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211.
Ghosh KS Debnath J Dutta P Sahoo BK Dasgupta S 《Bioorganic & medicinal chemistry》2008,16(6):2819-2828
In this study, compounds with a carboxy ester in lieu of the phosphate ester at the 3'-position have been employed to inhibit the ribonucleolytic activity of ribonuclease A (RNase A). Phosphates at the 3'-position of pyrimidine bases are well-known inhibitors of the protein. We have investigated the inhibition of RNase A by 3'-O-carboxy esters of thymidine. The compounds behave as competitive inhibitors with inhibition constants ranging from 42 to 95 microM. The mode of inhibition has also been confirmed by (1)H NMR studies of the active site histidines of RNase A. Docking studies have further substantiated the experimental results. The compounds are also found to inhibit the ribonucleolytic activity of angiogenin, a homologous protein and potent inducer of blood vessel formation. 相似文献
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214.
Arkadeb Dutta Praveen Vats Vijay K. Singh Yogendra K. Sharma Som N. Singh Shashi B. Singh 《International journal of biometeorology》2009,53(5):397-407
Mitochondrial ß-oxidation of fatty acid provides a major source of energy in mammals. High altitude (HA), characterized by hypobaric hypoxia and low ambient temperatures, causes alteration in metabolic homeostasis. Several studies have depicted that hypoxic exposure in small mammals causes hypothermia due to hypometabolic state. Moreover, cold exposure along with hypoxia reduces hypoxia tolerance in animals. The present study investigated the rate of β-oxidation and key enzymes, carnitine palmitoyl transferase-I (CPT-I) and hydroxyacyl CoA dehydrogenase (HAD), in rats exposed to cold-hypobaric hypoxic environment. Male Sprague Dawley rats (190–220 g) were randomly divided into eight groups (n?=?6 rats in each group): 1 day hypoxia (H1); 7 days hypoxia (H7); 1 day cold (C1); 7 days cold (C7); 1 day cold-hypoxia (CH1); 7 days cold-hypoxia (CH7) exposed; and unexposed control for 1 and 7 days (UC1 and UC7). After exposure, animals were anaesthetized with ketamine (50 mg/kg body weight) and xylazine (10 mg/kg body weight) intraperitonialy and sacrificed. Mitochondrial CPT-I, HAD, 14C-palmitate oxidation in gastrocnemius muscle and liver, and plasma leptin were measured. Mitochondrial CPT-I was significantly reduced in muscle and liver in CH1 and CH7 as compared to respective controls. HAD activity was significantly reduced in H1 and CH7, and in H1, H7, CH1, and CH7 as compared to unexposed controls in muscle and liver, respectively. A concomitant decrease in 14C-palmitate oxidation was found. Significant reduction in plasma leptin in hypoxia and cold-hypoxia suggested hypometabolic state. It can be concluded that ß-oxidation of fatty acids is reduced in rats exposed to cold-hypoxic environment due to the persisting hypometabolic state in cold-hypoxia exposure. 相似文献
215.
Processing of the 3′ terminus of tRNA in many organisms is carried out by an endoribonuclease termed RNase Z or 3′-tRNase, which cleaves after the discriminator nucleotide to allow addition of the universal -CCA sequence. In some eubacteria, such as Escherichia coli, the -CCA sequence is encoded in all known tRNA genes. Nevertheless, an RNase Z homologue (RNase BN) is still present, even though its action is not needed for tRNA maturation. To help identify which RNA molecules might be potential substrates for RNase BN, we carried out a detailed examination of its specificity and catalytic potential using a variety of synthetic substrates. We show here that RNase BN is active on both double- and single-stranded RNA but that duplex RNA is preferred. The enzyme displays a profound base specificity, showing no activity on runs of C residues. RNase BN is strongly inhibited by the presence of a 3′-CCA sequence or a 3′-phosphoryl group. Digestion by RNase BN leads to 3-mers as the limit products, but the rate slows on molecules shorter than 10 nucleotides in length. Most interestingly, RNase BN acts as a distributive exoribonuclease on some substrates, releasing mononucleotides and a ladder of digestion products. However, RNase BN also cleaves endonucleolytically, releasing 3′ fragments as short as 4 nucleotides. Although the presence of a 3′-phosphoryl group abolishes exoribonuclease action, it has no effect on the endoribonucleolytic cleavages. These data suggest that RNase BN may differ from other members of the RNase Z family, and they provide important information to be considered in identifying a physiological role for this enzyme.Maturation of tRNA precursors requires the removal of 5′ and 3′ precursor-specific sequences to generate the mature, functional tRNA (1). In eukaryotes, archaea, and certain eubacteria, the 3′-processing step is carried out by an endoribonuclease termed RNase Z or 3′-tRNase (2–6). However, in some bacteria, such as Escherichia coli, removal of 3′ extra residues is catalyzed by any of a number of exoribonucleases (7, 8). The major determinant for which mode of 3′-processing is utilized appears to be whether or not the universal 3′-terminal CCA sequence is encoded (2, 9). Thus, for those tRNA precursors in which the CCA sequence is absent, endonucleolytic cleavage by RNase Z right after the discriminator nucleotide generates a substrate for subsequent CCA addition by tRNA nucleotidyltransferase (1–3, 10). In view of this role for RNase Z in 3′-tRNA maturation, it is surprising that E. coli, an organism in which the CCA sequence is encoded in all tRNA genes (2), nevertheless contains an RNase Z homologue (11), because its action would appear not to be necessary. In fact, the physiological function of this enzyme in E. coli remains unclear, because mutants lacking this protein have no obvious growth phenotype (12). Hence, there is considerable interest in understanding the enzymatic capabilities of this enzyme.The E. coli RNase Z homologue initially was identified as a zinc phosphodiesterase (11) encoded by the elaC gene (now called rbn) (13). Subsequent work showed that the protein also displayed endoribonuclease activity on certain tRNA precursors in vitro (6, 14). However, more recent studies revealed that this protein actually is RNase BN, an enzyme originally discovered in 1983 and shown to be essential for maturation of those bacteriophage T4 tRNA precursors that lack a CCA sequence (15, 16). Using synthetic mimics of these T4 tRNA precursors, RNase BN was found to remove their 3′-terminal residue as a mononucleotide to generate a substrate for tRNA nucleotidyltransferase. Based on these reactions RNase BN was originally thought to be an exoribonuclease (13, 15, 17). However, subsequent work by us and others showed that it can act as an endoribonuclease on tRNA precursors (13, 18). RNase BN is required for maturation of tRNA precursors in E. coli mutant strains devoid of all other 3′-tRNA maturation exoribonucleases, although it is the least efficient RNase in this regard (7, 19). Thus, under normal circumstances, it is unlikely that RNase BN functions in maturation of tRNA in vivo except in phage T4-infected cells (15, 16).To obtain additional information on what types of RNA molecules might be substrates for RNase BN and to clarify whether it is an exo- or endoribonuclease, we have carried out a detailed examination of its catalytic properties and substrate specificity. We show here that RNase BN has both exo- and endoribonuclease activity and that it can act on a wide variety of RNA substrates. These findings suggest that E. coli RNase BN may differ from other members of the RNase Z family of enzymes. 相似文献
216.
Dennis A. Brown Manoj Mishra Suhong Zhang Swati Biswas Ingrid Parrington Tamara Antonio Maarten E.A. Reith Aloke K. Dutta 《Bioorganic & medicinal chemistry》2009,17(11):3923-3933
Here we report on the design and synthesis of several heterocyclic analogues belonging to the 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol series of molecules. Compounds were subjected to [3H]spiperone binding assays, carried out with HEK-293 cells expressing either D2 or D3 dopamine receptors, in order to evaluate their inhibition constant (Ki) at these receptors. Results indicate that N-substitution on the piperazine ring can accommodate various substituted indole rings. The results also show that in order to maintain high affinity and selectivity for the D3 receptor the heterocyclic ring does not need to be connected directly to the piperazine ring as the majority of compounds included here are linked either via an amide or a methylene linker to the heterocyclic moiety. The enantiomers of the most potent racemic compound 10e exhibited differential activity with (?)-10e (Ki; D2 = 47.5 nM, D3 = 0.57 nM) displaying higher affinity at both D2 and D3 receptors compared to its enantiomer (+)-10e (Ki; D2 = 113 nM, D3 = 3.73 nM). Additionally, compound (?)-10e was more potent and selective for the D3 receptor compared to either 7-OH-DPAT or 5-OH-DPAT. Among the bioisosteric derivatives, the indazole derivative 10g and benzo[b]thiophene derivative 10i exhibited the highest affinity for D2 and D3 receptors. In the functional GTPγS binding study, one of the lead molecules, (?)-15, exhibited potent agonist activity at both D2 and D3 receptors with preferential affinity at D3. 相似文献
217.
Ishani Deb Priyankar Paira Abhijit Hazra Sukdeb Banerjee Pradip Kumar Dutta Nirup Bikash Mondal Sumantra Das 《Bioorganic & medicinal chemistry》2009,17(16):5782-5790
Based on an established 3D pharmacophore, a series of quinoline derivatives were synthesized. The opioidergic properties of these compounds were determined by a competitive binding assay using 125I-Dynorphine, 3H-DAMGO and 125I-DADLE for κ, μ, and δ receptors, respectively. Results showed varying degree of activities of the compounds to κ and μ opioid receptors with negligible interactions at the δ receptor. The compound, S4 was the most successful in inhibiting the two most prominent quantitative features of naloxone precipitated withdrawal symptoms - stereotyped jumping and body weight loss. Determination of IC50 of S4 revealed a greater affinity towards μ compared to κ receptor. In conclusion, quinoline derivatives of S4 like structure offer potential tool for treatment of narcotic addictions. 相似文献
218.
Samikshan Dutta Jyothi Shaw Swagata Sinha Kanchan Mukhopadhyay 《Indian journal of human genetics》2009,15(1):28-31
Chromosomal abnormalities are thought to be the most common cause of mental retardation (MR). However, apart from a few selected types with typical aneuploidy, like Downs syndrome, Klinefelter syndrome, Turner syndrome, etc., the frequency of detectable chromosomal abnormalities in association with idiopathic MR is very low. In this study, we have investigated chromosomal abnormalities in female MR subjects (n = 150) by high-resolution GTG banding. Of them, 30 cases were diagnosed as Downs syndrome. Among the remaining (n = 120), chromosomal abnormalities/marked polymorphisms were detectable in only three MR cases (0.025). 相似文献
219.
Nikhil Jain Abu Rafay Khan Sushil Kumar Tomar Dipak Dutta Balaji Prakash 《Biochemical and biophysical research communications》2009,379(2):201-205
HflX is a GTP binding protein of unknown function. Based on the presence of the hflX gene in hflA operon, HflX was believed to be involved in the lytic-lysogenic decision during phage infection in Escherichia coli. We find that E. coli HflX binds 16S and 23S rRNA - the RNA components of 30S and 50S ribosomal subunits. Here, using purified ribosomal subunits, we show that HflX specifically interacts with the 50S. This finding is in line with the homology of HflX to GTPases involved in ribosome biogenesis. However, HflX-50S interaction is not limited to a specific nucleotide-bound state of the protein, and the presence of any of the nucleotides GTP/GDP/ATP/ADP is sufficient. In this respect, HflX is different from other GTPases. While E. coli HflX binds and hydrolyses both ATP and GTP, only the GTP hydrolysis activity is stimulated by 50S binding. This work uncovers interesting attributes of HflX in ribosome binding. 相似文献
220.