RESUMEN
Isocitrate lyase is important for lipid utilisation by Mycobacterium tuberculosis but its ICL2 isoform is poorly understood. Here we report that binding of the lipid metabolites acetyl-CoA or propionyl-CoA to ICL2 induces a striking structural rearrangement, substantially increasing isocitrate lyase and methylisocitrate lyase activities. Thus, ICL2 plays a pivotal role regulating carbon flux between the tricarboxylic acid (TCA) cycle, glyoxylate shunt and methylcitrate cycle at high lipid concentrations, a mechanism essential for bacterial growth and virulence.
Asunto(s)
Acetilcoenzima A/metabolismo , Isocitratoliasa/metabolismo , Mycobacterium tuberculosis/enzimología , Acetilcoenzima A/fisiología , Acilcoenzima A/metabolismo , Carbono/metabolismo , Ciclo del Ácido Cítrico , Cristalografía por Rayos X , Isocitratoliasa/química , Metabolismo de los Lípidos , Espectroscopía de Resonancia Magnética , Simulación del Acoplamiento Molecular , Dominios ProteicosRESUMEN
Traditional antitumor drugs inhibit the proliferation and metastasis of tumour cells by restraining the replication and expression of DNA. These drugs are usually highly cytotoxic. They kill tumour cells while also cause damage to normal cells at the same time, especially the hematopoietic cells that divide vigorously. Patients are exposed to other serious situations such as a severe infection caused by a decrease in the number of white blood cells. Energy metabolism is an essential process for the survival of all cells, but differs greatly between normal cells and tumour cells in metabolic pathways and metabolic intermediates. Whether this difference could be used as new therapeutic target while reducing damage to normal tissues is the topic of this paper. In this paper, we introduce five major metabolic intermediates in detail, including acetyl-CoA, SAM, FAD, NAD+ and THF. Their contents and functions in tumour cells and normal cells are significantly different. And the possible regulatory mechanisms that lead to these differences are proposed carefully. It is hoped that the key enzymes in these regulatory pathways could be used as new targets for tumour therapy.
Asunto(s)
Antineoplásicos/efectos adversos , Carcinogénesis/metabolismo , Neoplasias/metabolismo , Acetilcoenzima A/química , Acetilcoenzima A/metabolismo , Acetilcoenzima A/fisiología , Proliferación Celular/efectos de los fármacos , Progresión de la Enfermedad , Flavina-Adenina Dinucleótido/química , Flavina-Adenina Dinucleótido/metabolismo , Flavina-Adenina Dinucleótido/fisiología , Humanos , NAD/química , NAD/metabolismo , NAD/fisiología , Invasividad Neoplásica , Neoplasias/patología , Neoplasias/terapia , S-Adenosilmetionina/química , S-Adenosilmetionina/metabolismo , Tetrahidrofolatos/química , Tetrahidrofolatos/metabolismo , Tetrahidrofolatos/fisiologíaAsunto(s)
Genes de Cambio , Redes y Vías Metabólicas/genética , Células Madre Pluripotentes/metabolismo , Acetilcoenzima A/fisiología , Animales , Diferenciación Celular/genética , Células Madre Embrionarias/metabolismo , Células Madre Embrionarias/fisiología , Glucólisis/genética , Humanos , Fosforilación Oxidativa , Células Madre Pluripotentes/fisiologíaRESUMEN
Investiga o estatuto e as condições de emergência da categoria nosológica de síndrome do coração irritável presente nos discursos médicos anglo-americanos na segunda metade do século XIX. No contexto da Guerra Civil Americana, examina elementos sócio-históricos que configuraram a atenção médica sobre os sintomas de ordem cardíaca de soldados. Destacam-se os valores morais de médicos-militares frente aos sintomas de medo em combatentes, assim como as hipóteses etiológicas britânicas e norte-americanas que consolidaram o estatuto nosológico do sofrimento dos soldados com palpitações. Propõe análise da especificidade da síndrome do coração irritável frente às categorias nosológicas do medo descritas pela nosologia psiquiátrica atual.
This paper examines the characteristics and the conditions for the emergence of the nosological category known as irritable heart syndrome to be found in Anglo-American medical literature in the second half of the nineteenth century. In the context of the American Civil War, it looks at some of the socio-historical elements, which comprised the medical care given to certain cardiac symptoms shown by soldiers. It emphasizes the moral values influencing the medical attitudes of military physicians towards symptoms of fear experienced by combatants, as well as the British and American etiological theories, which contributed to the nosological characterization of the suffering of soldiers afflicted with palpitations. Finally, it offers a brief analysis of the specific nature of the medical category known as irritable heart syndrome in the light of the categories of fear described by current psychiatric nosology.
Asunto(s)
Acetilcoenzima A/fisiología , Aspergillus nidulans/metabolismo , Proteínas Fúngicas/fisiología , Fenilacetatos/metabolismo , Proteínas Represoras/fisiología , Ácido Acético/farmacología , Transporte BiológicoRESUMEN
Transcriptional activation is typically associated with increased acetylation of promoter histones. However, this paradigm does not apply to transcriptional activation of all genes. In this study we have characterized a group of genes that are repressed by histone acetylation. These histone hypoacetylation-activated genes (HHAAG) are normally repressed during exponential growth, when the cellular level of acetyl-CoA is high and global histone acetylation is also high. The HHAAG are induced during diauxic shift, when the levels of acetyl-CoA and global histone acetylation decrease. The histone hypoacetylation-induced activation of HHAAG is independent of Msn2/Msn4. The repression of HSP12, one of the HHAAG, is associated with well-defined nucleosomal structure in the promoter region, while histone hypoacetylation-induced activation correlates with delocalization of positioned nucleosomes or with reduced nucleosome occupancy. Correspondingly, unlike the majority of yeast genes, HHAAG are transcriptionally upregulated when expression of histone genes is reduced. Taken together, these results suggest a model in which histone acetylation is required for proper positioning of promoter nucleosomes and repression of HHAAG.
Asunto(s)
Acetilcoenzima A/fisiología , Cromatina/fisiología , Histonas/metabolismo , Activación Transcripcional , Acetilación , Cromatina/química , Proteínas de Choque Térmico/genética , Proteínas de Saccharomyces cerevisiae/genéticaRESUMEN
Glucose-derived pyruvate is a principal source of acetyl-CoA in all brain cells, through pyruvate dehydogenase complex (PDHC) reaction. Cholinergic neurons like neurons of other transmitter systems and glial cells, utilize acetyl-CoA for energy production in mitochondria and diverse synthetic pathways in their extramitochondrial compartments. However, cholinergic neurons require additional amounts of acetyl-CoA for acetylcholine synthesis in their cytoplasmic compartment to maintain their transmitter functions. Characteristic feature of several neurodegenerating diseases including Alzheimer's disease and thiamine diphosphate deficiency encephalopathy is the decrease of PDHC activity correlating with cholinergic deficits and losses of cognitive functions. Such conditions generate acetyl-CoA deficits that are deeper in cholinergic neurons than in noncholinergic neuronal and glial cells, due to its additional consumption in the transmitter synthesis. Therefore, any neuropathologic conditions are likely to be more harmful for the cholinergic neurons than for noncholinergic ones. For this reason attempts preserving proper supply of acetyl-CoA in the diseased brain, should attenuate high susceptibility of cholinergic neurons to diverse neurodegenerative conditions. This review describes how common neurodegenerative signals could induce deficts in cholinergic neurotransmission through suppression of acetyl-CoA metabolism in the cholinergic neurons.
Asunto(s)
Acetilcoenzima A/fisiología , Muerte Celular/fisiología , Supervivencia Celular/fisiología , Enfermedades Neurodegenerativas/patología , Receptores Colinérgicos/metabolismo , Encéfalo/metabolismo , Metabolismo Energético , HumanosRESUMEN
AIMS: To clarify the role of acetate in neurochemical mechanisms of the initial (inborn) tolerance to ethanol. METHODS: Rats with low and high inborn tolerance to hypnotic effect of ethanol were used. In the brain region homogenates (frontal and parietal cortex, hypothalamus, striatum, medulla oblongata) and brain cortex synaptosomes, the levels of acetate, acetyl-CoA, acetylcholine (AcH), the activity of pyruvate dehydrogenase (PDG) and acetyl-CoA synthetase were examined. RESULTS: It has been found that brain cortex of rats with high tolerance to hypnotic effect of ethanol have higher level of acetate and activity of acetyl-CoA synthetase, but lower level of acetyl-СCoA and activity of PDG. In brain cortex synaptosomes of tolerant rats, the pyruvate oxidation rate as well as the content of acetyl-CoA and AcH synthesis were lower when compared with intolerant animals. The addition of acetate into the medium significantly increased the AcH synthesis in synaptosomes of tolerant, but not of intolerant animals. Calcium ions stimulated the AcH release from synaptosomes twice as high in tolerant as in intolerant animals. Acetate eliminated the stimulating effect of calcium ions upon the release of AcH in synaptosomes of intolerant rats, but not in tolerant animals. As a result, the quantum release of AcH from synaptosomes in the presence of acetate was 6.5 times higher in tolerant when compared with intolerant rats. CONCLUSION: The brain cortex of rats with high inborn tolerance to hypnotic effect of ethanol can better utilize acetate for the acetyl-CoA and AcH synthesis, as well as being resistant to inhibitory effect of acetate to calcium-stimulated release of AcH. It indicates the metabolic and cholinergic mechanisms of the initial tolerance to ethanol.
Asunto(s)
Acetatos/metabolismo , Adaptación Fisiológica/genética , Trastornos Relacionados con Alcohol/genética , Depresores del Sistema Nervioso Central/metabolismo , Etanol/metabolismo , Sinaptosomas/efectos de los fármacos , Acetilcoenzima A/efectos de los fármacos , Acetilcoenzima A/genética , Acetilcoenzima A/fisiología , Acetilcolina/análisis , Acetilcolina/genética , Acetilcolina/fisiología , Adaptación Fisiológica/fisiología , Trastornos Relacionados con Alcohol/metabolismo , Animales , Encéfalo/metabolismo , Depresores del Sistema Nervioso Central/farmacología , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Etanol/farmacología , Humanos , Hipotálamo/metabolismo , Masculino , Bulbo Raquídeo/metabolismo , Complejo Piruvato Deshidrogenasa/efectos de los fármacos , Complejo Piruvato Deshidrogenasa/genética , Complejo Piruvato Deshidrogenasa/fisiología , Ratas , Ratas Wistar , Sinaptosomas/enzimologíaRESUMEN
Recent breakthrough studies suggest that metabolic signals such as AMP/NAD(+) and acetyl-CoA during fasting and feeding, respectively, translate the energetic cell status into specific transcriptional metabolic programs. Notably, NAD(+) and acetyl-CoA modulate chromatin packaging and gene expression as substrates of histone deacetylases or histone acetyltransferases, respectively. These energetic sensors regulate circadian rhythms and their related physiological processes. In addition, NAD(+) indirectly activates peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) during fasting, whereas acetyl-CoA inactivates PGC-1alpha upon feeding. In this review, we focus on recent evidence supporting the concept of an energetic code by which metabolic sensors control homeostasis during fasting and feeding and discuss its relevance to the pathophysiology of type 2 diabetes.
Asunto(s)
Células/metabolismo , Metabolismo Energético/fisiología , Homeostasis/fisiología , Acetilcoenzima A/metabolismo , Acetilcoenzima A/fisiología , Adenosina Trifosfato/metabolismo , Adenilato Quinasa/metabolismo , Animales , Fenómenos Fisiológicos Celulares , Ingestión de Alimentos/fisiología , Ayuno/metabolismo , Ayuno/fisiología , Humanos , Modelos Biológicos , Sirtuinas/metabolismo , Sirtuinas/fisiologíaRESUMEN
BACKGROUND: Acetate metabolism in Escherichia coli plays an important role in the control of the central metabolism and in bioprocess performance. The main problems related to the use of E. coli as cellular factory are i) the deficient utilization of carbon source due to the excretion of acetate during aerobic growth, ii) the inhibition of cellular growth and protein production by acetate and iii) the need for cofactor recycling (namely redox coenzymes and free CoASH) to sustain balanced growth and cellular homeostasis. RESULTS: This work analyzes the effect of mutations in the acetate excretion/assimilation pathways, acetyl-CoA synthethase (acs) and phosphotransacetylase (pta), in E. coli BW25113 grown on glucose or acetate minimal media. Biomass and metabolite production, redox (NADH/NAD+) and energy (ATP) state, enzyme activities and gene expression profiles related to the central metabolism were analyzed. The knock-out of pta led to a more altered phenotype than that of acs. Deletion of pta reduced the ability to grow on acetate as carbon source and strongly affected the expression of several genes related to central metabolic pathways. CONCLUSION: Results showed that pta limits biomass yield in aerobic glucose cultures, due to acetate production (overflow metabolism) and its inefficient use during glucose starvation. Deletion of pta severely impaired growth on acetate minimal medium and under anaerobiosis due to decreased acetyl-coenzyme A synthethase, glyoxylate shunt and gluconeogenic activities, leading to lower growth rate. When acetate is used as carbon source, the joint expression of pta and acs is crucial for growth and substrate assimilation, while pta deletion severely impaired anaerobic growth. Finally, at an adaptive level, pta deficiency makes the strain more sensitive to environmental changes and de-regulates the central metabolism.
Asunto(s)
Acetatos/metabolismo , Acetilcoenzima A/fisiología , Escherichia coli/enzimología , Fosfato Acetiltransferasa/fisiología , Acetilcoenzima A/metabolismo , Biomasa , Coenzima A Ligasas/genética , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/fisiología , Escherichia coli/crecimiento & desarrollo , Perfilación de la Expresión Génica , Técnicas de Inactivación de Genes , Mutación , NAD/metabolismo , Fosfato Acetiltransferasa/genética , Fosfato Acetiltransferasa/metabolismoRESUMEN
Zomepirac [ZP, 5-(chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid] was withdrawn from the market because of unpredictable allergic reactions that may have been caused by ZP-protein adducts formed by reaction of the reactive acyl glucuronide of ZP (ZP-O-G) with endogenous proteins. To test the hypothesis that the reactive ZP acyl coenzyme A thioester (ZP-CoA) was formed and potentially could contribute to formation of ZP-protein adducts, we investigated the acyl CoA-dependent metabolism of ZP in freshly isolated rat hepatocytes (1 mM) and in vivo (100 mg ZP/kg, ip) in rat livers (2 h after dose administration), rat bile (0-4 h), and rat urine (0-24 h). ZP-CoA was detected in freshly isolated hepatocytes and in vivo in rat livers by LC/MS/MS. In addition, the ZP glycine conjugate (ZP-Gly) and ZP taurine conjugates (ZP-Tau) were identified by LC/MS/MS in rat hepatocytes and in vivo in rat livers, rat urine, and rat bile. The identities of ZP-CoA, ZP-Gly, and ZP-Tau were confirmed by comparison of retention times and MS/MS spectra with those of authentic standards. Moreover, the ZP acyl carnitine ester was detected in rat urine and rat bile based upon (i) the chlorine isotope pattern, (ii) MS/MS spectra showing significant ions characteristic for carnitine (m/z 60, 144 and loss of m/z 59) and ZP (m/z 139), and (iii) accurate mass measurements with a mass accuracy of 0.2 ppm. ZP-CoA serves as an obligatory intermediate in the formation of ZP-Gly, ZP-Tau, and ZP carnitine ester, and it is therefore of mechanistic significance that these conjugates were identified. Finally, time-dependent concentration profiles obtained in experiments with rat hepatocytes and in vivo from quantitative analysis of rat livers indicate that ZP-CoA, in addition to ZP-O-G, may contribute to formation of the potentially toxic covalent ZP-protein adducts.
Asunto(s)
Acetilcoenzima A/fisiología , Hepatocitos/metabolismo , Hígado/metabolismo , Tolmetina/análogos & derivados , Animales , Biotransformación , Carnitina/metabolismo , Cromatografía Líquida de Alta Presión , Glicina/metabolismo , Masculino , Espectrometría de Masas , Ratas , Ratas Sprague-Dawley , Taurina/metabolismo , Tolmetina/metabolismo , Tolmetina/toxicidadRESUMEN
We have investigated several factors which influence acetyl-CoA carboxylase (ACCase) activity in lysed spinach chloroplasts. (1) When assayed after rapid lysis of light-incubated chloroplasts, ACCase activity was 2-fold higher than activity from dark-incubated chloroplasts. Within 5 min after lysis, activity from dark-incubated chloroplasts increased, suggesting a transient inactivation or inhibition of ACCase in the dark. (2) When lysed chloroplast suspensions were incubated with 30 to 100 microM acetyl-CoA before starting assays, activity was 4-fold higher than if suspensions were not preincubated with acetyl-CoA. CoA, malonyl-CoA, propionyl-CoA, and butyryl-CoA also activated ACCase. Full acetyl-CoA activation required MgATP and was essentially complete after 8 min. ACCase activity decreased upon removal of acetyl-CoA by gel filtration and was partially restored by readdition of acetyl-CoA. Thus, ACCase activation by acetyl-CoA was reversible. (3) Dithiothreitol and thioredoxin stimulated ACCase activity, but only in preparations where ACCase activity was low. (4) ACCase was assayed in concentrations of ATP, ADP, NADPH, NADP+, Mg2+, and CO2/HCO-3, which are estimated to occur in the stroma of chloroplasts under illumination or darkness. ACCase activity from lysed chloroplast suspensions was 10-fold higher when illuminated conditions were used. However, this activity was still 5-fold to 10-fold lower than the rates required to sustain known in vivo rates of fatty acid synthesis and in vitro rates achieved under optimum assay conditions with saturating substrates.
Asunto(s)
Acetil-CoA Carboxilasa/metabolismo , Cloroplastos/enzimología , Spinacia oleracea/enzimología , Acetilcoenzima A/fisiología , Acilcoenzima A/fisiología , Cloroplastos/química , Coenzima A/fisiología , Oscuridad , Ditiotreitol/farmacología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/efectos de la radiación , Concentración de Iones de Hidrógeno , Luz , Malonil Coenzima A/fisiología , Fracciones Subcelulares/química , Fracciones Subcelulares/enzimología , Tiorredoxinas/farmacologíaRESUMEN
The filamentous fungus Aspergillus nidulans is able to grow on phenylacetic acid (PhAc) as the sole carbon source and has a highly specific phenylacetic acid transport system mediating the uptake of this aromatic compound. This transport system is also able to transport some phenoxyacetic acid (PhOAc), although less efficiently. Maximal uptake rates were observed at 37 degrees C in 50 mM phosphate buffer (pH 7.0). Under these conditions, uptake was linear for at least 1 minute, with K(m) values for PhAc and PhOAc of 74 and 425 microM, respectively. The PhAc transport system is strongly induced by PhAc and, to a lesser extent by PhOAc and other phenyl derivatives. The utilization of glucose (and other sugars), glycerol or acetate results in a substantially reduced uptake. This negative effect caused by certain carbon sources is independent of the creA gene, the regulatory gene mediating carbon catabolite repression. Negative regulation by acetate is prevented by a loss-of-function mutation in the gene encoding acetyl-CoA synthetase, strongly suggesting that this regulation is mediated by the intracellular pool of acetyl-CoA.
Asunto(s)
Acetilcoenzima A/fisiología , Aspergillus nidulans/metabolismo , Proteínas Fúngicas/fisiología , Fenilacetatos/metabolismo , Proteínas Represoras/fisiología , Ácido Acético/farmacología , Transporte BiológicoRESUMEN
This paper review data indicating that the concentration of acetyl-CoA in cytoplasm of cholinergic terminals is an important factor which may determine the rate and size of quantal acetylcholine in different physiologic and pathologic conditions.
Asunto(s)
Acetilcoenzima A/fisiología , Acetilcolina/metabolismo , Encefalopatías/metabolismo , Encéfalo/metabolismo , Sinaptosomas/metabolismo , Ácido 3-Hidroxibutírico/farmacología , Aluminio/farmacología , Animales , Encéfalo/efectos de los fármacos , Fibras Colinérgicas/metabolismo , Citoplasma/metabolismo , Diabetes Mellitus/metabolismo , Metabolismo Energético/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Ácido Pirúvico/metabolismo , Ratas , Sinaptosomas/efectos de los fármacosRESUMEN
We examined whether hyperinsulinemia is associated with changes in the amount of L-carnitine and acetyl-L-carnitine in the muscle and whether the source of acetyl-coenzyme A (CoA) (glucose or free fatty acids [FFAs]) influences its further metabolism to acetyl-L-carnitine or through tricarboxylic acid in the skeletal muscle of man in vivo. Twelve healthy men (aged 45 +/- 2 years; body mass index, 25.2 +/- 1.0 kg/m2) were studied using a 4-hour euglycemic-hyperinsulinemic clamp (1.5 mU/kg/min) and indirect calorimetry. Although the mean muscle free L-carnitine and acetyl-L-carnitine concentrations remained unchanged during hyperinsulinemia in the group as a whole, the individual changes in muscle free L-carnitine and acetyl-L-carnitine concentrations were inversely related (r = -.72, P < .02). The basal level of acetyl-L-carnitine was inversely related to the rate of lipid oxidation (r = -.70, P < .02). In a stepwise linear regression analysis, 77% of the variation in the change of acetyl-L-carnitine concentrations was explained by the basal muscle glycogen level (inversely) and nonoxidative glucose disposal rate (directly) during hyperinsulinemia (P < .001); by adding the final FFA concentration (inverse correlation) to the model, 88% of the variation was explained (P < .001). In conclusion, (1) hyperinsulinemia does not enhance skeletal muscle free L-carnitine or acetyl-L-carnitine concentrations in-man, and (2) the acetyl group of acetyl-L-carnitine in human skeletal muscle in vivo is probably mostly derived from glucose and not through beta-oxidation from fatty acids.
Asunto(s)
Acetilcarnitina/metabolismo , Glucosa/metabolismo , Hiperinsulinismo/metabolismo , Metabolismo de los Lípidos , Músculo Esquelético/metabolismo , Acetilcoenzima A/análisis , Acetilcoenzima A/metabolismo , Acetilcoenzima A/fisiología , Acetilcarnitina/análisis , Acetilcarnitina/fisiología , Adulto , Calorimetría Indirecta , Ácidos Grasos no Esterificados/análisis , Ácidos Grasos no Esterificados/metabolismo , Glucógeno/análisis , Glucógeno/metabolismo , Humanos , Hiperinsulinismo/fisiopatología , Insulina/farmacología , Modelos Lineales , Masculino , Persona de Mediana Edad , Músculo Esquelético/química , Músculo Esquelético/fisiología , Oxidación-ReducciónRESUMEN
The pineal gland synthesizes its hormone melatonin (O-methyl-N-acetylserotonin) from serotonin. Acetyl-CoA: serotonin N-acetyltransferase (SNAT), the enzyme that catalyzes the committed step in this biosynthesis, is largely restricted to the pineal gland and is regulated by adrenergic and circadian mechanisms. Another enzyme, acetyl-CoA: arylamine N-acetyltransferase (ANAT), having an apparently similar activity, is also present in the pineal. This enzyme, however, is not rhythmically regulated. SNAT activity of cultured chick pineal cells was obtained without ANAT after ammonium sulfate precipitation. ANAT activity was retained without SNAT activity after pre-incubation at 37 degrees C. Thus, each enzyme could be examined independently. Overlap in substrate specificity between the two enzymes was minimal. Kinetic analysis of the separated enzyme activities revealed that while SNAT operates via a random or ordered bi bi mechanism, ANAT catalysis occurs through a ping pong bi bi mechanism with substrate inhibition by acetyl-CoA. By size-exclusion chromatography, ANAT was confirmed to be 30-35 kDa, and SNAT was estimated at 15-20 kDa. Taken together, these results indicate that the two enzymes differ in their structure, reactivity, stability, and mechanism of catalysis.
Asunto(s)
Acetilcoenzima A/fisiología , Arilamina N-Acetiltransferasa/fisiología , Ritmo Circadiano/fisiología , Glándula Pineal/enzimología , Sulfato de Amonio/farmacología , Animales , Embrión de Pollo , Cinética , Melatonina , Glándula Pineal/fisiología , Triptaminas/farmacologíaRESUMEN
Oxidation of derivatives and precursors of pantothenic acid was studied in alcohol dehydrogenase reactions. Despite the presence of free hydroxymethyl groups in a number of pantothenic acid derivatives only panthenol with Km = 8 x 10(-3) M was shown to serve as a substrate for alcohol dehydrogenase from horse liver tissue (EC 1.1.1.1) Pantethine, sodium phosphopantothenate, CoA and acetyl-CoA decreased the rate of ethanol oxidation, where pantethine and sodium phosphopantothenate were competitive inhibitors, while CoA and acetyl-CoA inhibited the enzyme noncompetitively Ki = 1.2 x 10(-2) M, 2.1 x 10(-2) M, 4.4 x 10(-4) M and 5.1 x 10(-4) M, respectively. Metabolic precursors, which were different from pantothenic acid in their structure, were not involved in the alcohol dehydrogenase reaction. Possible regulation of alcohol intoxication using derivatives and precursors of vitamin B3 is discussed.
Asunto(s)
Alcohol Deshidrogenasa/metabolismo , Ácido Pantoténico/metabolismo , Acetilcoenzima A/fisiología , Alcohol Deshidrogenasa/antagonistas & inhibidores , Animales , Coenzima A/fisiología , Caballos , Hígado/enzimología , Oxidación-Reducción , Ácido Pantoténico/análogos & derivados , Especificidad por SustratoRESUMEN
Acetyl-coenzyme A (CoASAc) inhibits the rate of incorporation of amino acid into protein in a cell-free system of mouse liver. The effect is more pronounced when exogenous mRNA (tobacco mosaic virus or globin mRNA) rather than endogenous messages are used. Micromolar concentrations of the cofactor block initiation, while millimolar concentrations cause a more general inhibition of the translation process, that affects, in addition, the elongation step. Inclusion of [1-14C]acetyl-CoA in a protein synthesis reaction mixture results in a very rapid and selective labelling of a protein of 200 kd of the 'pH 5' fraction. The possible involvement of the acetylating event in the regulation of protein synthesis is discussed.
Asunto(s)
Acetilcoenzima A/fisiología , Biosíntesis de Proteínas/fisiología , Acetilación , Animales , Sistema Libre de Células , Centrifugación por Gradiente de Densidad , Electroforesis en Gel de Poliacrilamida , Fluorometría , Regulación de la Expresión Génica , Concentración de Iones de Hidrógeno , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C3H , Polirribosomas/metabolismo , Proteínas/metabolismo , ARN Mensajero/genética , ARN Viral/genética , Virus del Mosaico del Tabaco/genéticaRESUMEN
Cardiomyopathies are often caused by a metabolic defect. Carnitine deficiency and mitochondrial defects in the metabolism of acyl-CoA, including defects in oxidative phosphorylation, start the same circular mechanism of mitochondrial doom. Patients with cardiomyopathy due to carnitine loss are cured by carnitine supplementation. In such a patient we found defective oxidative phosphorylation in isolated muscle mitochondria. The stimulation of the respiratory rate with all substrates by ADP was decreased, probably the cause of inhibition of the adenine nucleotide translocator by accumulating long-chain acyl-CoA. The same condition was encountered in patients with Duchenne muscular dystrophy, who often get cardiomyopathy in the course of the disease process.