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)

Purified human C5 was converted non-enzymically to an activated form as defined by its ability to participate in reactive lysis. This conversion occurred following exposure to systems that generate oxygen radicals, namely addition of H2O2 in the presence of ascorbic acid and iron or the addition of xanthine oxidase, acetaldehyde and iron. The conversion of C5 to a functionally active species was iron-dependent and inhibited by hydroxyl radical scavengers such as DMSO. The findings suggest that OH. is the active oxygen species that converts C5. The conversion product of C5, termed C5(H2O2), is C5b-like due to its ability to bind C6 and cause reactive lysis. C5(H2O2) is much more stable than C5b obtained by complement convertases. Although C5(H2O2) has lost the binding site of native C5 for C3b it can be cleaved by complement-derived convertases; the cleavage is, however, less efficient than in the case of native C5. The resulting cleavage product, which is C5a-like, is chemotactic although C5(H2O2) is not chemotactic. C5(H2O2) serves as a better substrate for plasma kallikrein than native C5, resulting in the generation of a C5a-like chemotactic product. These data indicate that oxygen radicals can bring about a conformational change in C5, causing it to behave as a functionally activated molecule of the complement system. This may have implications for the role of complement and its activation in the inflammatory response.
Mol Immunol 1989 Dec
PMID:Non-enzymic activation of the fifth component of human complement, by oxygen radicals. Some properties of the activation product, C5b-like C5. 256 Nov 80

Young adult Wistar rats received 40 mg/kg of cyclosporin perorally for 21 days. Cyclosporin induced almost total disappearance of thymic medulla, whereas the cortex remained preserved. Although the density of cortical macrophages did not change significantly, their characteristics altered markedly and they became enlarged and rounded. In addition to an increase in acid phosphatase and nonspecific esterase activities, cortical macrophages developed very strong succinic dehydrogenase and chloroacetate esterase activities and a fine, granular, aldehyde fuchsin-positive cytoplasmic content. However, these cytoplasmic granules were PAS-negative and were not sudanophilic. Cortical macrophages retained their normal antigenic properties (which were studied by the use of ED1, ED2 and R-MC 41 monoclonal antibodies). Phagocytic cells in the remaining medullary islands retained their usual characteristics. The changes in cortical macrophages after cyclosporin treatment are discussed, especially in relation to the characteristics of macrophages of the cortico-medullary zone in the normal rat thymus.
Virchows Arch B Cell Pathol Incl Mol Pathol 1989
PMID:Macrophages of the rat thymus after cyclosporin treatment. Histochemical, enzymehistochemical and immunohistochemical study. 256 84

Plasmodium falciparum was shown to synthesize pteroylpolyglutamate de novo from guanosine 5'-triphosphate (GTP), p-aminobenzoate (PABA), and L-glutamate (L-Glu). The parasite also had the capacity to synthesize pteroylpolyglutamate from both intact and degradation moieties (p-aminobenzoylglutamate and pterin-aldehyde) of exogenous folate added into the growth medium. The major product was identified as 5-methyl-tetrahydroteroylpentaglutamate following exposure to pteroylpolyglutamate hydrolase and oxidative degradation of the C9-N10 bond in the molecule and identification of products by reversed-phase high performance liquid chromatography. Inhibition of pteroylpentaglutamate synthesis from the radiolabelled metabolic precursors (GTP, PABA, L-Glu) and folate by the antifolate antimalarials, pyrimethamine and sulfadoxine at therapeutic concentrations, may suggest the existence of a unique biosynthetic pathway in the malaria parasite.
Mol Biochem Parasitol 1989 Jan 01
PMID:De novo and salvage biosynthesis of pteroylpentaglutamates in the human malaria parasite, Plasmodium falciparum. 264 36

The mutagenicity of crotonaldehyde in Salmonella typhimurium TA100 cannot be demonstrated in the standard plate incorporation assay. However, as reported earlier by our group, this alpha, beta-unsaturated aldehyde is clearly mutagenic in the liquid assay modification of this testing procedure. Carried out because of the doubts recently expressed by Cooper et al. (Environ Mutagen 9:289-295, 1987) concerning the observed mutagenicity of crotonaldehyde in S. typhimurium TA100, this study confirms that this compound is clearly a direct (without activation by mammalian microsomes)-acting mutagen in S. typhimurium TA100 under appropriate conditions in the preincubation assay. The observed mutagenicity is increased by extended preincubation time and increased bacterial cell densities.
Environ Mol Mutagen 1989
PMID:Crotonaldehyde is mutagenic in Salmonella typhimurium TA100. 267 26

Onchidal has been identified as the major lipid-soluble component of the defensive secretion of the mollusc Onchidella binneyi, and it has been proposed as the compound responsible for the chemical protection of Onchidella [Bioorg. Chem. 7:125-131 (1978)]. In support of this hypothesis, we now report that onchidal can be found in several different species of Onchidella and that it is toxic to fish. Because onchidal is an acetate ester similar to acetylcholine, its ability to interact with nicotinic acetylcholine receptors and acetylcholinesterase was investigated. Although onchidal did not prevent the binding of 125I-alpha-bungarotoxin to nicotinic acetylcholine receptors, it inhibited acetylcholinesterase in a progressive, apparently irreversible, manner. The apparent affinity of onchidal for the initial reversible binding to acetylcholinesterase (Kd) was approximately 300 microM, and the apparent rate constant for the subsequent irreversible inhibition of enzyme activity (kintact) was approximately 0.1 min-1. Onchidal was a substrate for acetylcholinesterase, and approximately 3250 mol of onchidal were hydrolyzed/mol of enzyme irreversibly inhibited. The calculated kcat for onchidal was 325 min-1. Irreversible inhibition resulted from either onchidal itself or a reactive intermediate in the enzyme-catalyzed hydrolysis of onchidal, rather than from the hydrolysis products of onchidal. Irreversible inhibition of enzyme activity was prevented by coincubation with reversible agents that either sterically block (edrophonium and decamethonium) or allosterically modify (propidium) the acetylcholine binding site. Enzyme activity was not regenerated by incubation with oxime reactivators; therefore, the mechanism of irreversible inhibition does not appear to involve acylation of the active site serine. Because onchidal contains a potentially reactive alpha,beta-unsaturated aldehyde, irreversible inhibition of acetylcholinesterase may result from formation of a novel covalent bond between the toxin and the enzyme. Thus, this novel toxin could potentially be exploited in the design of a new class of anticholinesterase insecticides and in the identification of amino acids that contribute to the binding and hydrolysis of acetylcholine.
Mol Pharmacol 1989 Sep
PMID:Onchidal: a naturally occurring irreversible inhibitor of acetylcholinesterase with a novel mechanism of action. 277 21

Naphthol AS D chloroacetate esterase (NASDCE)-positive macrophages are positioned in the cortico-medullary zone (CMZ) of the normal rat thymus. These cells contain the very strongly NASDCE-positive granules of varying size in the cytoplasm. An identical distribution within the thymic parenchyma and an identical morphological appearance is observed in CMZ macrophages after staining with aldehyde fuchsin. The incubation of thymic sections in 10% formalin at pH 7.0 for 48 h does not inhibit the activity of NASDCE in CMZ macrophages. The activity of nonspecific esterase is almost totally abolished by this treatment: only the single, largest globular inclusion within some of the cells remains weakly or moderately positive. The granular content of the CMZ macrophages does not stain metachromatically with toluidine blue and these cells are endogenous peroxidase-negative. NASDCE-positive thymic macrophages are easily distinguished from: a) NASDCE-positive mast-cells, which are confined to the capsular and septal connective tissue and contain densely packed metachromatic granules, and b) NASDCE-positive neutrophilic granulocytes, which have a specific morphological appearance and show very strong endogeneous peroxidatic activity.
Virchows Arch B Cell Pathol Incl Mol Pathol 1985
PMID:Naphthol AS D chloroacetate esterase-positive macrophages in the cortico-medullary zone of the normal rat thymus. 286 65

Secondary lymphoid follicles in peripheral lymphoid organs (parathymic, mesenteric and inguinal lymph nodes and spleen) from young adult Wistar rats of both sexes were studied. Different numbers of tingible body macrophages containing aldehyde fuchsin-positive cytoplasmic granules of varying size, were present in the germinal centers. An identical staining pattern to that obtained with aldehyde fuchsin in terms of the number, distribution and size of positive cells was seen after staining for succinic dehydrogenase.
Virchows Arch B Cell Pathol Incl Mol Pathol 1986
PMID:Succinic dehydrogenase activity in germinal center macrophages in peripheral lymphoid organs of the rat. 288 60

Differences in the pharmacokinetics of alcohol absorption and elimination are, in part, genetically determined. There are polymorphic variants of the two main enzymes responsible for ethanol oxidation in liver, alcohol dehydrogenase and aldehyde dehydrogenase. The frequency of occurrence of these variants, which have been shown to display strikingly different catalytic properties, differs among different racial populations. Since the activity of alcohol dehydrogenase in liver is a rate-limiting factor for ethanol metabolism in experimental animals, it is likely that the type and content of the polymorphic isoenzyme subunit encoded at ADH2, beta-subunit, and at ADH3, the gamma-subunit, are contributing factors to the genetic variability in ethanol elimination rate. The recent development of methods for genotyping individuals at these loci using white cell DNA will allow us to test this hypothesis as well as any relationship between ADH genotype and the susceptibility to alcoholism or alcohol-related pathology. A polymorphic variant of human liver mitochondrial aldehyde dehydrogenase, ADLH2, which has little or no acetaldehyde oxidizing activity has been identified. Individuals with the deficient ALDH2 phenotype do not have altered ethanol elimination rates but they do exhibit high blood acetaldehyde levels and dysphoric symptoms such as facial flushing, nausea and tachycardia, after drinking alcohol. Because acetaldehyde is so reactive, it binds to free amino groups of proteins including a 37 kilodalton hepatic protein-acetaldehyde adduct and may elicit an antibody response. We would predict that individuals who have low ALDH2 activity because of liver disease or because they have the inactive ALDH2 variant isoenzyme might form more protein-acetaldehyde adducts and elicit a greater immune response. These adducts may represent good biological markers of alcohol abuse and may also play a role in liver injury due to chronic alcohol consumption.
Mol Aspects Med 1988
PMID:Genetic polymorphism of enzymes of alcohol metabolism and susceptibility to alcoholic liver disease. 306 25

Starting with adhC mutants of Escherichia coli in which alcohol dehydrogenase (ADH) and acetaldehyde CoA dehydrogenase (ACDH) are expressed constitutively at high levels, we selected mutants with still higher levels of both enzymes. Selection for growth on ethanol in the presence of inhibitors of ADH gave several mutants that had from 2- to 10-fold increases in the levels of both enzymes. These mutations were found to map far from the adhC locus at around 90 min. Such adhR mutants were unable to grow on acetate or ethanol in certain media unless supplemented with extra manganese. This growth disability was suppressed by secondary mutations, one of which, aceX, increased sensitivity to several toxic metals and may perhaps derepress Mn transport. When the adhR mutation expressing the highest ADH and ACDH levels was present together with fadR and atoC mutations (allowing efficient catabolism of acetoacetyl-CoA) and with an aceX mutation, the resulting strains became capable of using n-butanol as sole carbon and energy source. The use of butanol by E. coli illustrates the artificial evolution of a new catabolic pathway, in this case by the selection of four successive regulatory mutations (fadR, adhC, atoC, and adhR) together with the poorly defined aceX mutation. Each stage in the acquisition of this novel pathway confers the ability to use a new growth substrate: decanoic acid (fadR), ethanol (adhC), butyric acid (atoC), and butanol (adhR, when present with aceX).
J Mol Evol 1987
PMID:Regulatory mutations that allow the growth of Escherichia coli on butanol as carbon source. 311 74

Because natural populations of Drosophila melanogaster are polymorphic for different allozymes of alcohol dehydrogenase (ADH) and because D. melanogaster is more tolerant to the toxic effects of ethanol than its sibling species D. simulans, information regarding the sensitivities of the different forms of ADH to the products of ethanol degradation are of ecological importance. ADH-F, ADH-S, ADH-71k of D. melanogaster and the ADH of D. simulans were inhibited by NADH, but the inhibition was relieved by NAD+. The order of sensitivity to NADH was ADH-F less than ADH-71k, ADH-S less than ADH-simulans with ADH-F being about four times less sensitive than the D. melanogaster enzymes and 12 times less sensitive than the D. simulans enzyme. Acetaldehyde inhibited the ethanol-to-acetaldehyde activity of the ADHs, but at low acetaldehyde concentrations ethanol and NAD+ reduced the inhibition. ADH-71k and ADH-F were more subject to the inhibitory action of acetaldehyde than ADH-S and ADH-simulans, with ADH-71k being seven times more sensitive than ADH-S. The pattern of product inhibition of ADH-71k suggests a rapid equilibrium random mechanism for ethanol oxidation. Thus, although the ADH variants only differ by a few amino acids, these differences exert a far larger impact on their intrinsic properties than previously thought. How differences in product inhibition may be of significance in the evolution of the ADHs is discussed.
J Mol Evol
PMID:Alcohol dehydrogenase polymorphism in Drosophila: enzyme kinetics of product inhibition. 314 35


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