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

The cytotoxic activity of mitoxantrone and related anthracenediones has been ascribed to the ability of these compounds to interfere with DNA topoisomerase II function, resulting in DNA cleavage stimulation. The molecular details of enzyme inhibition by these intercalating agents remain to be defined. In an attempt to identify the structural determinants for optimal activity, the molecular and cellular effects of a series of heteroanalogues bearing different side-chains were examined in relation to the physico-chemical and DNA binding properties of these compounds. The results indicated that substitution of a pyridine ring for the dihydroxyphenylene ring in the planar chromophore caused a marked reduction of cytotoxic activity and of the ability to stimulate topoisomerase II-mediated DNA damage in intact cells and with simian virus 40 DNA in vitro. Although all tested derivatives were shown to intercalate into DNA, their DNA binding affinities were appreciably lower than that of mitoxantrone. The behavior of 2-aza derivatives more closely resembled that of ametantrone, suggesting that the potency of agents of this class is influenced more by the presence of hydroxyl groups than by the phenylene ring. The observation that a dramatic reduction (or loss) of the ability of aza derivatives to stimulate DNA cleavage is associated with a marked reduction of cytotoxic potency supports a primary role of topoisomerase II-mediated effects in the mechanism of action of the effective agents of this class. Because appreciable cytotoxic activity and significant in vivo antitumor efficacy are retained by compounds inactive (or poorly active) in inhibition of topoisomerase II, these results are consistent with multiple effects of anthracenediones at the cellular level.
Mol Pharmacol 1995 Jul
PMID:Topoisomerase II DNA cleavage stimulation, DNA binding activity, cytotoxicity, and physico-chemical properties of 2-aza- and 2-aza-oxide-anthracenedione derivatives. 762 72

We have isolated cDNA clones encoding the pentose phosphate pathway enzymes 6-phosphogluconate dehydrogenase (6PGDH, EC 1.1.1.44) and glucose 6-phosphate dehydrogenase (G6PDH, EC 1.1.1.49) from alfalfa (Medicago sativa L.). These exhibit extensive nucleotide and amino acid sequence similarity to the corresponding genes from bacteria, Drosophila and mammals. Transcripts encoding both enzymes are expressed at high levels in roots and nodules. Exposure of alfalfa suspension cells to an elicitor from yeast cell walls results in co-ordinated increases in transcription rates for both genes, followed by increased steady state transcript levels but only slightly increased extractable enzyme activities, at the onset of accumulation of isoflavonoid phytoalexins. Levels of NADPH and NADP remain relatively constant in alfalfa cells following elicitation. The rapid transcriptional activation of 6PGDH and G6PDH does not therefore appear to be a response to altered pyridine nucleotide redox state. These genes appear to respond to early events in elicitor-mediated signalling rather than to subsequent elicitor-induced changes in secondary metabolism. Hydrogen peroxide, a potential signal for elicitation of anti-oxidative genes in biologically stressed plant cells, did not induce 6PGDH or G6PDH transcripts or enzymatic activity.
Plant Mol Biol 1995 Aug
PMID:Stress responses in alfalfa (Medicago sativa L.) XIX. Transcriptional activation of oxidative pentose phosphate pathway genes at the onset of the isoflavonoid phytoalexin response. 764 Mar 60

The pyridine nucleotide transhydrogenase of Escherichia coli is composed of two types of subunits, alpha and beta. Trypsin digestion of the purified enzyme generates fragments of the alpha subunit. The beta subunit is uncleaved unless NADP(H) is present (Tong, R.C.W., Glavas, N.A. and Bragg. P.D. (1991) Biochim. Biophys. Acta 1080, 19-28). Purified transhydrogenase bound to either NAD- or NADP-agarose was treated with trypsin. The alpha subunit was cleaved to 16, 29 and 43 kDa fragments in both cases. The beta subunit remained bound to NAD-agarose but was released as two cleavage fragments (25 and 30 kDa) from NADP-agarose. The beta subunit of the transhydrogenase bound to NAD-agarose was cleaved by trypsin in the presence of NADP(H) to yield 25 and 30 kDa fragments of the beta subunit. These results suggest that the beta subunit contains two pyridine nucleotide-binding sites.
Biochem Mol Biol Int 1995 Feb
PMID:Evidence for the presence of two pyridine nucleotide-binding sites on the beta subunit of the Escherichia coli pyridine nucleotide transhydrogenase. 766 84

It is conceivable that androstenedione contributes indirectly to 5 alpha-dihydrotestosterone formation in human prostate by its intraprostatic conversion to testosterone. This reversible conversion is catalyzed by the enzyme 17 beta-hydroxysteroid oxidoreductase (17 beta-HSOR). At present, rather limited information on kinetic parameters like specific concentration (Vmax), affinity to steroid substrates (KmS) and to pyridine nucleotides (KmN) of 17 beta-HSOR is available. Thus, we determined those aforementioned kinetic parameters in epithelium and stroma of normal human prostate (NPR) and benign prostatic hyperplasia (BPH). The main results were: (1) the mean KmS of 17 beta-HSORred/NADPH was significantly (P < 0.0001) lower than those of all other 17 beta-HSORs. (2) In almost all cases the mean Vmax was higher in BPH than NPR. (3) In all cases, the mean Vmax/KmS ratios of 17 beta-HSORred were higher than those of 17 beta-HSORox. The highest ratio was found regarding 17 beta-HSORred/NADPH in BPH stroma. (4) In stroma, a significantly positive correlation of Vmax/KmS of 17 beta-HSORred/NADPH with age was found. (5) The lowest KmN was found regarding NADP+, followed by NADPH. It is concluded that in human prostate the balance of the reversible conversion of testosterone to androstenedione is shifted potentially towards testosterone, particularly in BPH stroma.
J Steroid Biochem Mol Biol 1993 Jul
PMID:17 beta-hydroxysteroid oxidoreductase in epithelium and stroma of human prostate. 768 61

Recent studies suggest that taurine (2-aminoethanesulfonic acid) is involved in the regulation of protein phosphorylation in excitable tissues such as the retina, brain and heart. In order to determine the structural requirements for the effect of taurine on the phosphorylation of a 44 kDa protein(s), a series of taurine analogues were tested in an in vitro assay using a subcellular mitochondrial fraction of rat heart. Inhibitors of the phosphorylation of the 44 kDa protein include taurine and close structural analogues of taurine such as aminoethylhydrogen sulfate and alpha-sulfo-beta-alanine. Secondary amines with the taurine structure partially locked into a saturated 5-membered ring such as (+/-)piperidine-3-sulfonic acid and 1,2,3,4-tetrahydroquinoline-8-sulfonic acid also possess inhibitory activity. Sulfone analogues of taurine such as 2-aminoethylmethylsulfone, a non-restricted taurine analogue with maximal conformational flexibility about its amino and sulfone moieties, and (+/-)3-aminotetrahydrothiopyran-1,1-dioxide, an analogue containing the sulfone moiety in a six-membered ring structure, were found to be more potent inhibitors of phosphorylation than taurine despite the fact that the sulfone moiety is neither an isosteric nor isoelectronic substitution for the sulfonic acid moiety. The results of this study indicate that the inhibition of the phosphorylation of the 44 kDa protein in a rat heart mitochondrial fraction is relatively specific for the taurine structure. Two analogues of taurine with unsaturated rings containing a primary sulfonic acid and a secondary amine, pyridine-3-sulfonic acid and quinoline-8-sulfonic acid, were observed to be stimulators of the phosphorylation of the 44 kDa protein. In addition, 2-aminobenzenesulfonic acid also stimulated phosphorylation. Phase separation experiments with Triton X-114 suggest that the 44 kDa phosphoprotein is a soluble protein and not an integral membrane protein of the mitochondria. Phosphate incorporation into specific amino acids was determined by two-dimensional electrophoresis on celluloses plates and was found exclusively in the serine residues.
J Mol Cell Cardiol 1994 Dec
PMID:Effects of taurine and taurine analogues on the phosphorylation of a 44 kDa protein present in a mitochondrial subfraction of the rat heart: partial characterization of the 44 kDa phosphoprotein. 773 Oct 61

The interaction of renal clearance between nilvadipine metabolites, M3 and M7, in male and female rats including protein binding and renal excretion was investigated to clarify the mechanisms involved. In male rats, active renal secretion of M7 (the 5-carboxylic acid pyridine derivative) was reduced in inverse proportion to the molar ratio of the plasma concentration M3/M7 after an i.v. dose of M3 (the 3-carboxylic acid pyridine derivative), and the dosed M3 was excreted only by glomerular filtration. In female rats, the active renal secretion of M7 was unaffected after an i.v. dose of M3, and the dosed M3 was excreted by active secretion. These results indicate an interference of the active secretion of M7 in male rats by M3 on competitive interaction at the renal tubular secretion, even though M3 was excreted only via a filtration process. Female rats may have two distinct and separate active renal secretion mechanisms for M7 and M3, even though these carboxylic acid compounds were eliminated by active transport in the kidney.
Res Commun Mol Pathol Pharmacol 1994 Nov
PMID:Interaction of renal excretion between nilvadipine metabolites, M3 and M7 in rats: characterization of sex-dependent and sex-independent active secretion in the kidney. 788 69

The pyridine nucleotides have important non-redox activities as cellular effectors and metabolic regulators [1-3]. The enzyme-catalyzed cleavage of the nicotinamide-ribosyl bond of NAD+ and the attendant delivery of the ADPRibosyl moiety to acceptors is central to these many diverse biological activities. Included are the medically important NAD-dependent toxins associated with cholera, diphtheria, pertussis, and related diseases [4]; the reversible ADPRibosylation-mediated biological regulatory systems [5,6]; the synthesis of poly(ADPRibose) in response to DNA damage or cellular division [7]; and the synthesis of cyclic ADPRibose as part of an independent, calcium-mediated regulatory system [8]. As will be presented in this chapter, all evidence points to both the chemical and enzyme-catalyzed cleavage of the nicotinamide-ribosyl bond being dissociative in character via an oxocarbenium intermediate.
Mol Cell Biochem 1994 Sep
PMID:NAD hydrolysis: chemical and enzymatic mechanisms. 789 70

Nicotinamide (NIC) is known to increase the synthesis of pyridine nucleotides and also to inhibit the hydrolysis of them to ADP-ribose, which in turn is involved in Ca2+ release from mitochondria via the ADP ribosylation of crucial mitochondrial proteins. In this work, we test the potential ability of NIC to be a late protective agent against CCl4-induced liver necrosis. We observed that 1 g/kg po NIC, 30 min before or 6 or 10 hr after CCl4 (1 ml/kg), given ip as a 20% (v/v) solution in olive oil, was able to significantly prevent the necrogenic effect of the hepatotoxin at 24 hr as evidenced by determination of isocitric dehydrogenase activity in plasma or by histological observation. NIC administration 6 hr after CCl4 prevented fatty liver induced by hepatotoxin at 24 hr. NIC did not modify CCl4-induced lipid peroxidation process at 1 hr after CCl4 and decreased the covalent binding of 14CCl4 to lipids. NIC decreased the levels of 14CCl4 reaching the liver when given 30 min before hepatotoxin but not when given 6 hr after it. NIC lowered body temperature of rats at 1, 3, and 6 hr and augmented it at 24 hr after CCl4. NIC concentrations in liver as determined by GC/MS/SIM analysis were 21 micrograms/g liver 1 hr after administration and 53 micrograms/g at 3 hr. Late preventive effects of NIC against CCl4 induced liver necrosis when given at 6 or 10 hr after CCl4 are compatible with the hypothesis that NIC restores mitochondrial ability for Ca2+ uptake. This hypothesis remains to be proved and is being further challenged in our laboratory.
Exp Mol Pathol 1994 Jun
PMID:Nicotinamide late protective effects against carbon tetrachloride-induced liver necrosis. 795 79

Maps for the interaction energy of acetone, pyrrole, furan, and pyridine with a positive unitary charge were computed using ab initio techniques, together with their molecular electrostatic potentials at the same points. The difference between the interaction and electrostatic potential maps yielded polarization maps for the molecules. Finally, maps for the interaction with a negative charge were obtained as the difference between the polarization and electrostatic potential maps. The calculations were carried out for three planes, 2 Bohr radii, 4 Bohr radii, and 8 Bohr radii from the plane containing the heavy atoms for all the molecules. At larger distances, the interaction and electrostatic maps resemble each other qualitatively; however, at shorter distances, where the polarization effects are more significant, the differences between the maps are notable. Interaction and polarization maps can be routinely evaluated for medium-sized molecules, and are likely to become an important tool in drug design and chemical reactivity.
J Mol Graph 1994 Mar
PMID:Molecular polarization maps as a tool for studies of intermolecular interactions and chemical reactivity. 801 99

Chinese hamster ovary (CHO) cells show a cell density-dependent modification of ATP levels during the growth cycle. Cells were seeded at a density of 500,000 cells/75 cm2 flask in 10 ml of growth medium and at various time intervals, samples were taken and assayed for cell number, for adenine (ATP, ADP, AMP) and pyridine (NAD+, NADP+) nucleotide levels and for the activity of some glycolytic enzymes. Glucose consumption was also evaluated. Experimental results indicated that the rate of cell growth was exponential for up to the 4th day of culture after which the cell number remained pratically unchanged up to the 9th day. Under these experimental conditions we found that, whereas the intracellular levels of NAD+ and some glycolytic enzymes were not significantly affected, a drop in ATP content was apparent after 48 hr of culture. The decline in ATP levels progressively increased, reaching a maximum after 4 days of culture, and then remained unchanged. In order to evaluate whether this effect on ATP was determined by a reduced availability of nutritional factors or was really a function of cell density, we also performed experiments similar to those reported above, with the exception that the cells were grown in 40 ml of culture medium. Under these experimental conditions, the exponential growth was longer (in comparison with the cell growth in 10 ml of medium) and a plateau was reached after 6 days of culture.(ABSTRACT TRUNCATED AT 250 WORDS)
Biochem Mol Biol Int 1994 Feb
PMID:Cell density-dependent regulation of ATP levels during the growth cycle of cultured Chinese hamster ovary cells. 801 30


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>