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)

MyristoylCoA:protein N-myristoyltransferase (Nmt) catalyses the co-translational, covalent attachment of myristate (C14:0) to the amino-terminal glycine residue of a number of eukaryotic proteins involved in cellular growth and signal transduction. The NMT1 gene is essential for vegetative growth of Saccharomyces cerevisiae. Studies were carried out to determine if Nmt is also essential for vegetative growth of the pathogenic fungus Candida albicans. A strain of C. albicans was constructed in which one copy of NMT was partially deleted and disrupted. A Gly-447-->Asp mutation was introduced into the second NMT allele. This mutation produced marked reductions in catalytic efficiency at 24 and 37 degrees C, as judged by in vitro kinetic studies of the wild-type and mutant enzymes which had been expressed in, and purified from, Escherichia coli. The growth characteristics of isogenic NMT/NMT, NMT/delta nmt, and nmt delta/nmtG447D C. albicans strains were assessed under a variety of conditions. Only the nmt delta/nmtG447D strain required myristate for growth. This was true at both 24 and 37 degrees C. Palmitate could not substitute for myristate. Incubation of nmt delta/nmtG447D cells at 37 degrees C in the absence of myristate resulted in cell death as observed by the inability to form colonies on media supplemented with 500 microM myristate. Studies in an immunosuppressed-mouse model of C. albicans infection revealed that the NMT/delta nmt strain produced 100% lethality within 7 d after intravenous administration while the isogenic nmt delta/nmtG447G strain produced no deaths even after 21 d. These observations establish that Nmt is essential for vegetative growth of C. albicans and suggest that inhibitors of this acyltransferase may be therapeutically useful fungicidal agents.
Mol Microbiol 1995 Apr
PMID:Genetic studies reveal that myristoylCoA:protein N-myristoyltransferase is an essential enzyme in Candida albicans. 756 86

Intra-alveolar clot formation is a common finding in acute and chronic inflammatory lung diseases. Incorporation of lipophilic surfactant components into a growing fibrin clot has recently been reported (Am. J. Respir. Cell Mol. Biol. 1993; 9:213-220). In the present study, we investigated the influence of such surfactant incorporation on the elastic properties and water permeability of the fibrin polymer. Thrombelastography and compaction experiments were employed for assessment of the elastic properties, and the permeability characteristics of the clot material were addressed in fibrin-packed columns. Two calf lung surfactant extracts (CLSE and Alveofact), Curosurf, and a synthetic phospholipid mixture (dipalmitoylphosphatidylcholine, phosphatidylglycerol, and palmitic acid at a ratio of 68.5:22.5:9 [wt/wt]) were used. The presence of surfactant did not affect the cleavage of fibrinopeptide A upon incubation of fibrinogen with thrombin (enzyme-linked immunosorbent assay technique). Similarly, kinetics and extent of factor XIII-induced covalent crosslinkage of the fibrin network remained unchanged in the presence of surfactant (sodium dodecyl sulfate polyacrylamide gel electrophoresis and D-Dimer quantification upon subsequent clot lysis). All surfactants, however, dose-dependently decreased the elastic modulus of the arising fibrin polymer. The maximal amplitude in thrombelastography was reduced, and the recovery of fluid after centrifugation of the fibrin clot increased. Fibrin clots embedding natural surfactant material displayed reduced permeability for saline as compared with control fibrin polymers. Subsequent washout of lipids from these clots with Triton X-100 resulted in increased hydraulic conductivity. This was accompanied by an increase in pore size, suggesting altered architecture of the fibrin matrix generated in the presence of surfactant.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1995 Dec
PMID:Surfactant incorporation markedly alters mechanical properties of a fibrin clot. 757 9

The recently discovered endogenous agonist for the cannabinoid receptor, anandamide (arachidonylethanolamide), can be formed enzymatically by the condensation of arachidonic acid with ethanolamine. 5Z,8Z,11Z-Eicosatrienoic acid (mead acid) has been found to substitute for arachidonic acid in the sn-2 position of phospholipids and accumulate during periods of dietary fatty acid deprivation in rats. In the present study, the chemically synthesized ethanolamide of mead acid was evaluated as a potential agonist at the two known subtypes of cannabinoid receptor: CB1 (central) and CB2 (peripheral). This compound was equipotent to anandamide in competing with [3H]CP55,940 binding to plasma membranes prepared from L cells expressing the human CB1 receptor and from ATt-20 cells expressing the human CB2 receptor. Mead ethanolamide was also equipotent to anandamide in inhibiting forskolin-stimulated cAMP accumulation in cells expressing the CB1 receptor. It inhibited N-type calcium currents with a lower potency than anandamide. Mead and arachidonic acid were equally efficacious as substrates for the enzymatic synthesis of their respective ethanolamides in rat and adult human hippocampal P2 membranes. Palmitic acid was not an effective substrate for the enzymatic synthesis of palmitoyl ethanolamide. Mead ethanolamide exhibits several characteristics of a novel agonist to CB1 and CB2 receptors and may represent another candidate endogenous ligand for the CB1 receptor. Due to the anticonvulsant properties of GABA and the positional similarity of L-serine to ethanolamine in membrane phospholipids, these compounds were synthetically coupled to arachidonic acid, and their resulting arachidonamides were tested as potential cannabinoid agonists. The arachidonamides of GABA and L-serine were inactive in both binding and functional assays at the CB1 receptor.
Mol Pharmacol 1995 Aug
PMID:Mead ethanolamide, a novel eicosanoid, is an agonist for the central (CB1) and peripheral (CB2) cannabinoid receptors. 765 62

Long-term, serum supplemented cultures of rat adult ventriculocytes were utilized to study the tropic effects of the alpha-agonist phenylephrine and of the carnitine palmitoyltransferase I inhibitor etomoxir. Cell protein and the rate of incorporation of phenylalanine were measured, corrected for cellular DNA content and utilized as an index for hypertrophy and of anabolic activity of the cells, respectively. The mRNA level of ANF was utilized as an index for the pathological phenotypic change (i.e., switch to fetal gene program), and that of the Na-channel--a constantly expressed gene in normal and hypertrophic cardiomyocytes--served as an internal control. Both mRNAs were quantified at various stages in culture by competitive reverse transcriptase PCR. The size of control myocytes steadily increased for over 3 weeks. The cells were completely redifferentiated and reached a maximum of anabolic activity 2 weeks after plating. Secretion and mRNA levels of ANF were increased severalfold after 7-8 days. Addition of 10 microM phenylephrine considerably speeded up cell growth. Maximum anabolic activity and complete redifferentiation were reached already after 1 week. Levels of mRNA and of ANF release increased 30-40 fold. Interestingly, induction of ANF gene transcription lagged behind the redifferentiation of the cells. Ten microM etomoxir inhibited the oxidation of palmitic acid and stimulated that of exogenous glucose by adult cardiomyocytes. In spite of its clear effect on fuel utilization, etomoxir had no direct hypertrophic effect on the myocytes in culture and did not inhibit the stimulatory action of alpha-agonists. Reactivation of the fetal gene program, as visualized by ANF production, was not reversed by etomoxir.
Mol Cell Biochem 1995 Jan 12
PMID:Effect of alpha adrenergic stimulation and carnitine palmitoyl transferase I inhibition on hypertrophying adult rat cardiomyocytes in culture. 775 39

Most members of the family of G protein-coupled receptors have one or more conserved cysteine residues in their carboxy-terminal cytoplasmic tails which are believed to be consensus sites for palmitoylation. Indeed, a growing number of G protein-coupled receptors (rhodopsin, beta 2-, and alpha 2-adrenergic receptors) have now been shown to have palmitic acid covalently attached to this position. In the case of the beta 2-adrenergic receptor, it was also reported that mutation of the palmitoylated cysteine to glycine greatly diminished the ability of this receptor to interact with and activate Gs. Mutation of this conserved cysteine appears to have little or no effect on the ability of other members of this receptor family (rhodopsin, alpha 2-adrenergic and M2 muscarinic) to activate their cognate G proteins, however. The studies presented here were designed to determine whether another Gs-coupled receptor, the LH/CG receptor, is palmitoylated, and whether this modification is important for receptor function. To facilitate biochemical analysis, we examined these issues using cell lines stably transfected with the wild type LH/CG receptor (LHR-wt) or with a mutant receptor in which the two conserved cysteins were mutated to alanines (designated LHR-C621,622A). Our results show that LHR-wt is palmitoylated but that LHR-C621,622A is not. We also show that LHR-C621,622A is capable of binding human CG (hCG) and transducing the cAMP signal. The main difference that we detected between the wild type and mutant receptor is that the latter is trapped intracellularly and does not appear to mature into the 85 kilodalton protein previously identified as the mature cell surface LH/CG receptor.
Mol Endocrinol 1995 Feb
PMID:The lutropin/choriogonadotropin receptor is palmitoylated at intracellular cysteine residues. 777 64

Oligopeptides are an important source of nutrients, but can serve also as signals for intercellular communication. Oligopeptide-binding proteins seem likely to play a role both in oligopeptide transport and in communication processes. One such protein, AmiA, has been identified in Streptococcus pneumoniae. amiA is the first gene of an operon, ami, which encodes a multicomponent oligopeptide transporter belonging to the family of ABC transporters (or traffic ATPases). This transporter was the first system of this type described in Gram-positive bacteria. To investigate the role and the subcellular location of the putative oligopeptide-binding protein in a bacterium devoid of periplasm, AmiA null mutants were first constructed. None was affected for oligopeptide uptake by the Ami system. Since this apparent dispensability of AmiA could result from a functional redundancy, we looked for chromosomal genes encoding homologues of AmiA. Two homologous genes were identified by DNA-DNA hybridization at low stringency with an amiA probe. Both genes (aliA and aliB) were cloned and shown to encode putative lipoproteins highly homologous to AmiA (close to 60% amino acid identity). Examination of all combinations of amiA, aliA and aliB mutations indicated that these proteins have overlapping specificities toward oligopeptides. The triple mutant is as deficient for oligopeptide transport as mutants in the amiCDE or F genes, which demonstrates that an oligopeptide-binding component is absolutely required for transport by the Ami system. Metabolic labelling with [3H]palmitic acid and cell fractionation were used to demonstrate that the three proteins are indeed membrane-bound lipoproteins in S. pneumoniae. This supports our previous hypothesis that substrate-binding lipoproteins are functionally equivalent to the periplasmic substrate-binding component of ABC transporters of Gram-negative bacteria. Finally, the observation that competence for genetic transformation was drastically reduced in a particular AliB mutant suggests that oligopeptide sensing is important for triggering competence.
J Mol Biol 1994 Aug 05
PMID:Three highly homologous membrane-bound lipoproteins participate in oligopeptide transport by the Ami system of the gram-positive Streptococcus pneumoniae. 805 6

Permeabilization of inner mitochondrial membrane by palmitic acid in the presence of Ca2+ (cyclosporin A-sensitive stimulation of respiration, decrease of delta psi and high amplitude swelling) is accompanied by activation of the external pathway of NADH oxidation in liver mitochondria. The "pore"-sealing agents (cyclosporin A, Mg2+ with ADP, and L-carnitine with ATP) are equally effective in preventing the induction of external pathway of NADH oxidation by Ca2+ with palmitate. However, activities of these agents are different in respect to recoupling of permeabilized mitochondria. Participation of cyclosporin A-sensitive "pore" in the fatty acid- and Ca(2+)-dependent induction of external pathway of NADH oxidation and in Ca(2+)-dependent uncoupling is discussed.
Biochem Mol Biol Int 1994 Apr
PMID:Fatty acid-induced Ca(2+)-dependent uncoupling and activation of external pathway of NADH oxidation are coupled to cyclosporin A-sensitive mitochondrial permeability transition. 806 32

The major nonpolar iodolipid formed in horse thyroid cells has recently been identified as 2-iodohexadecanal (2-IHDA). We have investigated in vitro the effect of 2-IHDA on the NADPH-oxidase, NADPH-cytochrome c reductase, and thyroid peroxidase (TPO) activities of a porcine thyroid plasma membrane preparation. 2-IHDA inhibited NADPH-oxidase activity, with half-inhibition at 3-5 microM, but it had no effect on NADPH-cytochrome c reductase. It inhibited the TPO-catalyzed iodination of protein, but not iodide oxidation. Hexadecanal also inhibited NADPH-oxidase. Inhibition by the non-iodinated lipid aldehydes depended on the length of their aliphatic chain: dodecanal and tridecanal gave maximal inhibition. Free iodide, 2-iodohexadecanol and palmitic acid all had no inhibitory effect. Washing treated membranes showed that the inhibition of NADPH-oxidase by hexadecanal was fully reversible, whereas that of 2-IHDA and other iodinated or brominated alkanals was irreversible. Thus the interaction between some residues of the thyroid NADPH-oxidase and the lipid aldehyde groups was favored or stabilized by the iodine atom. Modification of primary amine and thiol groups of NADPH-oxidase inhibited its activity. These groups could also be the target of lipid aldehydes. We suggest that 2-IHDA, because it inhibits TPO and more profoundly the H2O2-generating system in thyroid plasma membrane, modulates iodide metabolism in the thyrocyte and may mediate the Wolff-Chaikoff effect.
Mol Cell Endocrinol 1994 Feb
PMID:Inhibition of thyroid NADPH-oxidase by 2-iodohexadecanal in a cell-free system. 818 56

Axenic strains of Blastocystis hominis incorporated 32P, added to the medium as orthophosphate, into a number of phospholipids, including sphingomyelin, cardiolipin, phosphatidic acid, the phosphoglycerides of choline, ethanolamine, serine, and inositol and some other minor phospholipids. Radioactive palmitate and glycerol provided in the growth medium introduced radiolabel into diacylglycerols, triacylglycerols, and all major phosphoglycerides found in the organism. Palmitate is a major fatty acid of cholesterol esters in B. hominis, but radioactive palmitate did not enter the cholesterol ester pool. Radioactive acetate was not incorporated into any lipids. Cholesterol and cholesterol esters of the organism were not labeled when cells were grown in the presence of radioactive glucose, mevalonic acid, or mevalonolactone. Radioactive cholesterol added to the medium became stably associated with B. hominis cells, but none of the radioactive cholesterol entered the cholesterol ester pool. Cholesterol-[3H]-palmitate added to the medium became stably associated with the organism, and most of the radioactivity associated with the cells remained in the cholesterol ester fraction on extended incubation. These results show that this parasitic protozoan has the capacity to synthesize most cellular lipids de novo, but suggest that it acquires free cholesterol and intact cholesterol esters directly from growth medium.
Comp Biochem Physiol Biochem Mol Biol 1994 Apr
PMID:Lipid biosynthesis by axenic strains of Blastocystis hominis. 820 79

The effect of TPP+ on the fatty acid or FCCP-induced uncoupling in rat heart mitochondria was studied. It was found that (a) TPP+ increases the stimulation of oxygen consumption by palmitic acid or FCCP in the presence of oligomycin, (b) TPP+ greatly enhances the palmitic acid or FCCP-induced delta psi decrease. Both effects of TPP+ were strongly suppressed by carboxyatractylate in the case of palmitate but were not in the case of FCCP. The role of ATP/ADP-antiporter in the TPP+ and palmitic acid effects is discussed.
Biochem Mol Biol Int 1993 Aug
PMID:Carboxyatractylate inhibits the potentiating effect of lipophylic cation TPP+ on uncoupling activity of fatty acid. 822 Feb 60


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