Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Repeat tracts of guanine bases found in DNA and RNA can form tetraplex structures in the presence of a variety of monovalent cations. Evidence suggests that guanine tetraplexes assume important functions within chromosomal telomeres, immunoglobulin switch regions, and the human immunodeficiency virus genome. The structure of a parallel-stranded tetraplex formed by the hexanucleotide d(TG4T) and stabilized by sodium cations was determined by x-ray crystallography to 1.2 angstroms resolution. Sharply resolved sodium cations were found between and within planes of hydrogen-bonded guanine quartets, and an ordered groove hydration was observed. Distinct intra- and intermolecular stacking arrangements were adopted by the guanine quartets. Thymine bases were exclusively involved in making extensive lattice contacts.
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PMID:The high-resolution crystal structure of a parallel-stranded guanine tetraplex. 803 94

Saccharomyces cerevisiae myristoyl-CoA:protein N-myristoyltransferase (Nmt1p) is a monomeric enzyme that is essential for vegetative growth. Nmt1p catalyzes the co-translational transfer of myristate from CoA to the amino-terminal Gly of cellular proteins in an ordered Bi Bi reaction mechanism that initially involves binding of myristoyl-CoA to the apoenzyme. Forty one fatty acid analogs were synthesized to define features in the acyl chain of myristoyl-CoA which are important determinants of its recognition by Nmt1p's acyl-CoA binding site as well as to help us deduce the structure of the binding site itself. These analogs included dicarboxylic acids, omega-nitrocarboxylic acids, analogs equivalent in length to C13:0-C15:0 which contain electronegative halogens at their omega-termini, hydroxytetradecanoic acids with hydrogen replaced by OH from C3 to C13, and azidophenyl-containing fatty acids with the linear azide unit attached either meta or para to phenyl and with variations in the length of their methylene chains. These compounds were converted to their CoA derivatives using Pseudomonas acyl-CoA synthetase and then surveyed as substrates for purified Nmt1p in an in vitro assay system that included an octapeptide derived from residues 1-8 of the human immunodeficiency virus Pr55gag polyprotein precursor. The results suggest that the myristoyl-CoA binding site contains a conical-shaped "receptor" that interacts with the omega-terminus of the bound acyl chain of acyl-CoAs. The acuteness of this cone determines the enzyme's capacity to accommodate steric bulk at the omega-terminus as well as Nmt1p's sensitivity to the distance between the eclipsed C5-C6 bond of a bound acyl chain and its omega-terminus. The activity profile of the various analog-CoAs also indicates that the enzyme's myristoyl-CoA binding site can accommodate fatty acid analogs with marked increases in polarity at their omega-terminus (compared to C14:0) as long as their chain length is equivalent to that of myristate.
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PMID:The substrate specificity of Saccharomyces cerevisiae myristoyl-CoA: protein N-myristoyltransferase. Polar probes of the enzyme's myristoyl-CoA recognition site. 810 19

Structures of two enzyme-inhibitor complexes of human immunodeficiency virus-1 protease with allophenylnorstatine derivatives were obtained from molecular dynamics simulation in aqueous solution. The stronger inhibitor gave considerably smaller fluctuation at P3 site, which formed hydrogen bonding with the enzyme flap region.
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PMID:Solution structure of HIV-1 protease-allophenylnorstatine derivative inhibitor complex obtained from molecular dynamics simulation. 812 61

The National Cancer Institute is pursuing preclinical development of michellamine B (MB), a novel dimeric polyhydroxylated naphthalene-tetrahydroisoquinoline alkaloid isolated from Ancistrocladus abbreviatus, as an anti-human immunodeficiency virus (HIV) agent. MB protects human lymphoid cells from the cytopathic effects of both HIV-1 and HIV-2 in vitro. A specific, sensitive, and convenient method for assaying the compound in biological fluids has been developed. Samples were prepared for analysis by initial treatment with dilute trichloroacetic acid followed by thorough mixing with a solution of the internal standard (alpha-naphthoflavone) in acetonitrile to denature macromolecules. The supernatant afforded by centrifugation, upon dilution with the aqueous component of the liquid chromatographic eluent, was loaded onto a 4-microns Nova-Pak phenyl column (3.9 mm x 15 cm). Chromatography was performed at ambient temperature using an isocratic mobile phase composed of 10 mM octyl sodium sulfate and 15 microM tetrabutylammonium hydrogen sulfate in acetonitrile/0.05 M ammonium formate buffer, pH 4.0 (46/54, v/v), at a flow rate of 0.6 ml/min. The intense native fluorescence of MB, which exhibited excitation and emission maxima in the mobile phase at 232 and 393 nm, respectively, provided a highly sensitive and selective means of detection. Mean values of the retention times for the drug and internal standard determined over 11 months were 10.71 +/- 0.53 and 13.14 +/- 0.52 min, respectively (SD, n = 52). Employing a sample volume of 50 microliters, the lowest concentration of MB included in the standard curves of mouse, dog, and human plasma, 10 ng/ml (11.4 nM), was quantified with coefficients of variation less than 10%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Determination of michellamine B in biological fluids by high-performance liquid chromatography with fluorescence detection. 813 66

An important aspect of infection by the human immunodeficiency virus (HIV-1) type 1 is its long clinical latency period, suggesting that the provirus may remain latent for extended periods of time after primary infection. Numerous factors such as cytokines, tumor promoters, co-infection by several viruses and physical agents are able to reactivate latent virus. Since a common denominator, shared by several of these agents, is their ability to cause stress conditions, we have examined the effects of an oxidative stress mediated by reactive oxygen species on HIV-1 latently infected monocytes (U1) or lymphocytes (ACH-2). Exposure of these two cell lines to hydrogen peroxide causes a decrease of cell viability but among the cells surviving the treatment, a HIV-1 reactivation can be observed as measured by increased RT activities depicted in cell supernatants or by the appearance of HIV-1 antigens inside cells. Singlet oxygen (1O2) when generated either in the cytoplasm or in the cell nucleus can also promote an important HIV-1 reactivation from treated cells. However, extracellular generation of 1O2 cannot trigger the HIV-1 reactivation although this kind of treatment is highly cytotoxic. These experiments demonstrate that different reactive oxygen species are able to lead to an intracellular pro-oxidant state initiating one or several signalling pathways which lead in fine to the HIV-1 LTR transactivation by regulatory proteins.
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PMID:HIV-1 reactivation after an oxidative stress mediated by different reactive oxygen species. 819 37

Retroviral genomes consist of two identical RNA molecules joined noncovalently near their 5' ends, at domains called dimerization linked sequences (DLS). This physical linkage of the genomic RNAs is considered important for the control of several steps in the viral life cycle, such as recombination, translation, and encapsidation. The putative DLS of human immunodeficiency virus-1 (HIV-1), a 111-nucleotide, purine-rich stretch of RNA, has been found necessary and sufficient for a salt-induced dimerization of the genome in vitro. Our investigation into the mechanism of this dimerization reveals sharply varying influences of the different alkali cations on both the formation and the stabilization of the dimer, a pattern closely related to that of telomeric G-DNA complexes. To probe this phenomenon, we have carried out experiments using short antisense DNA oligomers to define the segments of the DLS that are required for dimerization and methylation protection to implicate sets of guanines in forming Hoogsteen hydrogen bonds within the dimer. Cumulatively, these data provide further evidence for the existence of guanine quartets within the dimerized HIV-1 DLS. We propose models in which guanine quartets not only allow the homodimerization of HIV-1 and other retroviral genomic RNAs but also permit the two RNA strands in a dimer to exist in an overall parallel orientation, as has been observed by electron microscopy.
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PMID:Mode of dimerization of HIV-1 genomic RNA. 821 11

The higher susceptibility to serious bacterial infections of patients, particularly children, infected with the human immunodeficiency virus (HIV) may be due in part to defective function of their phagocytic cells. We examined the ability of polymorphonuclear cells and monocytes of HIV-infected children and adults to generate superoxide anion (SO) and hydrogen peroxide (HP) and compared it with that of cells from normal children and adults. SO was measured by reduction of cytochrome c and HP by horseradish peroxidase-dependent oxidation of phenol red. The cells were incubated in 96-well plates at 37 degrees C for 2 h before the assay and the nonadherent cells then removed. Readings for SO were taken at 10, 30, 60, and 120 min after stimulation with phorbol myristate acetate; HP production was assayed after 90 min. The SO and HP production by polymorphonuclear cells and monocytes from both HIV-infected children and adults was consistently found to be markedly lower than that of cells from age-matched controls. The magnitude of the difference in response between patients and control cells also increased with increasing incubation time. Thus, phagocytic cells from HIV-infected children and adults are defective in their ability to generate reactive oxygen intermediates, and this defect may make them more vulnerable to bacterial and fungal infections.
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PMID:Decreased superoxide anion and hydrogen peroxide production by neutrophils and monocytes in human immunodeficiency virus-infected children and adults. 825 91

Mechanistic information and structure-based design methods have been used to design a series of nonpeptide cyclic ureas that are potent inhibitors of human immunodeficiency virus (HIV) protease and HIV replication. A fundamental feature of these inhibitors is the cyclic urea carbonyl oxygen that mimics the hydrogen-bonding features of a key structural water molecule. The success of the design in both displacing and mimicking the structural water molecule was confirmed by x-ray crystallographic studies. Highly selective, preorganized inhibitors with relatively low molecular weight and high oral bioavailability were synthesized.
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PMID:Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. 827 12

8E5 is a chronically human immunodeficiency virus (HIV)-infected human T cell line, which we have previously shown to be extremely susceptible to hydrogen peroxide (H2O2)-induced apoptosis due to a HIV-associated catalase deficiency. Here we report that HIV gene expression additionally renders 8E5 cells 10-fold more sensitive than either uninfected A3.01 cells or HIV-infected but nonexpressing 8E5L cells to killing by 15-hydroperoxyeicosatetraenoic acid (15-HPETE), as well as several other hydroperoxy fatty acids. Whereas the viability of A3.01 and 8E5L cells was relatively unaffected by exposure to 10 microM 15-HPETE, similarly treated 8E5 cells underwent apoptosis, as demonstrated by morphological changes and the presence of fragmented DNA. The unique susceptibility of 8E5 cells was attributable to their inability to convert 15-HPETE to 15-hydroxy-eicosatetraenoic acid (15-HETE) owing to a marked reduction in glutathione peroxidase activity. Since oxidized lipids have been reported to accumulate in oxidatively stressed, HIV-infected individuals, a HIV-associated glutathione peroxidase deficiency may contribute to the depletion of CD4 T cells that occurs in the acquired immune deficiency syndrome (AIDS).
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PMID:Lipid hydroperoxides induce apoptosis in T cells displaying a HIV-associated glutathione peroxidase deficiency. 828 27

We report comprehensive NMR studies in solution of the human-immunodeficiency-virus (HIV)-1 protease. Stable solutions of the protease were obtained by complexing the protein to a designed cyclic urea inhibitor DMP 323. A variety of triple-resonance experiments provided essentially complete 1H, 13C and 15N NMR signal assignments of the protease. These assignments, together with short-range NOE constraints, coupling constants and hydrogen-exchange data, yielded the secondary structure of the protease in solution. The results reported herein open the way to the determination of the high-resolution three-dimensional solution structures of protease/inhibitor complexes, as well as to studies of protease dynamics and solvent interactions.
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PMID:Secondary structure and signal assignments of human-immunodeficiency-virus-1 protease complexed to a novel, structure-based inhibitor. 830 36


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