Disease relevance of oxobutyrate

• Succinylacetone (SA) (4,6-dioxoheptanoic acid) is an abnormal metabolite produced in patients with hereditary tyrosinemia as a consequence of an inherited deficiency of fumaryl acetoacetate hydrolase activity [1].
• Cholescintigraphy with 2,6-diethylphenylcarbahoylmethyl diacetic acid 99mTc was performed in 24 cholecystectomized patients with recurrent biliary-like pain, laboratory evidence of bile stasis, normal hepatocellular function tests, and no evidence of choledocholithiasis [2].
• Acetone metabolism in the aerobic bacterium Xanthobacter strain Py2 proceeds by a carboxylation reaction forming acetoacetate as the first detectable product [3].
• Addition of acetoacetate but not DL-3-hydroxybutyrate to the culture medium resulted in a significant increase in the activity of 3-ketoacid CoA-transferase and also in the rate of acetoacetate oxidation in neuroblastoma cells but not glioma cells [4].
• Arteriovenous differences for acetoacetate, beta-hydroxybutyrate, glucose, lactic acid, and glutamine and other amino acids were measured across Morris hepatomas 5123C, 7777, and 7288CTCF and Walker sarcocarcinoma 256 in vivo in rats fasted for 2 days [5].

Psychiatry related information on oxobutyrate

• Total and individual non-esterified fatty acids (NEFA), pyruvate, lactate, alpha ketoglutarate, acetoacetate, beta hydroxybutyrate, glucose and insulin were measured in horses during an 80 km endurance ride and during four days of food deprivation [6].

High impact information on oxobutyrate

• Regulation of exogenous and endogenous glucose metabolism by insulin and acetoacetate in the isolated working rat heart. A three tracer study of glycolysis, glycogen metabolism, and glucose oxidation [7].
• The oxidation of acetoacetate by isolated rat heart mitochondria resulted in depressed state 3 respiration as well as in a decrease in [CoASH] [8].
• Whereas hearts perfused with either acetoacetate or glucose were similar with respect to their function for the first 20 min, changes in tissue metabolites were already observed within 5 min of perfusion at near-physiological workloads [9].
• After 60 min of perfusion, hearts utilizing acetoacetate exhibited lower systolic and diastolic pressures and lower cardiac outputs [9].
• Concomitantly, fasting resulted in a decline (day 1 vs. day 5) in serum concentrations of somatomedin C (1.31 +/- 0.22 vs. 0.77 +/- 0.18 U/ml) and glucose (4.9 +/- 0.2 vs. 3.2 +/- 0.2 mmol/liter), and a marked rise in free fatty acid (0.43 +/- 0.12 vs. 1.55 +/- 0.35 mmol/liter) and acetoacetate (35 +/- 6 vs. 507 +/- 80 nmol/liter) [10].

Chemical compound and disease context of oxobutyrate

• In STZ-induced (65 mg/kg) diabetic rats, MDL 29311 attenuated the increase in plasma nonesterified fatty acids during an 18-h fast; had little or no effect on glucagon, pyruvate, lactate, beta-hydroxybutyrate, acetoacetate, or cholesterol; and did not induce hypoglycemia in rats fasted up to 64 h [11].
• During phase I, mevalonate or its catabolites may accumulate in intact cells of Pseudomonas sp. M and acetoacetate, a competitive inhibitor of HMG-CoA reductase (Ki = 3.2 mM), may feedback inhibit the enzyme under these conditions [12].
• In nephrectomized rats with normal blood pH and in rats with metabolic alkalosis the ratio between beta-hydroxybutyrate and acetoacetate is very high in comparison with rats having metabolic acidosis [13].
• To examine the effect of ketosis, U937 monocytes were cultured with ketone bodies (acetoacetate [AA], beta-hydroxybutyrate [BHB]) in the presence or absence of high glucose levels in the medium at 37 degrees C for 24 h [14].
• Epoxide metabolism in Xanthobacter autotrophicus Py2 results in the conversion of epoxypropane to acetoacetate [15].

Biological context of oxobutyrate

• Under particular circumstances like lactation and fasting, the blood-borne monocarboxylates acetoacetate, beta-hydroxybutyrate, and lactate represent significant energy substrates for the brain [16].
• The carboxylation of acetone was coupled to the hydrolysis of ATP and formation of 1 mol AMP and 2 mol inorganic phosphate per mol acetoacetate formed [3].
• We devised a procedure for determining, in a perfused liver system, the first-order rate constant for the decarboxylation of acetoacetate (0.29 +/- 0.09 h-1, S.E., n = 8) [17].
• We conclude that in STZ-D, ketosis does not stimulate hepatic lipogenesis via cytosolic activation of acetoacetate [18].
• (c) The interaction of the terminal CH3CO group of acetoacetate with the active site causes a 200,000-fold increase in kappacat/Km, corresponding to a decrease in delta G++ OF 7.2 kcal/mol compared with an unsubstituted acid of the same pK [19].

Anatomical context of oxobutyrate

• Considering the interaction of substrates, isolated colonic epithelial cells utilized respiratory fuels in the preferential order of butyrate greater than acetoacetate greater than glutamine greater than glucose [20].
• Hydroxybutyrate and acetoacetate (AC), alone or in combination, either failed to affect or decreased CYP2E1 mRNA levels by up to 90% relative to untreated hepatocytes [21].
• The fastest-growing tumor studied (7288Ctc) contains about the same amount of CoA transferase activity as rat skeletal muscle (i.e., an activity of about 0.1 mumole of acetoacetate used per min per g tissue) [22].
• Pyruvate and acetoacetate transport in mitochondria. A reappraisal [23].
• U937 cells were cultured with ketone bodies (acetoacetate [AA] and beta-hydroxybutyrate [BHB]) in the presence or absence of high levels of glucose in medium at 37 degrees C for 24 h [24].

Associations of oxobutyrate with other chemical compounds

• Both the acetoacetate/beta-hydroxybutyrate ratio of the liver, which reflects mitochondrial free NAD+/NADH ratio, and the heptic energy charge decreased in accordance with the decrease of mitochondrial phosphorylative activity after the ligation [25].
• Component II catalyzed the NADPH-dependent cleavage and carboxylation of the beta-ketothioether to form acetoacetate and coenzyme M [26].
• The metabolism of glucose, lactate, acetoacetate, glycerol, and free fatty acids by subcutaneous adipose tissue plus skin was also unchanged [27].
• The regulation of acetoacetyl-CoA synthetase activity by modulators of cholesterol synthesis in vivo and the utilization of acetoacetate for cholesterogenesis [28].
• Reactions that generate and remove acetoacetyl-CoA and acetoacetate were measured in mitochondria and cytosol of rat liver [29].

Gene context of oxobutyrate

• Unsaturated fatty acids and acetoacetate also reduced ABCA1 promotor activity in RAW264.7 macrophages that were transfected with a 968-bp ABCA1 promotor/luciferase gene construct [30].
• Acetoacetate activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase in primary cultured rat hepatocytes: role of oxidative stress [31].
• Polyunsaturated fatty acids and acetoacetate downregulate the expression of the ATP-binding cassette transporter A1 [30].
• Glucagon replacement (2 ng . kg-1 . min-1) during insulin deficiency failed to enhance ketogenesis or lipolysis but lowered the beta-hydroxybutyrate/acetoacetate concentration ratios [32].
• N-acetylcysteine (NAC) prevented the IL-6 secretion in acetoacetate-treated U937 monocytes [14].

Analytical, diagnostic and therapeutic context of oxobutyrate

• In general, the xenografts utilized ketone bodies. beta-Hydroxybutyrate was consumed by 82% and acetoacetate by 73% of the tumors, the uptake rates being linearly related to the respective availabilities [33].
• Determination of the mole percent enrichment of blood acetoacetate and D-beta-hydroxybutyrate was performed by gas chromatography/mass spectrometry [34].
• With total caloric restriction prior to therapy, all patients became hypoglycemic (109 +/- 18 leads to 37 +/- 3.5 mg/dl, mean +/- SEM) and ketonemic (beta-hydroxybutyrate 0.10 +/- 0.02 leads to 3.04 +/- 0.63 mM and acetoacetate 0.05 +/- .01 leads to 0.80 +/- 0.15 mM) within 30 hours [35].
• Arterial ketone body ratio (AKBR [acetoacetate/beta-hydroxybutyrate]) was measured in nineteen patients under medical supportive therapy for fulminant hepatic failure (FHF), in order to evaluate its predictive value relative to liver transplantation [36].
• 2. Starvation alone raised the rates of production and utilization of beta-hydroxybutyrate plus acetoacetate about 3.7-fold, but lowered their metabolic clearance rates by about 50% [37].

References