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PubMed1985

New anthracycline glycosides obtained by the nitrous acid deamination of daunorubicin, doxorubicin and their configurational analogues.

The new anthracyclines 7-O-(2,3,5-trideoxy-3-C-formyl-alpha-L-threo-pentofuranosyl)daunomyci none (8) and -adriamycinone (10) have been obtained upon nitrous acid deamination of daunorubicin and doxorubicin respectively. Deamination of the L-ribo analogue of daunorubicin (6) gave a mixture of 2,3,6-trideoxy-L-glycero-hexopyranosid-4-ulose (alpha-L-cinerulosyl) (11) and 2,6-dideoxy-alpha-L-arabino-hexopyranosyl (12) glycosides. The corresponding adriamycinone glycosides 13 and 14, obtained by deamination of the doxorubicin L-ribo analogue 7, were found to display an outstanding antileukemic activity in mice.

Animals↗
PubMedDate not supplied

Oxidative deamination of thialysine by snake venom L-aminoacid oxidase.

Thialysine is oxidatively deaminated by snake venom L-aminoacid oxidase at alkaline pH. The oxygen consumption curves show a characteristic diphasic course: the quick uptake of half a mole of oxygen per mole of substrate, in aggreement with a typical oxidative deamination, is followed by a slow extra oxygen consumption. The first product of the reaction is the corresponding alpha-oxo-epsilon-amino acid, which spontaneously cyclizes to the internal Schiff base 5-6-dihydro-delta 3,1,4-thiazin-3-carboxylic acid (TZCA). This latter has been identified by its UV absorption spectrum, by some chemical reactions, by paper chromatography, and by the production of cystamine and glyoxylic acid after prolonged oxidation of thialysine followed by acid hydrolysis. The possibility of an alpha-beta elimination reaction giving rise to cysteamine from thialysine, coupled to the oxidative deamination, has been excluded.

Amino Acid Oxidoreductases↗
PubMedDate not supplied

[Disorders of oxidative deamination of biogenic amines in the myocardium in experimental atherosclerosis].

Statistically significant inhibition of oxidative deamination of several biogenic amines was found in mitochondrial fraction of heart muscle from rabbits and rats with experimental atherosclerosis and hypercholesterolemia, caused by various methods. Sensitivity of oxidative deamination of tryptamine to inhibitory effect of clorgyline (selective inhibitor of mitochondrial monoamine oxidases) was unaltered in rats with experimental hypercholesterolemia. The rate of oxidative deamination of beta-phenyl ethylamine, tryptamine, benzylamine as well as histamine and putrescine was inhibited after treatment of the mitochondrial fragments from healthy rabbit and rat heart muscles with preparations of oxidized linoleic and linolenic acids, concentration of which was increased in tissues under conditions of atherosclerosis.

Animals↗
PubMed1984

Sites of methyl esterification and deamination on the aspartate receptor involved in chemotaxis.

The receptors involved in bacterial chemotaxis are post-translationally modified by specific enzymes which catalyze the deamination of glutaminyl residues and the methyl esterification and demethylation of glutamyl residues. In this work we identify the sites of these covalent modifications on the aspartate receptor from Salmonella typhimurium. These were identified using the properties of the Staphylococcus aureus V8 protease which cleaves peptide bonds following glutamyl but not glutaminyl residues. We show here that bonds following methyl-esterified glutamyl residues are also resistant to the protease. A comparison of the fragments obtained after V8 protease cleavage of methyl-esterified (or deaminated) peptides with the fragments from the corresponding unmodified peptides immediately yields the sites of modification. Three of the four methyl-esterified glutamyl residues are located near the middle of the receptor amino acid sequence; one of these is synthesized as a glutaminyl residue and is deaminated by the esterase to form a glutamyl residue. The fourth site of methyl esterification is located near the carboxyl terminus. All four sites occupy analogous positions in a well-conserved arrangement of residues which may form a binding site for the esterase and the methyltransferase.

Amino Acid Sequence↗
PubMed1993

Chemical characteristics of N-aminated nucleic acid bases. Nitrosation of aromatic N-amino group and accompanying reductive deamination.

Primary NH2 group attached to the pyridine-type or pyrrole-type nitrogen underwent sequential nitrosation and reductive deamination by the treatment with NaNO2-AcOH. Secondary NHR group attached to the pyridine-type nitrogen underwent also the reductive deamination. In contrast, secondary NHR group attached to the pyrrole-type nitrogen gave the corresponding N-nitroso derivative under the same conditions. Mechanism of the reductive deamination is discussed.

Amines↗
PubMed1995

Opposite effects of polyamines on glutamate deamination in isolated renal tubules and permeabilized kidney cortex mitochondria of rabbit.

The effect of polyamines on glutamate deamination has been studied in both isolated tubules and permeabilized kidney cortex mitochondria of rabbit. Spermine, spermidine and putrescine resulted in a decrease of ammonium release in isolated renal tubules incubated with glutamate in the presence of MSO and AOA, inhibitors of glutamine synthetase and aminotransferases, respectively. This was not due to the inhibition of glutamate transport across renal tubular membranes since transport of [14C]glutamate into brush border membranes vesicles was not decreased by polyamines. In contrast, polyamines stimulated glutamate deamination in permeabilized mitochondria. This effect was additive to the action of ADP, an allosteric activator of glutamate dehydrogenase. Since these compounds decreased both glutamate-induced mitochondrial swelling as well as [14C]glutamate accumulation in mitochondria, the inhibitory effect of polyamines on glutamate deamination in renal tubules might be due to a diminished glutamate transport across the mitochondrial membrane.

Animals↗
PubMed1996

Counteracting the mutagenic effect of hydrolytic deamination of DNA 5-methylcytosine residues at high temperature: DNA mismatch N-glycosylase Mig.Mth of the thermophilic archaeon Methanobacterium thermoautotrophicum THF.

Spontaneous hydrolytic deamination of DNA 5-methylcytosine residues gives rise to T/G mismatches which are pre-mutagenic lesions requiring DNA repair. For fundamental reasons, the significance of this and other processes lowering genetic fidelity must be accentuated at elevated temperatures, making thermophilic organisms attractive objects for studying how cells cope with thermal noise threatening the integrity of their genetic information. Gene mig of Methanobacterium thermoautotrophicum THF, an anaerobic archaeon with an optimal growth temperature of 65 degrees C, was isolated and its product (Mig.Mth; EC3.2.2-) shown to be a T/G-selective DNA thymine N-glycosylase with the properties required for counteracting the mutagenic effect of hydrolytic 5-meC deamination. The enzyme acts on T/G and U/G oppositions with similar efficiency; G/G, A/G, T/C and U/C are minor substrates; no other opposition of common nucleobases is attacked and no removal of U from single-stranded DNA is observed. Substrate preferences are modulated by sequence context. Together with the results presented here, one example of an enzyme directed against the hydrolytic deamination damage of 5-meC is known from each of the three phylogenetic kingdoms; entry into the repair pathway is glycosylytic in the eukaryotic and the archaeal case, whereas the eubacterial repair starts with an endonucleolytic DNA incision.

5-Methylcytosine↗
PubMed2000

A spectrophotometric method for determining the oxidative deamination of methylamine by the amine oxidases.

Previously published studies on the oxidative deamination of methylamine by the amine oxidases have determined the formation of radioactively labeled formaldehyde from [(14)C]methylamine. The present work describes a coupled spectrophotometric assay, using formaldehyde dehydrogenase, for the continuous determination of the oxidative deamination of methylamine by semicarbazide-sensitive amine oxidase (SSAO) and its potential use for determining methylamine concentrations in plasma. In this assay, the formaldehyde produced by methylamine deamination is further oxidized to formate, with the reduction of NAD(+), by formaldehyde dehydrogenase. The NADH generated is monitored continuously at 340 nm. Interference from the presence of a rotenone-insensitive NADH oxidase activity in crude tissue homogenates and microsomal fractions can be minimized by pretreating samples with Triton X-100 or substituting NAD(+) by APAD(+) in the coupled assay. This relatively inexpensive and reproducible assay procedure avoids the use of radioactively labeled material.

Aldehyde Oxidoreductases↗
PubMed1998

Deamination of methylamine and angiopathy; toxicity of formaldehyde, oxidative stress and relevance to protein glycoxidation in diabetes.

Semicarbazide-sensitive amine oxidase (SSAO) is located in the vascular smooth muscles, retina, kidney and the cartilage tissues, and it circulates in the blood. The enzyme activity has been found to be significantly increased in blood and tissues in diabetic patients and animals. Methylamine and aminoacetone are endogenous substrates for SSAO. The deaminated products are formaldehyde and methylglyoxal respectively, as well as H2O2 and ammonia, which are all potentially cytotoxic. Formaldehyde and methylglyoxal are cytotoxic towards endothelial cells. Excessive SSAO-mediated deamination may directly initiate endothelial injury and plaque formation, increase oxidative stress, which can potentiate oxidative glycation, and/or LDL oxidation and damage vascular systems. Formaldehyde is also capable of exacerbating advanced glycation, and thus increase the complexity of protein cross-linking. Uncontrolled SSAO-mediated deamination may be involved in the acceleration of the clinical complications in diabetes.

Amine Oxidase (Copper-Containing)↗
PubMed1991

The two-step model of UV mutagenesis reassessed: deamination of cytosine in cyclobutane dimers as the likely source of the mutations associated with photoreactivation.

A large increase in the incidence of bacteriophage mutants is found after photoreactivation of UV-irradiated phage S13. The increase was seen only when the irradiated phage were stored before they were photoreactivated; the maximum mutation frequency was achieved after storage for 2 h at 4 degrees C or 30 min at 37 degrees C. The mutations can be attributed entirely to deamination of cytosine in cyclobutane dimers. Naked S13 DNA was stored for 2 h at 37 degrees C after being irradiated with wavelengths greater than or equal to 290 nm in the presence of 0.2% acetophenone, which sensitizes the formation of thymine-thymine but not cytosine-containing dimers; the specific mutation frequency was 7.2-fold lower compared to the frequency produced by irradiation in the absence of the photosensitizer, confirming that cytosine dimers are a major source of mutations. These results undermine the basis for the two-step model of UV mutagenesis in which a distinctly separate misincorporation step is supposed to precede the lesion bypass step; instead the results support a different two-step model, in which a deamination step precedes the bypass. The S13 capsid appears to completely inhibit the putative deamination reaction at about 75% of the dimer sites.

Coliphages↗
PubMed2002

Involvement of semicarbazide-sensitive amine oxidase-mediated deamination in atherogenesis in KKAy diabetic mice fed with high cholesterol diet.

AIMS/HYPOTHESIS: Semicarbazide-sensitive amine oxidase has been recognised to be a potential risk factor in vascular disorders associated with diabetic complications and to be related to mortality in patients suffering from heart disease. This enzyme, associated with the vascular system, catalyses the deamination of methylamine and aminoacetone, and also acts as an adhesion molecule related to leucocyte trafficking and inflammation. The deaminated products include the toxic aldehydes, formaldehyde and methylglyoxal, respectively, hydrogen peroxide and ammonia. MATERIALS AND METHODS: In this study, the KKAy mouse, a strain possessing features closely resembling those of Type II (non-insulin-dependent) diabetes mellitus has been used to substantiate the hypothesis. Vascular lesions were induced via chronic feeding of a high cholesterol diet. RESULTS: Both MDL-72974A, a selective mechanism-based semicarbazide-sensitive amine oxidase inhibitor and aminoguanidine effectively inhibited aorta semicarbazide-sensitive amine oxidase activity, and caused a substantial increase in urinary methylamine, and a decrease in formaldehyde and methylgloxal levels. Inhibition of semicarbazide-sensitive amine oxidase also reduced oxidative stress, as shown by a reduction of malondialdehyde excretion. Both MDL-72974A and aminoguanidine reduced albuminuria, proteinuria and the number of atherosclerotic lesions in animals fed with a cholesterol diet over a period of treatment for 16 weeks. CONCLUSION/INTERPRETATION: Increased semicarbazide-sensitive amine oxidase-mediated deamination could be involved in the cascade of atherogenesis related to diabetic complications.

Albuminuria↗
PubMed1988

Anticonvulsant activity of deaminated analogues of glutamic acid diethyl ester (GDEE).

GDEE, a specific but low-potency antagonist of the quisqualate or 'Type 2' excitatory amino acid receptor, blocks seizures induced by homocysteine and quisqualic acid. Deaminated analogues of GDEE were examined for anticonvulsant activity in mice, for the purpose of determining the structural properties of GDEE required for anticonvulsant activity. The deaminated derivative of GDEE, diethyl glutarate (5 carbon chain) inhibited homocysteine thiolactone (HTL)-induced seizures with an ED50 of 533 mg/kg. A similar compound with carbon chain length increased by two (diethyl pimelate; 7 carbons) was less effective. Decreases or further increases in carbon chain length resulted in a nearly complete loss of activity. Dimethyl glutarate (5 carbons) and dimethyl adipate (6 carbons) were similar to diethyl glutarate in potency, blocking HTL-induced seizures with ED50s of about 625 and 540 mg/kg, respectively. Diethyl ethylmalonate, diethyl maleate, and diethyl fumarate were much less effective. Diethyl glutarate, but not diethyl succinate (4 carbons), blocked seizures induced by intracerebral quisqualic acid. None of the agents tested blocked pentylenetetrazole-induced seizures. Thus a number of deaminated structural variants of GDEE have anticonvulsant activity equal to that of GDEE. The amino group of GDEE appears therefore to be irrelevant for its anticonvulsant effect.

Animals↗
PubMed1970

L-serine deaminating enzymes in Escherichia coli crude extracts.

(a) The measured L-serine deaminating activity of a crude bacterial extract may originate from L-serine deaminase, from biosynthetic L-threonine deaminase, or from degradative L-serine deaminase. Nevertheless, the contribution of the individual enzymes can be determined.(b) About a half of the L-serine deaminating activity of wild type E. coli bacteria, grown in synthetic minimal medium, originates from L-serine deaminase and about half from biosynthetic L-threonine deaminase.(c) Ninety percent of L-serine deaminating activity of wild type E. coli bacteria, grown in yeast extract-tryptone medium, originates from L-serine deaminase, and the remainging ten percent from the degradative L-threonine deaminase.(d) Conditions have been established in which threonine deaminases are eliminated and the activity of L-serine deaminase alone could be measured, even in crude extracts.

Journal Article↗
PubMed2002

Repair of deaminated bases in DNA.

Deamination of DNA bases can occur spontaneously, generating highly mutagenic lesions such as uracil, hypoxanthine, and xanthine. When cells are under oxidative stress that is induced either by oxidizing agents or by mitochondrial dysfunction, additional deamination products such as 5-hydroxymethyluracil (5-HMU) and 5-hydroxyuracil (5-OH-Ura) are formed. The cellular level of these highly mutagenic lesions is increased substantially when cells are exposed to DNA damaging agent, such as ionizing radiation, redox reagents, nitric oxide, and others. The cellular repair of deamination products is predominantly through the base excision repair (BER) pathway, a major cellular repair pathway that is initiated by lesion specific DNA glycosylases. In BER, the lesions are removed by the combined action of a DNA glycosylase and an AP endonuclease, leaving behind a one-base gap. The gapped product is then further repaired by the sequential action of DNA polymerase and DNA ligase. DNA glycosylases that recognize uracil, 5-OH-Ura, 5-HMU (derived from 5-methylcytosine) and a T/G mismatch (derived from a 5-methylcytosine/G pair) are present in most cells. Many of these glycosylases have been cloned and well characterized. In yeast and mammalian cells, hypoxanthine is efficiently removed by methylpurine N-glycosylase, and it is thought that BER might be an important pathway for the repair of hypoxanthine. In contrast, no glycosylase that can recognize xanthine has been identified in either yeast or mammalian cells. In Escherichia coli, the major enzyme activity that initiates the repair of hypoxanthine and xanthine is endonuclease V. Endonuclease V is an endonuclease that hydrolyzes the second phosphodiester bond 3' to the lesion. It is hypothesized that the cleaved DNA is further repaired through an alternative excision repair (AER) pathway that requires the participation of either a 5' endonuclease or a 3'-5' exonuclease to remove the damaged base. The repair process is then completed by the sequential actions of DNA polymerase and DNA ligase. Endonuclease V sequence homologs are present in all kingdoms, and it is conceivable that endonuclease V might also be a major enzyme that initiates the repair of hypoxanthine and xanthine in mammalian cells.

Animals↗
PubMed1988

Primary deuterium isotope effects for the 3-methylaspartase-catalyzed deamination of (2S)-aspartic acid, (2S,3S)-3-methylaspartic acid, and (2S,3S)-3-ethylaspartic acid.

3-Methylaspartate ammonia-lyase catalyzes the deamination of (2S)-aspartic acid 137 times more slowly than the deamination of (2S,3S)-3-methylaspartic acid but catalyzes the amination of fumaric acid 1.8 times faster than the amination of mesaconic acid [Botting, N.P., Akhtar, M., Cohen, M. A., & Gani, D. (1988) Biochemistry (preceding paper in this issue)]. In order to understand the mechanistic basis for these observations, the deamination reaction was examined kinetically with (2S)-aspartic acid, (2S,3S)-3-methylaspartic acid, (2S,3S)-3-ethylaspartic acid, and the corresponding C-3-deuteriated isotopomers. Comparison of the double-reciprocal plots of the initial reaction velocities for each of the three pairs of substrates revealed that the magnitude of the primary isotope effect on both Vmax and V/K varied with the substituent at C-3 of the substrate. 3-Methylaspartic acid showed the largest isotope effect (1.7 on Vmax and V/K), 3-ethylaspartic acid showed a smaller isotope effect (1.2 on Vmax and V/K), and aspartic acid showed no primary isotope effect at all. These results, which are inconsistent with earlier reports that there is no primary isotope effect for 3-methylaspartic acid [Bright, H. J. (1964) J. Biol. Chem. 239, 2307], suggest that for both 3-methylaspartic acid and 3-ethylaspartic acid elimination occurs via a predominantly concerted mechanism whereas for aspartic acid an E1cb mechanism prevails.(ABSTRACT TRUNCATED AT 250 WORDS)

Ammonia-Lyases↗
PubMed2002

15N kinetic isotope effects on uncatalyzed and enzymatic deamination of cytidine.

15N isotope effects and solvent deuterium isotope effects have been measured for the hydrolytic deamination of cytidine catalyzed by Escherichia coli cytidine deaminase and for the uncatalyzed reaction proceeding spontaneously in neutral solution at elevated temperatures. The primary (15)(V/K) arising from the exocyclic amino group for wild-type cytidine deaminase acting on its natural substrate, cytidine, is 1.0109 (in H(2)O, pH 7.3), 1.0123 (in H(2)O, pH 4.2), and 1.0086 (in D(2)O, pD 7.3). Increasing solvent D(2)O content has no substantial effect on k(cat) but enhances k(cat)/K(m), with a proton inventory showing that the fractionation factors of at least two protons increase markedly during the reaction. Mutant cytidine deaminases with reduced catalytic activity show more pronounced (15)N isotope effects of 1.0124 (Glu91Ala), 1.0134 (His102Ala), and 1.0158 (His102Asn) at pH 7.3 in H(2)O, as expected for processes in which the chemical transformation of the substrate becomes more rate determining. The isotope effect of mutant His102Asn is 1.033 after correcting for protonation of the -NH(2) group, and represents the intrinsic isotope effect on C-N bond cleavage. This result allows an estimation of the forward commitment of the reaction with the wild-type enzyme. The observed (15)N kinetic isotope effect of the pyrimidine N-3, for wild-type cytidine deaminase acting on cytidine, is 0.9879, which is consistent with protonation and rehybidization of N-3 with hydroxide ion attack on the adjacent carbon to create a tetrahedral intermediate. These results show that enzymatic deamination of cytidine proceeds stepwise through a tetrahedral intermediate with ammonia elimination as the major rate-determining step. The primary (15)N isotope effects observed for the uncatalyzed reaction at pH 7 (1.0021) and pH 12.5 (1.0034) were found to be insensitive to changing temperatures between 100 and 185 degrees C. These results show that the uncatalyzed and the enzymatic deaminations of cytidine proceed by similar mechanisms, although the commitment to C-N bond breaking is greater for the spontaneous reaction.

Cytidine↗
PubMed1980

Mutagenic deamination of cytosine residues in DNA.

Spontaneous deamination converts cytosine to uracil, which is excised from DNA by the enzyme uracil-DNA glycosylase, leading to error-free repair. 5-Methylcytosine residues are deaminated to thymine, which cannot be excised and repaired by this system. As a result, 5-methylcytosine residues are hotspots for spontaneous transitions, as demonstrated in the lacI gene of Escherichia coli. We show here that in bacteria which lack uracil-DNA glycosylase (Ung-) and cannot excise uracil residues from DNA, the rate of spontaneous transition at cytosine residues is raised to the hotspot rate at 5-methylcytosine residues. These studies provide direct evidence that the deamination of cytosine is a significant source of spontaneous mutations.

Cytidine Deaminase↗
PubMed2003

Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase.

The expression of activation-induced cytidine deaminase (AID) is prerequisite to a "trifecta" of key molecular events in B cells: class-switch recombination and somatic hypermutation in humans and mice and gene conversion in chickens. Although this critically important enzyme shares common sequence motifs with apolipoprotein B mRNA-editing enzyme, and exhibits deaminase activity on free deoxycytidine in solution, it has not been shown to act on either RNA or DNA. Recent mutagenesis data in Escherichia coli suggest that AID may deaminate dC on DNA, but its putative biochemical activities on either DNA or RNA remained a mystery. Here, we show that AID catalyzes deamination of dC residues on single-stranded DNA in vitro but not on double-stranded DNA, RNA-DNA hybrids, or RNA. Remarkably, it has no measurable deaminase activity on single-stranded DNA unless pretreated with RNase to remove inhibitory RNA bound to AID. AID catalyzes dC --> dU deamination activity most avidly on double-stranded DNA substrates containing a small "transcription-like" single-stranded DNA bubble, suggesting a targeting mechanism for this enigmatic enzyme during somatic hypermutation.

Animals↗