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 glycogen concentration in liver is altered in various pathophysiologic states. In fasted rats, it is higher in diabetic, and lower in adrenalectomized rats compared to control animals. In fed rats, it is lower in diabetic, and little changed in adrenalectomized animals compared to controls. We were interested in determining whether the activity of glycogenin, a self-glycosylating protein that initiates the synthesis of new glycogen molecules, could explain these differences in liver glycogen concentration. Glycogenin activity was measured by the incorporation of 14C-glucose from UDP-U-14C-glucose into an acid-precipitable product before and after amylase treatment of liver extracts. The glycogenin activity was similar in normal, diabetic and adrenalectomized fasted animals, regardless of the hepatic glycogen concentration. In fasted rats, glycogenin was present predominantly as the free-form of the enzyme, i.e., not attached to an amylase-digestible glycan, presumably glycogen. In contrast, in fed rats, the majority, if not all of the glycogenin was incorporated into a glycogen-like (proteoglycan) molecule. Proteoglycan synthase activity, previously identified in normal fed rats, also was present in diabetic and adrenalectomized fed rats, and the activity was similar. Thus, the altered ability to store hepatic glycogen in diabetic fed and fasted and adrenalectomized fasted rats cannot be explained by decreases in glycogenin or proteoglycan synthase activities, at least as measured using the present assays.
Cell Mol Biol (Noisy-le-grand) 1998 Sep
PMID:Liver glycogenin activity in diabetic and adrenalectomized rats. 976 98

Presence of homo- and hetero-tetrameric rice sucrose synthase (RSS) isoforms in etiolated rice seedlings was demonstrated by immunoprecipitation using monospecific antibodies. Three RSS isozymes with various pI values were purified by ammonium sulfate fractionation, Sepharose CL-6B gel filtration, DEAE-Sephacel and Mono-Q ion exchange chromatographies. They were characterized as heterotetramers composed of RSS1 and RSS2 subunits. All of them used UDP as the best substrate. The presence of divalent metal ions increased the activities of synthesis but inhibited the cleavage of sucrose.
Biochem Mol Biol Int 1998 Sep
PMID:Purification and characterization of sucrose synthase isozymes from etiolated rice seedlings. 978 45

The protective effect of several classes of compounds against the toxic and neoplastic effects of xenobiotics has been attributed to the induction of noncytochrome P450 (P450) drug metabolizing enzymes. Glutathione S-transferases (GST), NAD(P)H: quinone oxidoreductase (QOR), and UDP-glucuronosyltransferases (UGT) play a prominent role in detoxification and can be induced by oltipraz and other N-heterocyclic compounds in rats. In contrast to the induction of these enzymes by aryl hydrocarbon (Ah)-receptor agonists, induction by oltipraz and 1,7-phenanthroline is not accompanied by CYP1A induction. This study investigated the induction of drug metabolizing enzymes following administration of oltipraz and 1,7-phenanthroline in four mouse strains (C57B6A-J, Frings x C57B6J, Frings, CF-1) exhibiting varying degrees of responsiveness to an Ah-receptor agonist. The relative Ah responsiveness was determined in all strains by the induction of hepatic Cypla after three daily doses of 3-methylcholanthrene (20 mg/kg). After treatment with 1,7-phenanthroline and oltipraz (150 mg/kg i.g.) daily for 3 days, all strains showed similar induction of GST and QOR activities for each inducer. Both compounds were equally effective in elevating GST activity, but 1,7-phenanthroline was more effective than oltipraz in elevating QOR activity. In addition to GST and QOR changes, 1,7-phenanthroline significantly elevated UGT (1-naphthol) activity in the Frings strain. Neither compound produced significant changes in Cypla parameters. The independence of 1,7-phenanthroline and oltipraz induction of GST and QOR from Cypla-responsiveness is in line with the concept that N-heterocycle-containing inducers act by mechanisms other than an Ah-receptor-dependent pathway in which the P450 response has been masked or prevented.
J Biochem Mol Toxicol 1999
PMID:Induction of drug metabolizing enzymes by 1,7-phenanthroline and oltipraz in mice is unrelated to Ah-responsiveness. 989 Jan 92

Bovine adrenal zona fasciculata (AZF) cells express a noninactivating K+ current (IAC) that sets the resting membrane potential and may mediate depolarization-dependent cortisol secretion. External ATP stimulates cortisol secretion through activation of a nucleotide receptor. In whole-cell patch clamp recordings from bovine AZF cells, we found that ATP selectively inhibited IAC K+ current by a maximum of 75.7 +/- 3% (n = 13) with a 50% inhibitory concentration of 1.3 microM. A rapidly inactivating A-type K+ current was not inhibited by ATP. Other nucleotides, including ADP and the pyrimidines UTP and UDP, also inhibited IAC, whereas 2-methylthio-ATP (2-MeSATP) and CTP were completely ineffective. The rank order of potency for six nucleotides was UTP = ADP > ATP > UDP >> 2-MeSATP = CTP. At maximally effective concentrations, UTP, ADP, and UDP inhibited IAC current by 81.4 +/- 5.2% (n = 7), 70.7 +/- 7.2% (n = 4), and 65.2 +/- 7.9% (n = 5), respectively. Inhibition of IAC by external ATP was reduced from 71. 3 +/- 3.2% to 22.8 +/- 4.5% (n = 18) by substituting guanosine 5'-O-2-(thio) diphosphate for GTP in the patch pipette. Inhibition of IAC by external ATP (10 microM) was markedly suppressed (to 17.3 +/- 5.5%, n = 9) by the nonspecific protein kinase antagonist staurosporine (1 microM) and eliminated by substituting the nonhydrolyzable ATP analog 5-adenylyl-imidodiphosphate or UTP for ATP in the pipette. ATP-mediated inhibition of IAC was not altered by the kinase C antagonist calphostin C, the calmodulin inhibitory peptide, or by buffering the intracellular (pipette) Ca++ with 20 mM 1,2-bis-(2-aminophenoxy)ethane-N, N,N',N'-tetraacetic acid. In current clamp recordings, ATP and UTP (but not CTP) depolarized AZF cells at concentrations that inhibited IAC K+ current. These results demonstrate that bovine AZF cells express a nucleotide receptor with a P2Y3 agonist profile that is coupled to the inhibition of IAC K+ channels through a GTP-binding protein. The inhibition of IAC K+ current and associated membrane depolarization are the first cellular responses demonstrated to be mediated through this receptor. Nucleotide inhibition of IAC proceeds through a pathway that is independent of phospholipase C, but that requires ATP hydrolysis. The identification of a new signaling pathway in AZF cells, whereby activation of a nucleotide receptor is coupled to membrane depolarization through inhibition of a specific K+ channel, suggests a mechanism for ATP-stimulated corticosteroid secretion that depends on depolarization-dependent Ca++ entry. This may be a means of synchronizing the stress-induced secretion of corticosteroids and catecholamines from the adrenal gland.
Mol Pharmacol 1999 Feb
PMID:Purine and pyrimidine nucleotides inhibit a noninactivating K+ current and depolarize adrenal cortical cells through a G protein-coupled receptor. 992 30

Toxoplasma gondii is an obligate intracellular parasite of the phylum apicomplexa and a common and often life-threatening opportunistic infection associated with AIDS. A family of parasite-specific glycosylphosphatidylinositols containing a novel glucosylated side chain has been shown to be highly immunogenic in humans (Striepen et al. (1997) J. Mol. Biol. 266, 797-813). In contrast to trypanosomes in T. gondii side chain modification takes place before addition to protein in the endoplasmic reticulum. The biosynthesis of these modifications was studied in an in vitro system prepared from hypotonically lysed T. gondii parasites. Radiolabeled glucose-containing glycosylphosphatidylinositol precursors were synthesized by T. gondii membrane preparations upon incubation with uridine diphosphate-[3H]glucose. Synthesis of glucosylated glycolipids took place only in the presence of exogenous uridine diphosphate-glucose and was stimulated by unlabeled uridine diphosphate-glucose in a dose-dependent manner. In contrast to glycosylphosphatidylinositol mannosylation, glucosylation was shown to be insensitive to amphomycin treatment. In addition, the glucose analogue 2-deoxy-D-glucose was used to trace the glycosylphosphatidylinositol glucosylation pathway. Detailed analysis of glycolipids synthesized in vitro in the presence of UDP and GDP derivatives of D-glucose and 2-deoxy-D-glucose ruled out an involvement of dolichol phosphate-glucose and demonstrates direct transfer of glucose from uridine diphosphate-glucose.
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PMID:Glucosylation of glycosylphosphatidylinositol membrane anchors: identification of uridine diphosphate-glucose as the direct donor for side chain modification in Toxoplasma gondii using carbohydrate analogues. 993 Oct 13

Uridine diphosphate galacturonate 4-epimerases (UDPGLEs) are enzymes that convert UDP-glucuronate into UDP-galacturonate. Although the presence of UDPGLEs has been reported in prokaryoic and eukaryotic organisms, the genes coding for these enzymes are completely unknown. The galacturonic acid-containing capsular polysaccharide of Streptococcus pneumoniae type 1 is synthesized through the action of a specific UDPGLE. We have constructed a defined deletion mutant in the cap1J gene (one of the 15 cap1 genes responsible for the synthesis of the type 1 capsule) that exhibited an unencapsulated phenotype. This mutant was unable to synthesize UDPGLE, suggesting that Cap1J was the type 1-specific UDPGLE of S. pneumoniae. Escherichia coli cells harbouring the recombinant plasmid pRMM38 (cap1J) overproduced a 40 kDa protein, characterized as Cap1J on the basis of the N-terminal amino acid sequence analysis, and expressed high levels of enzymatically active Cap1J epimerase. Cap1J was partially purified, although purification to electrophoretic homogeneity inactivated the enzyme irreversibly. The enzyme has the following characteristics: K(m) for UDP-glucuronate, 0.24 mM; pH optimum, 7.5; equilibrium constant (in the direction of UDP-galacturonate formation), 1.3; and an approximate M(r) of 80,000 for the active form. The Cap1J protein exhibited a fluorescence emission spectrum similar to that of NADH. Upon inactivation with p-hydroxymercuribenzoate, the addition of NAD+ and 2-mercaptoethanol were sufficient to reactivate the enzyme. Among several compounds tested, UDP-galactose and UDP-xylose exhibited the highest inhibition of the UDPGLE activity. Inactivation of UDPGLE activity was also observed in the presence of UMP and several reducing sugars. To our knowledge, this is the first example of a thoroughly molecular characterization of a UDPGLE.
Mol Microbiol 1999 Jan
PMID:First molecular characterization of a uridine diphosphate galacturonate 4-epimerase: an enzyme required for capsular biosynthesis in Streptococcus pneumoniae type 1. 1002 85

The suppressor mutation, named sfhC21, that allows Escherichia coli ftsH null mutant cells to survive was found to be an allele of fabZ encoding R-3-hydroxyacyl-ACP dehydrase, involved in a key step of fatty acid biosynthesis, and appears to upregulate the dehydrase. The ftsH1(Ts) mutation increased the amount of lipopolysaccharide at 42 degrees C. This was accompanied by a dramatic increase in the amount of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase [the IpxC (envA) gene product] involved in the committed step of lipid A biosynthesis. Pulse-chase experiments and in vitro assays with purified components showed that FtsH, the AAA-type membrane-bound metalloprotease, degrades the deacetylase. Genetic evidence also indicated that the FtsH protease activity for the deacetylase might be affected when acyl-ACP pools were altered. The biosynthesis of phospholipids and the lipid A moiety of lipopolysaccharide, both of which derive their fatty acyl chains from the same R-3-hydroxyacyl-ACP pool, is regulated by FtsH.
Mol Microbiol 1999 Feb
PMID:Balanced biosynthesis of major membrane components through regulated degradation of the committed enzyme of lipid A biosynthesis by the AAA protease FtsH (HflB) in Escherichia coli. 1004 27

Transposon Tn 1546 confers resistance to glycopeptide antibiotics in enterococci and encodes two D,D-peptidases (VanX and VanY) in addition to the enzymes for the synthesis of D-alanyl-D-lactate (D-Ala-D-Lac). VanY was produced in the baculovirus expression system and purified as a proteolytic fragment that lacked the putative N-terminal membrane anchor of the protein. The enzyme was a Zn2+-dependent D,D-carboxypeptidase that cleaved the C-terminal residue of peptidoglycan precursors ending in R-D-Ala-D-Ala or R-D-Ala-D-Lac but not the dipeptide D-Ala-D-Ala. The specificity constants kcat/Km were 17- to 67-fold higher for substrates ending in the R-D-Ala-D-Ala target of glycopeptides. In Enterococcus faecalis, VanY was present in membrane and cytoplasmic fractions, produced UDP-MurNAc-tetrapeptide from cytoplasmic peptidoglycan precursors and was required for high-level glycopeptide resistance in a medium supplemented with D-Ala. The enzyme could not replace the VanX D,D-dipeptidase for the expression of glycopeptide resistance but a G237D substitution in the host D-Ala:D-Ala ligase restored resistance in a vanX null mutant. Deletion of the membrane anchor of VanY led to an active D,D-carboxypeptidase exclusively located in the cytoplasmic fraction that did not contribute to glycopeptide resistance in a D-Ala-containing medium. Thus, VanX and VanY had non-overlapping functions involving the hydrolysis of D-Ala-D-Ala and the removal of D-Ala from membrane-bound lipid intermediates respectively.
Mol Microbiol 1998 Nov
PMID:Requirement of the VanY and VanX D,D-peptidases for glycopeptide resistance in enterococci. 1009 30

UDP -N- acetylmuramoyl- L -alanine: D -glutamate (MurD) ligase catalyses the addition of d -glutamate to the nucleotide precursor UDP -N- acetylmuramoyl- L -alanine (UMA). The crystal structures of three complexes of Escherichia coli MurD with a variety of substrates and products have been determined to high resolution. These include (1) the quaternary complex of MurD, the substrate UMA, the product ADP, and Mg2+, (2) the quaternary complex of MurD, the substrate UMA, the product ADP, and Mn2+, and (3) the binary complex of MurD with the product UDP - N- acetylmuramoyl- L -alanine- D -glutamate (UMAG). The reaction mechanism supported by these structures proceeds by the phosphorylation of the C-terminal carboxylate group of UMA by the gamma-phosphate group of ATP to form an acyl-phosphate intermediate, followed by the nucleophilic attack by the amino group of D-glutamate to produce UMAG. A key feature in the reaction intermediate is the presence of two magnesium ions bridging negatively charged groups.
J Mol Biol 1999 Jun 11
PMID:Determination of the MurD mechanism through crystallographic analysis of enzyme complexes. 1035 30

Acylglucuronides formed from carboxylic acids by UDP-glucuronosyltransferases (UGTs) are electrophilic metabolites able to covalently bind proteins. In this study, we demonstrate the reactivity of the acylglucuronide from the nonsteroidal anti-inflammatory drug, ketoprofen, toward human and rat liver UGTs. Ketoprofen acylglucuronide irreversibly inhibited the glucuronidation of 1-naphthol and 2-naphthol catalyzed by human liver microsomes or by the recombinant rat liver isoform, UGT2B1, which is the main isoform involved in the glucuronidation of the drug. A decrease of about 35% in the glucuronidation of 2-naphthol was observed when ketoprofen acylglucuronide was produced in situ in cultured V79 cells expressing UGT2B1. Inhibition was always associated with the formation of microsomal protein-ketoprofen adducts. The presence of these covalent adducts within the endoplasmic reticulum of cells expressing UGT2B1 was demonstrated following addition of ketoprofen to culture medium by immunofluorescence microscopy with antiketoprofen antibodies. Immunoblots of liver microsomes incubated with ketoprofen acylglucuronide and probed with antiketoprofen antibodies revealed the presence of several protein adducts; among those was a major immunoreactive protein at 56 kDa, in the range of the apparent molecular mass of UGTs. The adduct formation partially prevented the photoincorporation of the UDP-glucuronic acid (UDP-GlcUA) analog, [beta-32P]5N3UDP-GlcUA, on the UGTs, suggesting that ketoprofen glucuronide covalently reacted with the UDP-GlcUA binding domain. Finally, UGT purification from rat liver microsomes incubated with ketoprofen glucuronide led to the isolation of UGT adducts recognized by both anti-UGT and antiketoprofen antibodies, providing strong evidence that UGTs are targets of this metabolite.
Mol Pharmacol 1999 Jul
PMID:Human and rat liver UDP-glucuronosyltransferases are targets of ketoprofen acylglucuronide. 1038 4


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