of proteins with bioactive surfaces is modeled using a semi-empirical molecular orbital theory (AM-1). The model calculates the optimized molecular structures of an amino acid (L-alanine) interacting with a cyclotetrasiloxane silica cluster (a four-membered hydrated silica ring). The calculated heats of formation for various orientations of alanine show +5 kcal/mol difference for binding via the -NH2 group following a condensation reaction with a pentacoordinate Si intermediate. Hydrogen bonding of the alanine via the -COOH group occurs with +13 to +15 kcal/mole differences in heats of formation and imposes a highly specific geometric orientation on the amino acid. Association of a diatomic N2 molecule with the silica cluster before interaction with alanine inhibits formation of an intermolecular bond, as is observed experimentally in studies of silica-alanine epitaxy.
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PMID:AM-1 molecular orbital calculations of silica-alanine-nitrogen interaction. 802 3

We developed a method of measuring the mole quantity of pulmonary angiotensin-converting enzyme (ACE) bound by a partially saturating dose of an ACE inhibitor injected i.v. For each test animal (11 guinea pigs), tracer (nonsaturating) doses of the ACE substrate [14C]benzoyl-Ala-Gly-Pro (14C-BAGP) and the ACE inhibitor 3H-RAC-X-65 were coinjected at timed intervals for a total of four studies per animal. The injectate used for the second study contained, in addition, a partially saturating dose of unlabeled RAC-X-65. With indicator-dilution techniques supplemented with measurements of fractional hydrolysis of 14CBAGP and uptake of 3H-RAC-X-65 during a single transit through the pulmonary vascular bed, the following parameters were computed: plasma flow (Qp), (kcat/Km)[E] vector c, k1[E] vector c and Eb, where [E] is the concentration of active ACE, Eb is the mole quantity of ACE bound by inhibitor, kcat/Km is the second-order rate constant for substrate hydrolysis, k1 is the inhibitor-ACE association rate constant and vector c is capillary mean transit time. As shown elsewhere (Catravas et al., 1990; Catravas and White, 1984), the product of Qp (in liters per second) multiplied by (kcat/Km)[E] vector c is (kcat/Km)E, and the product of Qp multiplied by k1[E] vector c is k1E, where E is the mole quantity of ACE. Values of (kcat/Km)Eb and k1Eb were computed and divided by Eb to obtain kcat/Km and k1. The fractional degree of inhibition conferred by a partially saturating dose of an ACE inhibitor can be understood to be the ratio Eb/ET, where ET is total ACE. With Eb in moles and the ratio Eb/ET, we computed the mole quantity of ET. By measuring the rate of recovery of ACE activity following partial inhibition of ACE, an apparent dissociation rate constant, k(dissoc), was computed. With k(dissoc) and K1, an apparent Ki was computed. The following computations were obtaine: ET of 0.90 +/- 0.20 (S.E.M.) nmol; kcat/Km, 5.16 +/- 0.89E + 06 M-1.sec-1; k1, 1.26 +/- 0.21E + 06 M-1.sec-1; k(dissoc), 6.47 +/- 0.63E - 04 sec-1 and Ki, 5.13E - 10 M. Although we focused on the characterization of ACE, the methods developed are general and may be applicable to studies of other vascular surface proteins, including other enzymes and hormone receptors.
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PMID:Estimation of rate constants for reactions of pulmonary microvascular angiotensin converting enzyme with an inhibitor and a substrate in vivo. 803 24

The amino acid (AA) synthetic ability and requirements of human infants are undefined. A stable isotope tracer technique was employed in neonates to assess conversion of uniformly labeled 13C glucose into biochemically nonessential AA (NEAA). Ten neonates (5 males, 5 females) were studied at a mean age of 7 +/- 2.0 (SEM) days. The mean gestational age was 35.5 +/- 1.1 weeks, and the mean weight at time of study was 2,191 +/- 181 g. Six infants were fed enterally, and four received only intravenous 10% dextrose (D10W). Blood samples were obtained before, and 30, 60, and 120 minutes after an orogastric bolus of D-[U-13C]glucose (100 mg/kg). The conversion of glucose carbon into seven NEAA was assessed by measuring their isotopic enrichments in plasma, using gas chromatography/mass spectrometry (GC/MS), and was expressed as mole percent excess (MPE), with detectable MPE defined as > or = 0.2. The isotopic enrichment of plasma glucose also was measured using GC/MS. Free plasma AA concentrations were assayed using an automated AA analyzer and expressed in micromoles per liter. The mean glucose enrichment was 9.33 +/- 1.8 MPE (range, 5.82 to 13.48). Detectable 13C-labeling of the NEAA was observed as follows: Glu in 100% of infants; Gly, 100%; Ala, 90%; Ser, 80%; Asp, 70%; Cys, 60%; and Pro, 60%. Detectable Pro enrichment was observed in none of three premature infants on D10W. Free plasma Cys concentration was markedly lower than normal (19.8 v 86 mumol/L).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A new stable isotope tracer technique to assess human neonatal amino acid synthesis. 852 36

Mutations in p53, a tumor suppressor gene, are one of the most common genetic lesions of human cancers. The relationship between p53 gene mutation and ultraviolet (UV) light has been demonstrated in skin cancers of sun-exposed sites. In this study, genomic DNA from 12 skin cancers was screened for mutations in exons 5 to 9 of this gene using the polymerase chain reaction--single strange configuration polymorphism (PCR-SSCP) analysis followed by DNA sequencing. DNA samples were obtained from 8 basal cell carcinomas (BCCs): 1 from an organoid nevus, 1 from a patient with basal cell nevus syndrome, 1 from a patient with xeroderma pigmentosum, and 1 from a recurrent and 4 from primary sporadic lesions on actinic damaged skin, and from 4 squamous cell carcinomas (SCCs): 1 from a burn scar, 1 from a patient with epidermodysplasia verruciformis, and 2 from actinic keratosis. Mutation of the p53 gene was detected in only 1 case of SCC which had arisen from actinic keratosis. The mutation occurred at codon 159 in exon 5 with a GCC to CCC base-pair substitution resulting in an amino acid change of alanine to proline. This mutation does not correspond to results of UV mutagenesis studies reported in the literature. Our findings imply that, although p53 gene mutation and UV exposure play an important role in the carcinogenesis of some skin cancers, they are not crucial, especially in skin cancers that develop from underlying skin disorders.
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PMID:p53 gene mutations in skin cancers with underlying disorders. 866 19

Cathepsin H (EC 3.4.22.16) from cow brain, purified to approximately 1800-fold with approximately 26% activity yield, hydrolysed BANA, Leu-2-NNap, Arg-2-NNap, and Met-2-NNap maximally at pH 6.5, 6.8, 7.0 and 7.2, respectively. It was activated by sulphydryl compounds and EDTA while sulphydryl alkylators and blockers were found to inhibit the enzyme activity. Met-2-NNap was found to be the best substrate followed by Thr-2-NNap, His-2-NNap, Leu-2-NNap, Arg-2-NNap and Ala-2-NNap, respectively. The Km values for hydrolysis of various substrates viz., Met-2-NNap, Leu-2-NNap, Arg-2-NNap, Arg-NNapOMe, Thr-2-NNap, His-2-NNap, BANA, Arg-pNA and Lys-pNA were 0.128, 0.167, 0.169, 0.288, 0.428, 0.500, 0.667, 0.195 and 0.476 mM, respectively. The temperature optima for hydrolysis of BANA and Leu-2-NNap were approximately 45 degrees C and approximately 50 degrees C with activation energies of approximately 13.7 and approximately 11.0 kcal mole-1, respectively. The enzyme was fairly stable upto 50 degrees C and between pH 4.0-7.5.
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PMID:Physico-chemical properties of brain cathepsin H. 871 50

High resolution 1H NMR spectroscopy was used to analyze temporal lobe biopsies obtained from patients with epilepsy. Heat-stabilized cerebrum, dialyzed cytosolic macromolecules, and perchloric acid extracts were studied using one- and two-dimensional spectroscopy. Anterior temporal lobe neocortex was enriched in GABA, glutamate, alanine, N-acetylaspartate, and creatine. Subjacent white matter was enriched in aspartate, glutamine, and inositol. The N-acetylaspartate/creatine mole ratio was lower in anterior temporal neocortex with mesial (0.66) than neocortical (0.80) temporal lobe epilepsy. Human brain biopsy samples were separated into crude and refined synaptosomes, neuronal cell bodies, and glia using density gradient centrifugation. Neuronal fractions were enriched in glutamate and N-acetylaspartate. Glial cell fractions were enriched in lactate, glutamine, and inositol. The creatine content was the same in biopsied epileptic cortex (8.8-8.9 mmol/kg) and normal in vivo occipital lobe (8.9 mmol/kg). Glutamate content was higher in epileptic cortex at biopsy (10.1-10.5 mmol/kg) than normal in vivo occipital lobe (8.8 mmol/kg). GABA content was higher in biopsies of epileptic cortex (2.3-2.2 mmol/kg) than in normal in vivo occipital lobe (1.2 mmol/kg). N-acetylaspartate content was lower in biopsied epileptic temporal cortex (5.8-6.8 mmol/kg) than normal in vivo occipital lobe (8.9 mmol/kg). Paired in vivo and ex vivo measurements are critical for a firm understanding of the changes seen in the 1H-spectra from patients with epilepsy.
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PMID:Symbiosis between in vivo and in vitro NMR spectroscopy: the creatine, N-acetylaspartate, glutamate, and GABA content of the epileptic human brain. 875 Mar 37

Treatment of the Class II fructose-1,6-bisphosphate aldolase of Escherichia coli with the arginine-specific alpha-dicarbonyl reagents, butanedione or phenylglyoxal, results in inactivation of the enzyme. The enzyme is protected from inactivation by the substrate, fructose 1,6-bisphosphate, or by inorganic phosphate. Modification with [7-14C] phenylglyoxal in the absence of substrate demonstrates that enzyme activity is abolished by the incorporation of approximately 2 moles of reagent per mole of enzyme. Sequence alignment of the eight known Class II FBP-aldolases shows that only one arginine residue is conserved in all the known sequences. This residue, Arg-331, was mutated to either alanine or glutamic acid. The mutant enzymes were much less susceptible to inactivation by phenylglyoxal. Measurement of the steady-state kinetic parameters revealed that mutation of Arg-331 dramatically increased the K(m) for fructose 1,6-bisphosphate. Comparatively small differences in the inhibitor constant Ki for dihydroxyacetone phosphate or its analogue, 2-phosphoglycolate, were found between the wild-type and mutant enzymes. In contrast, the mutation caused large changes in the kinetic parameters when glyceraldehyde 3-phosphate was used as an inhibitor. Kinetic analysis of the oxidation of the carbanionic aldolase-substrate intermediate of the reaction by hexacyanoferrate (III) revealed that the K(m) for dihydroxyacetone phosphate was again unaffected, whereas that for fructose 1,6-bisphosphate was dramatically increased. Taken together, these results show that Arg-331 is critically involved in the binding of fructose bisphosphate by the enzyme and demonstrate that it interacts with the C-6 phosphate group of the substrate.
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PMID:Identification of arginine 331 as an important active site residue in the class II fructose-1,6-bisphosphate aldolase of Escherichia coli. 877 Dec 8

The thermophilic Clostridium P2 was isolated from a semi-continuously fed reactor with high ammonium concentration. This bacterium formed substantial amounts of L-alanine as a major fermentation product from glucose, fructose and mannose. Low amounts of acetate, butyrate, carbon dioxide and hydrogen were also formed. A high partial pressure of hydrogen inhibited the degradation of the monosaccharides, whereas hydrogen removal, in the form of methanogenesis was found to be stimulatory. However, the amount of alanine produced per mole of hexose degraded did not change. Hexose degradation and alanine production were favoured by high ammonium concentrations. Nuclear magnetic resonance spectroscopy studies provided strong evidence that an active Embden-Meyerhof-Parnas pathway existed and that alanine was produced via an amination of pyruvate.
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PMID:Alanine as an end product during fermentation of monosaccharides by Clostridium strain P2. 882 81

Proline-rich peptides are known to adopt preferentially the extended polyproline II (PPII) helical conformation, which is involved in several protein-protein recognition events. By resorting to molecular modelling techniques, we wished to investigate the extent to which PPII helices could be used for the formation of isochelical peptide-DNA complexes leading to the selective recognition of the major groove of B-DNA. For that purpose, we have grafted to a cationic intercalator, 9-amino-acridine, an oligopeptide having the sequence: Pro- Arg-Pro-Pro-Arg-Pro-Pro-Arg-Pro-Pro-Asp-Pro-Pro. Each residue in the sequence was set in the D configuration, to prevent enzymatic hydrolysis, and each Arg residue was designed to target O6/N7 of a guanine base following the intercalation site. The Asp residue was designed to target a cytosine base, whilst simultaneously forming a bidentate complex with the Arg three residues upstream. Energy-minimization, using the JUMNA procedure, led to the following conclusions : 1) major groove binding is favoured over minor groove or exclusive binding to the phosphates by large energy differences, of over 50 and 90 kcal/mole, respectively: 2) the two best bound sequences are those having three successive guanine bases on the same DNA strand, immediately adjacent to the intercalation site. Sequence d(CGGGC G), encountered in the Primer Binding Site of the HIV retrovirus, thus ranks amongst the best-bound sequences; 3) replacement of an individual guanine amongst the three ones upstream of the intercalation site, by an adenine base, weakens by > 6 kcal/mole the binding energetics; 4) the conformational rigidity of the DNA-bound PPII helix should enable for a modulation of the base sequence selectivity, by appropriate replacements of the Arg and Asp residues. Thus sequence CGGCAAG, also encountered in the HIV genome, could be targeted by an oligopeptide having the sequence Pro-Arg-Pro-Pro-Asp-Pro-Pro-Asn-Pro-Pro-Asn-Pro-Pro-Arg-Ala.
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PMID:Can a polyproline II helical motif be used in the context of sequence-selective major groove recognition of B-DNA? A molecular modelling investigation. 891 63

Multiple parvalbumin isoforms have been detected in the tail (skeletal) muscle of the American alligator (Alligator mississipiensis). One of these isoforms (APV-1) has been highly purified and partially characterized. Protein purification involved mainly gel filtration and anion exchange chromatography, and characterization included gel electrophoresis, amino acid composition analysis, metal ion analysis, MALDI-TOF and ESI mass spectrometry, ultraviolet and fluorescence spectroscopy, and one- and two-dimensional 500 MHz proton NMR spectroscopy. The alligator isoforms are rich in phenylalanine and deficient in the other aromatic residues as is typical for parvalbumins. In fact, the one highly purified isoform that forms the basis of this study has only phenyl-alanine as an aromatic residue. Ion exchange chromatography further indicates that this isoform has a relatively high isoelectric point (pl approximately 5.0), indicating that it is an alpha-lineage parvalbumin. This alligator parvalbumin isoform is unusual in that it has an atypically high Ca2+ content (almost 3.0 mole of Ca2+ per mole of protein) following purification, a fact supported by terbium fluorescence titration experiments. Preliminary comparative analysis of the highly purified alligator parvalbumin isoform (in the Ca2-loaded state) by two-dimensional 1H-NMR (2D 1H TOCSY and 2D 1H NOESY) indicates that there is considerable similarity in structure between the alligator protein and a homologous protein obtained from the silver hake (a saltwater fish species).
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PMID:The isolation of parvalbumin isoforms from the tail muscle of the American alligator (Alligator mississipiensis). 907 74


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