Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.1.4 (deaminase)
5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A major aflatoxin G1 (AFG1)-albumin adduct has been identified and characterized in rats following exposure to AFG1. The product isolated from a Pronase digest of in vivo-modified albumin was identical by chromatographic retention time to the synthetic product obtained by the acylase-catalysed deacetylation product of N alpha-acetyl-L-lysine with 8,9-dihydro-8,9-dibromo-AFG1. The in vitro product, AFG1-lysine, was characterized by UV, fluorescence, 1H- and 13C-NMR spectroscopy and fast atom bombardment MS. A competitive enzyme-linked immunoassay for this adduct was established using polyclonal antibodies to AFB1 and this was used together with an HPLC-fluorescence technique to quantitate the in vivo formation of AFG1-albumin adducts in comparison to AFB1. A linear dose-response relationship was observed in rats following single exposures to 0.1-3 mg AFG1/kg body wt. The levels of AFG1-albumin adducts were determined to be 5.7- and 2.8-fold lower than with equivalent doses of AFB1 as determined by immunoassay and HPLC fluorescence respectively. The lower binding of AFG1 and the lower levels in the human food supply compared to AFB1 suggest that the newly identified adduct could be added as an internal standard for methods using the measurement of aflatoxin-albumin adducts to quantitate human exposure to aflatoxin.
Carcinogenesis 1991 Jan
PMID:Identification of an aflatoxin G1-serum albumin adduct and its relevance to the measurement of human exposure to aflatoxins. 189 57

Trisubstituted nitrosoureas are very stable in aqueous systems. But they are potent genotoxins in Chinese hamster V79-E cells, if no exogenous metabolizing system is added, and the mechanism of their genotoxic and carcinogenic activity has been largely unknown. This investigation shows that the sister-chromatid-exchange (SCE)-inducing capacity of 1,3-dimethyl-3-phenyl-1-nitrosourea (DMPNU) is eliminated by adding diisopropylflurophosphate (DFP) or porcine liver carboxylesterase to the incubation system. These effects are caused by two different mechanisms: (i) DFP inhibits endogenous amidases existing in V79-E cells, thus preventing the intracellular decomposition, which means an activation; and (ii) exogenous carboxylesterase cleaves DMPNU extracellularly, and the genotoxic decomposition product is obviously too short-lived to reach a critical intracellular target. A second trisubstituted nitrosourea, 3,3-diethyl-1-methyl-1-nitrosourea (DEMNU), which is mainly activated by monooxygenases, but in the absence of an exogenous metabolizing system also induces SCEs in V79-E cells, was studied in the same way. It was found that the 'direct' genotoxicity of DEMNU may be inhibited by DFP as well, but carboxylesterase decomposes this trialklynitrosourea with a much lower efficiency than DMPNU suggesting a low substrate affinity. The SCE-inducing capacity of both compounds is strongly influenced by the presence of calf serum in the culture medium. The nature of the serum factor is still unknown. Pathways for the amidase catalysis of DMPNU and for the activation of DEMNU by monooxygenases and amidases are proposed and discussed with respect to the topical or systemic carcinogenicity of these agents.
Carcinogenesis 1989 Oct
PMID:Serine hydrolases activate/inactivate trisubstituted nitrosoureas in dependence on intra- and extracellular enzyme location: an SCE study in Chinese hamster V79-E cells. 279 Nov 98

Aflatoxin B1 (AFB1) was shown to react primarily with one or more lysine residues in serum albumin (SA), accounting for more than half of the total binding to this protein. The radioactivity associated with SA following administration of [U-14C]AFB1 to rats was cleared with a half-life of 2.5 days, which is not significantly different from the half-life of unmodified albumin in the normal rat. The product isolated from a Pronase digest of in vivo-modified SA was identical by chromatographic retention time and u.v. and mass spectroscopy to the synthetic product obtained by the acylase-catalyzed deacetylation of the reaction product of N alpha-acetyl-L-lysine with 8,9-dihydro-8,9-dibromo-AFB1. The latter was characterized by u.v., fluorescence, 500 MHz 1H-n.m.r. and fast atom bombardment mass spectrometry. The spectral data strongly support a structure in which the terminal dihydrofuran ring of AFB1 has been converted to a pyrrolinone ring. It is proposed that the initial adduct is formed by condensation of the dialdehyde tautomer of 8,9-dihydro-8,9-dihydroxy-AFB1, with the epsilon-amino group of lysine, to form a Schiff base, and that the Schiff base undergoes an Amadori rearrangement to an alpha-amino ketone. The pyrrolinone ring is formed by condensation of the amino group with the remaining aldehyde to yield the final product. The purified product was relatively stable but was shown to decompose significantly under the conditions used to isolate it from modified SA.
Carcinogenesis 1987 Jun
PMID:Isolation and characterization of the major serum albumin adduct formed by aflatoxin B1 in vivo in rats. 311 39

Deacetylation of N-hydroxy-2-acetylaminofluorene (N-hydroxy-AAF) to N-hydroxy-2-aminofluorene (N-hydroxy-AF) has been proposed as one of the critical metabolic steps in the formation of hepatic DNA adducts and the initiation of liver tumors in 12-day-old male B6C3F1 mice. In this study, the importance of the microsomal deacetylase activity for N-hydroxy-AAF in the initiation of hepatocarcinogenesis in these mice was demonstrated by using a carboxylesterase and amidase inhibitor, bis(p-nitrophenyl)phosphate (BNPP), that is much less toxic in vivo than is paraoxon. Pre-incubation of liver microsomes from 12-day-old male B6C3F1 mice with 10(-3) M BNPP reduced the deacetylase activity by 80% while paraoxon inhibited the deacetylase activity completely at a concentration of 10(-4) M. Pretreatment of 12-day-old male B6C3F1 mice with 4 X 75 micrograms doses of BNPP/g body weight before the administration of N-hydroxy-AAF reduced the hepatic N-(dGuo-8-yl)-AF adduct levels to 1.09 and 0.68 pmol/mg DNA compared with 2.87 and 1.64 pmol/mg DNA for mice treated once with 0.06 or 0.03 mumol of N-hydroxy-AAF/g body weight respectively. However, BNPP pretreatments did not affect the levels of the acetylated DNA adducts, N-(dGuo-8-yl)-AAF and 3-(dGuo-N2-yl)-AAF, formed by these doses of N-hydroxy-AAF. The initiation of liver tumors by N-hydroxy-AAF was also inhibited by BNPP pretreatment. Thus, for mice that received single doses of 0.12, 0.06 and 0.03 mumol of N-hydroxy-AAF/g body weight, the multiplicities of liver tumors at 10 months were reduced by BNPP pretreatments to 5.6, 1.0 and 0.3 compared with multiplicities of 11.8, 4.8 and 1.7 without pretreatment respectively. On the other hand, BNPP pretreatments had no significant inhibitory effects on the levels of the hepatic DNA-N-(dGuo-8-yl)-AF adduct or on the liver tumor multiplicities induced by comparable doses of N-hydroxy-AF. It is concluded that deacetylation of N-hydroxy-AAF to N-hydroxy-AF is essential for the metabolic activation, DNA-N-(dGuo-8-yl)-AF adduct formation and liver tumor initiation in infant male B6C3F1 mice by N-hydroxy-AAF.
Carcinogenesis 1988 Jul
PMID:The essential role of microsomal deacetylase activity in the metabolic activation, DNA-(deoxyguanosin-8-yl)-2-aminofluorene adduct formation and initiation of liver tumors by N-hydroxy-2-acetylaminofluorene in the livers of infant male B6C3F1 mice. 338 46

Acetamide is carcinogenic in rats and mice. To clarify the mechanism of carcinogenesis by acetamide, we investigated DNA damage by and acetamide metabolite, acetohydroxamic acid (AHA), using 32P-5'-end-labeled DNA fragments. AHA treated with amidase induced DNA damage in the presence of Cu(II) and displayed a similar DNA cleavage pattern of hydroxylamine. DNA damage was inhibited by both catalase and bathocuproine, suggesting that H2O2 and Cu(I) are involved. Carboxy-PTIO, a specific scavenger of nitric oxide (NO), partially inhibited DNA damage. The amount of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) by amidase-treated AHA was similar to that by hydroxylamine. ESR spectrometry revealed that amidase-treated AHA as well as hydroxylamine generated NO in the presence of Cu(II). From these results, it has been suggested that AHA might be converted into hydroxylamine by amidase. These results suggest that metal-mediated DNA damage mediated by amidase-catalyzed hydroxylamine generation plays an important role in the carcinogenicity of acetamide.
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PMID:Mechanism of metal-mediated DNA damage induced by a metabolite of carcinogenic acetamide. 1535 19

Infection with Helicobacter pylori (H. pylori) is a risk factor for the development of gastric cancer. Here we show that infection of gastric epithelial cells with 'cag' pathogenicity island (cagPAI)-positive H. pylori induced aberrant expression of activation-induced cytidine deaminase (AID), a member of the cytidine-deaminase family that acts as a DNA- and RNA-editing enzyme, via the IkappaB kinase-dependent nuclear factor-kappaB activation pathway. H. pylori-mediated upregulation of AID resulted in the accumulation of nucleotide alterations in the TP53 tumor suppressor gene in gastric cells in vitro. Our findings provide evidence that aberrant AID expression caused by H. pylori infection might be a mechanism of mutation accumulation in the gastric mucosa during H. pylori-associated gastric carcinogenesis.
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PMID:Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. 1741 70

RNA editing defines a molecular process by which a nucleotide sequence is modified in the RNA transcript and results in an amino acid change in the recoded message from that specified in the gene. We will restrict our attention to the type of RNA editing peculiar to mammals, i.e., nuclear C to U RNA editing. This category of RNA editing contrasts with RNA modifications described in plants, i.e., organellar RNA editing (reviewed in Ref 1). Mammalian RNA editing is genetically and biochemically classified into two groups, namely insertion-deletional and substitutional. Substitutional RNA editing is exclusive to mammals, again with two types reported, namely adenosine to inosine and cytosine to uracil (C to U). This review will examine mammalian C to U RNA editing of apolipoproteinB (apoB) RNA and the role of the catalytic deaminase Apobec-1. We will speculate on the functions of Apobec-1 beyond C to U RNA editing as implied from its ability to bind AU-rich RNAs and discuss evidence that dysregulation of Apobec-1 expression might be associated with carcinogenesis through aberrant RNA editing or altered RNA stability.
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PMID:APOBEC-1-mediated RNA editing. 2083 50

The beneficial effects of DNA cytidine deamination by activation-induced deaminase (AID; antibody gene diversification) and APOBEC3G (retrovirus restriction) are tempered by probable contributions to carcinogenesis. Multiple regulatory mechanisms serve to minimize this detrimental outcome. Here, we show that phosphorylation of a conserved threonine attenuates the intrinsic activity of activation-induced deaminase (Thr-27) and APOBEC3G (Thr-218). Phospho-null alanine mutants maintain intrinsic DNA deaminase activity, whereas phospho-mimetic glutamate mutants are inactive. The phospho-mimetic variants fail to mediate isotype switching in activated mouse splenic B lymphocytes or suppress HIV-1 replication in human T cells. Our data combine to suggest a model in which this critical threonine acts as a phospho-switch that fine-tunes the adaptive and innate immune responses and helps protect mammalian genomic DNA from procarcinogenic lesions.
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PMID:Phosphorylation directly regulates the intrinsic DNA cytidine deaminase activity of activation-induced deaminase and APOBEC3G protein. 2165 20

Human APOBEC3A is a single-stranded DNA cytidine deaminase that restricts viral pathogens and endogenous retrotransposons, and has a role in the innate immune response. Furthermore, its potential to act as a genomic DNA mutator has implications for a role in carcinogenesis. A deeper understanding of APOBEC3A's deaminase and nucleic acid-binding properties, which is central to its biological activities, has been limited by the lack of structural information. Here we report the nuclear magnetic resonance solution structure of APOBEC3A and show that the critical interface for interaction with single-stranded DNA substrates includes residues extending beyond the catalytic centre. Importantly, by monitoring deaminase activity in real time, we find that A3A displays similar catalytic activity on APOBEC3A-specific TTCA- or A3G-specific CCCA-containing substrates, involving key determinants immediately 5' of the reactive C. Our results afford novel mechanistic insights into APOBEC3A-mediated deamination and provide the structural basis for further molecular studies.
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PMID:NMR structure of human restriction factor APOBEC3A reveals substrate binding and enzyme specificity. 2369 84

Genetic information should be accurately transmitted from cell to cell; conversely, the adaptation in evolution and disease is fueled by mutations. In the case of cancer development, multiple genetic changes happen in somatic diploid cells. Most classic studies of the molecular mechanisms of mutagenesis have been performed in haploids. We demonstrate that the parameters of the mutation process are different in diploid cell populations. The genomes of drug-resistant mutants induced in yeast diploids by base analog 6-hydroxylaminopurine (HAP) or AID/APOBEC cytosine deaminase PmCDA1 from lamprey carried a stunning load of thousands of unselected mutations. Haploid mutants contained almost an order of magnitude fewer mutations. To explain this, we propose that the distribution of induced mutation rates in the cell population is uneven. The mutants in diploids with coincidental mutations in the two copies of the reporter gene arise from a fraction of cells that are transiently hypersensitive to the mutagenic action of a given mutagen. The progeny of such cells were never recovered in haploids due to the lethality caused by the inactivation of single-copy essential genes in cells with too many induced mutations. In diploid cells, the progeny of hypersensitive cells survived, but their genomes were saturated by heterozygous mutations. The reason for the hypermutability of cells could be transient faults of the mutation prevention pathways, like sanitization of nucleotide pools for HAP or an elevated expression of the PmCDA1 gene or the temporary inability of the destruction of the deaminase. The hypothesis on spikes of mutability may explain the sudden acquisition of multiple mutational changes during evolution and carcinogenesis.
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PMID:Genome-wide mutation avalanches induced in diploid yeast cells by a base analog or an APOBEC deaminase. 2403 93


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