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)

Deoxycytidylate deaminase, catalyzing the conversion of dCMP to dUMP, is an important enzyme in the de novo synthesis of thymidine nucleotides. It also may be involved in the action, as well as the metabolism of anticancer agents. Recently, several L- and D-configuration pyrimidine deoxynucleoside analogs were found to be potent antiviral and antitumor agents. Their interaction with dCMP deaminase as a monophosphate or a triphosphate metabolite is not clear. These include D-nucleoside analogs such as beta-D-2',3'-dideoxycytidine (ddC), beta-2'-fluoro-5-methyl-arabinofuranosyluracil (FMAU), 3'-azido-2',3'-dideoxythymidine (AZT), and 2',3'-didehydro-2',3'-dideoxythymidine (D4T) as well as L-nucleoside analogs such as beta-L-dioxolane-cytidine (L-OddC), beta-L-2',3'-dideoxy-3'-thiacytidine, beta-L-2',3'-dideoxy-5'-fluoro-3'-thia-cytidine (L-FSddC), beta-L-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine, and L-FMAU. None of the L-deoxycytidine analog monophosphates act as substrates or inhibitors. Among these pyrimidine deoxynucleoside analog monophosphates, D-FMAU monophosphate (MP) is the most potent competitive inhibitor, whereas L-FMAUMP has no inhibitory activity. Interestingly, AZTMP and D4TMP also have potent inhibitory activities on dCMP deaminase. Among the dCTP and TTP analogs examined, D- and L-FMAUTP were the most potent inhibitors and had the same extent of inhibitory effect. These results suggest that a chiral specificity for the substrate-binding site may exist, but there is no chiral specificity for the regulator-binding site. This is also supported by the observation that L-OddC and L-FSddC have inhibitory activities as triphosphates but not as monophosphates. None of the D- and L-dCTP analogs activated dCMP deaminase as dCTP. The biological activities of AZT and D4T could be partially attributable to their inhibitory activity against dCMP deaminase by their phosphorylated metabolites, whereas that of ddC and the L-deoxycytidine analogs may not involve dCMP deaminase directly.
Mol Pharmacol 2003 Jan
PMID:Assessment of the effect of phosphorylated metabolites of anti-human immunodeficiency virus and anti-hepatitis B virus pyrimidine analogs on the behavior of human deoxycytidylate deaminase. 1248 42

The replication-dependent histone mRNAs, the only eukaryotic mRNAs that do not have poly(A) tails, are present only in S-phase cells. Coordinate posttranscriptional regulation of histone mRNAs is mediated by the stem-loop at the 3' end of histone mRNAs. The protein that binds the 3' end of histone mRNA, stem-loop binding protein (SLBP), is required for histone pre-mRNA processing and is involved in multiple aspects of histone mRNA metabolism. SLBP is also regulated during the cell cycle, accumulating as cells enter S phase and being rapidly degraded as cells exit S phase. Mutation of any residues in a TTP sequence (amino acids 60 to 62) or mutation of a consensus cyclin binding site (amino acids 99 to 104) stabilizes SLBP in G2 and mitosis. These two threonines are phosphorylated in late S phase, as determined by mass spectrometry (MS) of purified SLBP from late S-phase cells, triggering SLBP degradation. Cells that express a stable SLBP still degrade histone mRNA at the end of S phase, demonstrating that degradation of SLBP is not required for histone mRNA degradation. Nuclear extracts from G1 and G2 cells are deficient in histone pre-mRNA processing, which is restored by addition of recombinant SLBP, indicating that SLBP is the only cell cycle-regulated factor required for histone pre-mRNA processing.
Mol Cell Biol 2003 Mar
PMID:Phosphorylation of stem-loop binding protein (SLBP) on two threonines triggers degradation of SLBP, the sole cell cycle-regulated factor required for regulation of histone mRNA processing, at the end of S phase. 1258 79

Mycobacterium tuberculosis TMP kinase (TMPK(Mtub)) represents a promising target for developing drugs against tuberculosis because the configuration of its active site is unique in the TMPK family. To help elucidate the phosphorylation mechanism employed by this enzyme, structural changes occurring upon binding of substrates and subsequent catalysis were investigated by protein crystallography. Six new structures of TMPK(Mtub) were solved at a resolution better than 2.3A, including the first structure of an apo-TMPK, obtained by triggering catalysis in a crystal of a TMPK(Mtub)-TMP complex, which resulted in the release of the TDP product. A series of snapshots along the reaction pathway is obtained, revealing the closure of the active site in going from an empty to a fully occupied state, suggestive of an induced-fit mechanism typical of NMPKs. However, in TMPK(Mtub) the LID closure couples to the binding with an unusual location for a magnesium ion coordinating TMP in the active site. Our data suggest strongly that this ion is required for catalysis, acting as a clamp, possibly in concert with Arg95, to neutralise electrostatic repulsion between the anionic substrates, optimise their proper alignment and activate them through direct and water-mediated interactions. The 3'-hydroxyl moiety of TMP, critical to metal stabilisation, appears to be a target of choice for the design of potent inhibitors. On the other hand, the usual NTP-bound magnesium is not seen in our structures and Arg14, a P-loop residue unique to TMPK(Mtub), may take over its role. Therefore, TMPK(Mtub) seems to have swapped the use of a metal ion as compared with e.g. human TMPK. Finally, TTP was observed in crystals of TMPK(Mtub), locked by Arg14, thus providing a structural explanation for the observed inhibitory effect of TTP putatively involved in a mechanism of feedback regulation of the enzymatic activity.
J Mol Biol 2003 Apr 11
PMID:Mycobacterium tuberculosis thymidylate kinase: structural studies of intermediates along the reaction pathway. 1266 32

Alpha-tocopherol transfer protein (alpha-TTP) is a liver protein responsible for the selective retention of alpha-tocopherol from dietary vitamin E, which is a mixture of alpha, beta, gamma, and delta-tocopherols and the corresponding tocotrienols. The alpha-TTP-mediated transfer of alpha-tocopherol into nascent VLDL is the major determinant of plasma alpha-tocopherol levels in humans. Mutations in the alpha-TTP gene have been detected in patients suffering from low plasma alpha-tocopherol and ataxia with isolated vitamin E deficiency (AVED). The crystal structure of alpha-TTP reveals two conformations. In its closed tocopherol-charged form, a mobile helical surface segment seals the hydrophobic binding pocket. In the presence of detergents, an open conformation is observed, which probably represents the membrane-bound form. The selectivity of alpha-TTP for RRR-alpha-tocopherol is explained from the van der Waals contacts occurring in the lipid-binding pocket. Mapping the known mutations leading to AVED onto the crystal structure shows that no mutations occur directly in the binding pocket.
J Mol Biol 2003 Aug 15
PMID:The molecular basis of vitamin E retention: structure of human alpha-tocopherol transfer protein. 1289 40

Results from two studies, the North American trial and the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability (TARGET) trial carried out in Europe/rest of the world comparing 'Arimidex' (anastrozole) 1 mg with tamoxifen 20 mg for treatment of advanced breast cancer in postmenopausal women, have previously been reported individually and as a prospectively combined analysis. For the combined analysis, at a median follow-up of 18.2 months anastrozole was shown to be superior to tamoxifen in terms of time to progression (TTP; P=0.022) in the hormone receptor-positive subgroup. Both treatments were well tolerated; anastrozole was associated with significantly fewer thromboembolic events (P=0.043) and fewer reports of vaginal bleeding. The survival analyses and safety update in the overall population and in the hormone receptor-positive subgroup from the combined data are now available. At a median follow-up of 43 months, 56.0% of patients in the anastrozole group and 56.1% of patients in the tamoxifen group had died. At the cut-off date, 2-year mortality rates were 31.7 and 32.5% with anastrozole and tamoxifen, respectively, in the overall population. Median time to death (TTD) was similar for both treatments (39 months versus 40 months, respectively; hazard ratio (HR) 0.97, lower 95% confidence limit (CL) 0.84). Similar findings were reported in the hormone receptor-positive population. With longer follow-up, both anastrozole and tamoxifen remained well tolerated. Sequencing data showed that patients crossed from anastrozole to tamoxifen or tamoxifen to anastrozole are similar regarding efficacy. In conclusion, these TTP, survival and tolerability data support the use of anastrozole as a first-line therapy of choice in postmenopausal women with advanced breast cancer.
J Steroid Biochem Mol Biol 2003 Sep
PMID:Advanced breast cancer updates on anastrozole versus tamoxifen. 1462 28

The Wnt/beta-catenin pathway rapidly induces the transcription of the cell-type-restricted transcription factor Pitx2 that is required for effective cell-specific proliferation activating growth-regulating genes. Here we report that Pitx2 mRNA displays a rapid turnover rate and that activation of the Wnt/beta-catenin pathway stabilizes Pitx2 mRNA as well as other unstable mRNAs, including c-Jun, Cyclin D1, and Cyclin D2, encoded by critical transcriptional target genes of the same pathway. Our data indicate that Pitx2 mRNA stabilization is due to a reduced interaction of Pitx2 3'UTR with the destabilizing AU-rich element (ARE) binding proteins (BPs) KSRP and TTP as well as to an increased interaction with a stabilizing ARE-BP, HuR. Pitx2 itself is a mediator of Wnt/beta-catenin-induced mRNA stabilization. Our previous and present data support the hypothesis that a single pathway can coordinately regulate sequential transcriptional and posttranscriptional events leading to an integrated functional gene regulatory network.
Mol Cell 2003 Nov
PMID:The Wnt/beta-catenin-->Pitx2 pathway controls the turnover of Pitx2 and other unstable mRNAs. 1463 78

For the study of probiotic microorganisms, the in vitro selection tests need to be based on a solid scientific foundation. Surface characteristics, one of the in vitro properties are used to evaluate the potentially probiotic strains of lactobacilli. Bacterial surface properties have been associated with attachment to a variety of substrata. Bacterial adhesion to tissues is considered the first step, and such adhesion can also determine the colonization capability of a microorganism. Through adhesion ability and colonization of tissues, probiotic microorganisms can prevent pathogen access by steric interactions or specific blockage on cell receptors. One of the main characteristics studied is the hydrophobic nature of the bacterial cell surface. To test this property, Rosenberg and Doyle divided microbial cell hydrophobicity assays into two categories. The first includes contact angle measurements (CAMs), partitioning of cells into one or another liquid phase (TTP), and adsorption of individual hydrophobic molecular probes at the cell surface. The second category includes microbial adhesion to hydrocarbons (MATH), hydrophobic interaction chromatography (HIC), and adhesion to polystyrene and other hydrophobic solid surfaces. The tests included in the first category measure hydrophobic properties of the outer cell surface as a whole; those in the second measure hydrophobicity in terms of adhesion. Finally, those bacterium classified as hydrophobic can be considered as able to mediate adhesion. The objective of this chapter is to describe three different methods applied in our laboratory for the study of bacterial surface properties. They can be used to screen characteristics of lactobacillus strains for probiotic purposes. They are: Microbial adhesion to hydrocarbons (MATH); Salt aggregation test (SAT); Hemagglutination (HA) reaction.
Methods Mol Biol 2004
PMID:Bacterial surface characteristics applied to selection of probiotic microorganisms. 1515 54

Multiple studies have shown that phospholamban (PLN) plays a key role in regulation of frequency-dependent increase of cardiac contraction, a hallmark of the contractile reserve in myocardium. However, the mechanisms underlying this relationship remain elusive. Phosphorylation of PLN occurs on residues: serine-16 (Ser(16)) and threonine-17 (Thr(17)) in vivo. In isolated wild-type cardiomyocytes, we found that increases of stimulation frequency from 0.5 to 5 Hz were associated with increased Thr(17) phosphorylation of PLN and cardiac contractility. To further delineate the role of PLN phosphorylation in the frequency-dependent increases of cardiac function, three transgenic mouse models, expressing wild-type, Ser16Ala (S16A), or Thr17Ala (T17A) mutant PLN in the null background were generated. Transgenic lines expressing similar levels of wild-type or mutant PLN were selected and isolated cardiomyocytes were paced from 0.5 to 5 Hz. Upon increases in pacing frequency, the fractional shortening (FS) and rates of contraction (+dL/dt) and relaxation (-dL/dt) increased in wild-type and S16A mutant PLN cardiomyocytes. In contrast, in myocytes expressing the T17A mutant PLN, there were no increases in FS and +/-dL/dt upon increasing the frequency of stimulation. The time to 50% peak shortening (TTP(50)) and to 50% relaxation (TTR(50)) were also abbreviated to a much higher extent (two-fold) in wild-type and S16A mutant compared to T17A mutant PLN cardiomyocytes. These results indicate that Thr(17) phosphorylation of PLN is the major contributor to frequency-dependent increases of contractile and relaxation parameters in mouse cardiomyocytes, although some increases in these parameters occur even in the absence of PLN phosphorylation. Thus, the positive force-frequency relationship in cardiomyocytes is mechanistically and mainly related to PLN phosphorylation.
J Mol Cell Cardiol 2004 Aug
PMID:Threonine-17 phosphorylation of phospholamban: a key determinant of frequency-dependent increase of cardiac contractility. 1527 30

Glucose-1-phosphate uridylyltransferase from E. coli K12 was used to convert uridine-5'-triphosphate and glucose-1-phosphate to UDP-D-glucose. The conversion was efficient and completed within 5 minutes under the employed conditions. In addition, thymidine-5'-monophosphate kinase and acetate kinase were proven to be non-specific, converting udridine-5'-monophosphate to uridine-5'-triphosphate with 55% conversion after 6 h, which was much slower than the production of TTP under the same conditions (complete conversion within one hour). Since these two reactions could proceed under the same conditions, a one-pot synthesis of UDP-D-glucose with ATP regeneration was designed from easily available starting materials, and conversion up to 40% by HPLC peak integration was achieved given a reaction time of 4 h.
J Biochem Mol Biol 2004 Jul 31
PMID:One-pot enzymatic synthesis of UDP-D-glucose from UMP and glucose-1-phosphate using an ATP regeneration system. 1546 40

Decapping is a key step in mRNA turnover. However, the composition and regulation of the human decapping complex is poorly understood. Here, we identify three proteins that exist in complex with the decapping enzyme subunits hDcp2 and hDcp1: hEdc3, Rck/p54, and a protein in decapping we name Hedls. Hedls is important in decapping because it enhances the activity of the catalytic hDcp2 subunit and promotes complex formation between hDcp2 and hDcp1. Specific decapping factors interact with the mRNA decay activators hUpf1 and TTP, and TTP enhances decapping of a target AU-rich element (ARE) RNA in vitro. Each decapping protein localizes in cytoplasmic processing bodies (PBs), and overexpression of Hedls produces aberrant PBs and concomitant accumulation of a deadenylated ARE-mediated mRNA decay intermediate. These observations suggest that multiple proteins involved in human decapping are important subunits of PBs and are activated on ARE-mRNAs by the protein TTP.
Mol Cell 2005 Dec 22
PMID:Multiple processing body factors and the ARE binding protein TTP activate mRNA decapping. 1636 15


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