A Study of the Substrate and Inhibitor Specificities of AMP Aminohydrolase, 5′-Nucleotidase, and Adenylate Kinase with Adenosine Carboxylates of Variable Chain Length

1980 ◽  
Vol 35 (3-4) ◽  
pp. 273-278
Author(s):  
Wilfried Meyer ◽  
Hartmut Follmann
Keyword(s):  
Adenylate Kinase ◽  
Molecular Conformation ◽  
Competitive Inhibition ◽  
Nucleotide Metabolism ◽  
Competitive Inhibitors ◽  
Methylene Groups ◽  
Proton Magnetic Resonance Signal ◽  
Adenine Base ◽  
Ribose Moiety

Abstract A series of AMP analogs in which a terminal carboxylate residue, linked to C4′ of the ribose moiety of adenosine by zero, one, or two methylene groups (1, 2 ,3) or by the unsaturated ethylidene link (4) replaces the phosphate anion, is tested for activity as substrates or effectors of three enzymes known to interact with AMP with a different degree of specificity. 2 - 4 are substrates of AMP aminohydrolase, 3 and 4 are competitive inhibitors of adenylate kinase, and all acids produce competitive inhibition of the least specific enzyme, 5′-nucleotidase. These activities can be cor­ related with the intramolecular flexibility of anionic substituent and adenine base which in turn is expressed in typical shifts of the proton magnetic resonance signal of purine H-8. The uronic acid 1, having a rigid molecular conformation, is inactive towards two AMP-dependent enzymes and little active with the third, indicating that this type of compound is not suitable as a nucleotide an­ tagonist whereas nucleoside carboxylates of type 2 and 3 have a higher potential as effectors of nucleotide metabolism.

In Silico Prediction and Validation of Oxygen-Regulated Protein N-myc Downstream Regulated Gene 3 and Virtual Screening of Competitive Inhibitors of L-Lactate as Therapeutics

2019 ◽  
Vol 16 (6) ◽  
pp. 637-644
Author(s):  
Hongyu Cao ◽  
Yanhua Wu ◽  
Xingzhi Zhou ◽  
Xuefang Zheng ◽  
Ge Jiang
Keyword(s):  
Active Sites ◽  
Competitive Inhibition ◽  
Hydrophobic Effect ◽  
3D Structure ◽  
Amino Acid Residues ◽  
In Silico Prediction ◽  
Hypoxic Response ◽  
Drug Candidates ◽  
Competitive Inhibitors ◽  
Extracellular Regulated Protein Kinases

Background: N-myc downstream regulated gene 3 (NDRG3) is a newly discovered oxygen-regulated protein which will bind with L-Lactate in hypoxia and further activate Raf (rapidly accelerated fibrosarcoma)-ERK (extracellular regulated protein kinases) pathway, promoting cell growth and angiogenesis. Methods: Competitive inhibition on the binding of NDRG3 and L-Lactate may be potentially a useful strategy for the repression of hypoxic response mediated by NDRG3. The threedimensional (3D) structure of NDRG3 was built by using homology modeling for its crystal structure was not available. Then, L-Lactate was docked into NDRG3, from which we knew it bound with amino acid residues Gln69, His183, Asn189, Ala72 and Pro66 of NDRG3 in the most possible active sites. Approximately 3000 compounds have been virtually screened and the 6 topranked compounds were selected as reference molecules to analyze their interaction relationships, which illustrated that some of them might form electrostatic interaction with Glu70 and Asp187, π-&π stack with Phe75 and Tyr180, hydrogen bonds with Gly71 and Asn189, hydrophobic effect with Ala72 and Ile184. Results: Novel molecules were designed through structural optimization of the 6 top-ranked compounds and subsequently their ADMET properties were predicted. Conclusion: These molecules may be potential drug candidates for the suppression of hypoxic response mediated by NDRG3 and targeted therapy for hypoxia-induced diseases.

scholarly journals Partial purification and properties of the two common inherited forms of human erythrocyte adenylate kinase

1972 ◽  
Vol 130 (3) ◽  
pp. 797-803 ◽  
Author(s):  
C. Brownson ◽  
N. Spencer
Keyword(s):  
Adenylate Kinase ◽  
Effect Of Temperature ◽  
Partial Purification ◽  
Heat Denaturation ◽  
Gel Chromatography ◽  
Molecular Weights ◽  
Purification And Properties ◽  
Increasing Temperature

1. The partial purification of adenylate kinase, types 1 and 2, from human erythrocytes is described. 2. Gel chromatography of both forms of the enzyme gave estimates of the molecular weights in the range 20000–23000. 3. Studies on crude haemolysates at various pH values indicated that the type 2 enzyme was less stable than the type 1. Heat denaturation studies on the partially purified enzymes confirmed these findings. 4. Measurements of rates of inhibition by iodoacetate and iodoacetamide showed that the type 2 enzyme reacts more readily than the type 1 enzyme with both reagents. 5. The effect of temperature on the initial velocity of ADP formation was measured at a single concentration of both AMP and MgATP2-. The two forms of the enzyme responded differently to increasing temperature.

Distribution of enzymes of adenylate and guanylate nucleotide metabolism in rat nephron

1982 ◽  
Vol 243 (4) ◽  
pp. F349-F355
Author(s):  
B. R. Cole ◽  
A. E. Hays ◽  
J. G. Boylan ◽  
H. B. Burch ◽  
O. H. Lowry
Keyword(s):  
Adenylate Kinase ◽  
Metabolic Pathways ◽  
High Energy ◽  
Nucleotide Metabolism ◽  
Thick Ascending Limb ◽  
Amp Deaminase ◽  
Patterns Of Distribution ◽  
Degradative Enzyme ◽  
Convoluted Tubules ◽  
Nephron Heterogeneity

In a previous study of discrete segments of rat nephron, we reported the levels of high-energy adenylate and guanylate phosphates to be highest in the distal straight and convoluted tubules. Those findings stimulated the study of the distribution of seven enzymes involved in the following metabolic pathways of these nucleotides [Formula: see text]. The patterns of distribution of enzymes in each pathway differed greatly. The phosphodiesterases, 1 and 2, were high in glomeruli and distal tubular segments and low in proximal segments. Adenylate kinase, 3, in contrast, was high in glomeruli, proximal segments, thick ascending limb of Henle, and distal convoluted tubules. Guanylate kinase levels, 4, however, were similar in all segments. The pattern of nucleosidediphosphate kinase, 5, was high in proximal convoluted, thick ascending limb, and distal convoluted tubules. The pattern of the degradative enzyme, 5'-nucleotidase, 6, whose levels were highest in proximal segments, was opposite from that of AMP deaminase, 7, highest in the distal nephrons. These dissimilar patterns underscore the extent of nephron heterogeneity.

The dynamic behaviour of nitrifying Activated sludge systems influenced by inhibiting wastewater compounds

1995 ◽  
Vol 31 (2) ◽  
pp. 115-124 ◽  
Author(s):  
O. Nowak ◽  
K. Svardal ◽  
P. Schweighofer
Keyword(s):  
Activated Sludge ◽  
Treatment Process ◽  
Dynamic Behaviour ◽  
Competitive Inhibition ◽  
Nitrification Inhibition ◽  
Peak Loads ◽  
Inhibitory Compounds ◽  
Competitive Inhibitors ◽  
Nitrification Process ◽  
Activated Sludge Systems

More or less severe nitrification inhibition was observed in several pilot and full-scale activated sludge plants treating industrial wastewaters. In order to control the treatment process under inhibiting conditions, extended nitrification models have been developed on base of the ‘Activated sludge model No. 1’. In the case of temperatures between 25 and 30°C, the nitrification process has been expressed as a two-step reaction with nitrite as intermediate. Model elements for competitive and non-competitive inhibition as well as for biodegradation of the inhibitor were added, if required. The dynamic behaviour of the investigated activated sludge systems indicates that there are biodegradable non-competitive inhibitors. Operational as well as simulation results show that nitrifying activated sludge plants may become acclimatized to inhibitory compounds but have to be protected from peak loads of both nitrogen and inhibitory compounds.

A Proton Magnetic Resonance Study of the Molecular Conformation of a Modified Nucleoside from Transfer RNA. Dihydrouridine

1971 ◽  
Vol 49 (12) ◽  
pp. 1279-1284 ◽  
Author(s):  
Roxanne Deslauriers ◽  
R. D. Lapper ◽  
Ian C. P. Smith
Keyword(s):  
Magnetic Resonance ◽  
Molecular Conformation ◽  
Cyanuric Acid ◽  
Chemical Shifts ◽  
Torsional Angle ◽  
Hydroxymethyl Group ◽  
Diamagnetic Anisotropy ◽  
Trna Species ◽  
Almost All ◽  
Ribose Moiety

The 220 MHz nuclear magnetic resonance (N.M.R.) spectra of dihydrouridine at 23 °C and 60 °C have been analyzed. From the N.M.R. data a conformational model is derived. The ribose moiety indicates a slight preference for the C3′exo and C2′endo conformations, although rapid interconversion between ring-puckered conformers is taking place. At high temperature the preference for C3′exo and C2′endo is less. The conformation of the exocyclic hydroxymethyl group is a rapid time average of all possible conformers with a preference for the gauche-gauche rotamer. By comparison with β-cyanuric acid riboside the chemical shifts of the ribose moiety in dihydrouridine are not influenced by the diamagnetic anisotropy of the keto group on the base, demonstrating that the base has the anti conformation with respect to the ribose ring. The dihydrouracil base does not exist in any of the classical puckered conformations, but manifests an average torsional angle of approximately 30° apparently due to rapid interconversion between various conformations. This distinguishes dihydrouridine from all other naturally occurring nucleosides, and may be the reason for its occurrence in almost all known tRNA species.

Characterization of substrate binding and enzymatic removal of a 3-methyladenine lesion from genomic DNA with TAG of MDR A. baumannii

2016 ◽  
Vol 12 (11) ◽  
pp. 3259-3265 ◽  
Author(s):  
Jyoti Singh Tomar ◽  
Manju Narwal ◽  
Pravindra Kumar ◽  
Rama Krishna Peddinti
Keyword(s):  
Genomic Dna ◽  
Substrate Binding ◽  
Binding Parameters ◽  
Competitive Inhibitors ◽  
Adenine Base

The binding parameters of substrates with enzyme TAG revealed that it exhibits selectivity for 3mA over the normal adenine base. The results obtained from the experiments are useful in designing of competitive inhibitors.

A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human

2007 ◽  
Vol 29 (2) ◽  
pp. 99-108 ◽  
Author(s):  
R. M. Salek ◽  
M. L. Maguire ◽  
E. Bentley ◽  
D. V. Rubtsov ◽  
T. Hough ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Multivariate Statistics ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Nucleotide Metabolism ◽  
Metabolic Changes ◽  
Stress Changes

Type 2 diabetes mellitus is the result of a combination of impaired insulin secretion with reduced insulin sensitivity of target tissues. There are an estimated 150 million affected individuals worldwide, of whom a large proportion remains undiagnosed because of a lack of specific symptoms early in this disorder and inadequate diagnostics. In this study, NMR-based metabolomic analysis in conjunction with multivariate statistics was applied to examine the urinary metabolic changes in two rodent models of type 2 diabetes mellitus as well as unmedicated human sufferers. The db/db mouse and obese Zucker ( fa/fa) rat have autosomal recessive defects in the leptin receptor gene, causing type 2 diabetes. 1H-NMR spectra of urine were used in conjunction with uni- and multivariate statistics to identify disease-related metabolic changes in these two animal models and human sufferers. This study demonstrates metabolic similarities between the three species examined, including metabolic responses associated with general systemic stress, changes in the TCA cycle, and perturbations in nucleotide metabolism and in methylamine metabolism. All three species demonstrated profound changes in nucleotide metabolism, including that of N-methylnicotinamide and N-methyl-2-pyridone-5-carboxamide, which may provide unique biomarkers for following type 2 diabetes mellitus progression.

scholarly journals Interaction of the lacZ β-galactosidase of Escherichia coli with some β-d-galactopyranoside competitive inhibitors

1979 ◽  
Vol 177 (1) ◽  
pp. 145-152 ◽  
Author(s):  
R. S. Thomas Loeffler ◽  
Michael L. Sinnott ◽  
Brian D. Sykes ◽  
Stephen G. Withers
Keyword(s):  
Escherichia Coli ◽  
Competitive Inhibition ◽  
Phenolic Hydroxy Group ◽  
Bivalent Metal ◽  
Transverse Relaxation ◽  
Competitive Inhibitors ◽  
Inhibition Constants ◽  
Increasing Temperature ◽  
Phenolic Hydroxy ◽  
Average Position

1. The location of the bivalent metal cation with respect to bound competitive inhibitors in Escherichia coli (!lacZ) β-galactosidase was investigated by proton magnetic resonance. 2. Replacement of Mg2+ by Mn2+ enhances both longitudinal and transverse relaxation of the methyl groups of the β-d-galactopyranosyltrimethylammonium ion, and of methyl 1-thio-β-d-galactopyranoside; linewidths are narrowed by increasing temperature. 3. The Mn2+ ion is located 8–9Å (0.8–0.9nm) from the centroid of the trimethylammonium group and 9Å (0.9nm) from the average position of the methylthio protons. 4. The effective charge at the active site was probed by measurement of competitive inhibition constants (Kio and Ki+ respectively) for the isosteric ligands, β-d-galactopyranosylbenzene and the β-d-galactopyranosylpyridinium ion. 5. The ratio of inhibition constants (Q=Ki+/Kio) obtained with 2-(β-d-galactopyranosyl)–naphthalene and the β-d-galactopyranosylisoquinolinium ion at pH7 with Mg2+–enzyme was identical, within experimental error, with that obtained with the monocyclic compounds. 6. The variation of Q for Mg2+–enzyme can be described by Q=0.1(1+[H+]/4.17×10−10)/1+[H+]/10−8). 7. This, in the theoretical form for a single ionizable group, is ascribed to the ionization of the phenolic hydroxy group of tyrosine-501. 8. The variation of Q for Mg2+-free enzyme is complex, probably because of deprotonation of the groups normally attached to Mg2+ as well as tyrosine-501.

Sign in / Sign up

Export Citation Format

Share Document