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PubMed1977

Hypoketonaemic effect of L-alamine. Specific decrease in blood concentrations of 3-hydroxybutyrate in the rat.

1. The injection of L-alanine (50-100 mg/kg) into 35-day-old rats that had been starveed for 48 h increased blood L-alanine concentration to values observed in fed animals and lowered the blood concentration of 3-hydroxybutyrate within 2 min. 2. This hypoketon aemic action of L-alanine was specific for 3-hydroxybutyrate, since the acetoacetate concentrations did not change significantly. 3. The decrease in 3-hydroxybutyrate elicited by L-alanine was not related to changes in the blood concentrations of insulin, glucagon, growth hormone, glucose, unesterified fatty acids, lactate or pyruvate. 4. The injection of L-alanine resulted in a decrease in total ketones that was apparently unrelated to their increased peripheral utilization. These results are interpreted as an anti-ketogenic action of L-alanine. 5. The data suggest that L-alamine lowers ketone-body formation in starved rats, possibly via an alteration in hepatic redox equilibrium.

Acetates↗
PubMed1986

Interactions between apo-(D-beta-hydroxybutyrate dehydrogenase) and phospholipids studied by intrinsic and extrinsic fluorescence.

Interactions of D-beta-hydroxybutyrate dehydrogenase with phospholipids were investigated by both intrinsic- and extrinsic-fluorescence approaches. The intrinsic fluorescence, mainly caused by tryptophan residues, increased upon re-activation in the presence of phospholipids bearing a positive charge, i.e. phosphatidylcholine, but decreased in the presence of non-re-activating phospholipids with a negative charge. This indicates either that the environment of tryptophan residues is affected by charges rather than by hydrophobic chains of phospholipids, or that the enzyme undergoes different conformational changes depending on the nature of the phospholipids. On the other hand, the graph of the temperature-dependence of the fluorescence intensities of the enzyme embedded in dimyristoylphosphatidylcholine liposomes exhibits a break around 21 degrees C. This indicates either that at least one tryptophan residue is closely in contact with the hydrophobic chains of phospholipids or that there is a change in the environment of tryptophan residues owing to the physical state of the phospholipids. The addition of D-beta-hydroxybutyrate apo-dehydrogenase to phospholipid liposomes containing diphenylhexatriene (a fluorescent probe) increased the diphenylhexatriene fluorescence polarization. Moreover, there was a partial fluorescence energy transfer from tryptophan to diphenylhexatriene. These results strongly favour the possibility that there is a portion of the enzyme polypeptide chain inserted into the phospholipid hydrophobic region. All these results demonstrate that D-beta-hydroxybutyrate apo-dehydrogenase interacts with both polar and hydrophobic parts of phospholipids and leads to small, but essential, conformational changes of the enzyme.

Apoenzymes↗
PubMed1997

Conversion of DL-threonine, D-threonine and 2-oxobutyrate into propionate and 2-hydroxybutyrate by Fusobacterium species.

The present investigation examined DL-threonine, D-threonine and 2-oxobutyrate conversion into propionate and 2-hydroxybutyrate by various type strains and clinical isolates of Fusobacterium. Except for Fus. naviforme, the type strains were able to produce varying degrees of propionate and/or 2-hydroxybutyrate from DL-threonine. Additionally, D-threonine was converted into an equimolar amount of propionate by Fus. necrophorum subsp. necrophorum, Fus. nucleatum subsp. nucleatum and Fus. varium, and to a lower but significant amount by Fus. mortiferum and Fus. perfoetens. However, the level of propionate remained unchanged for Fus. nucleatum subsp. fusiforme, Fus. nucleatum subsp. vincentii, Fus. naviforme, Fus. necrophorum subsp. funduliforme, Fus. gonidiaforme and Fus. russii. 2-Oxobutyrate was fermented to propionate by all type strains, although Fus. russii reduced it mainly to 2-hydroxybutyrate. Thus, an attempt was made to make use of these features in order to identify clinical isolates.

Fusobacterium↗
PubMed1999

Toxic ingestion of gamma-hydroxybutyric acid.

Gamma-hydroxybutyric acid (GHB) has become a popular new drug of abuse. Its effects include euphoria and disinhibition. Recently, several cases have been reported in the literature of life-threatening or lethal ingestions. We report the case of a 17-year-old male who became unresponsive after taking GHB. Gamma-hydroxybutyric acid is used outside the United States to treat narcolepsy. In the past, it was touted as a muscle-bulking aid and was taken by body-builders. It has also been implicated as a drug involved in "date-rapes." Patients who ingest excessive GHB have a markedly altered level of consciousness, as did the patient in this illustrative case. Neostigmine and physostigmine show promise as potential reversal agents. Gamma-hydroxybutyric acid overdose should be considered in any patient with altered mental status and a history of recreational drug abuse.

Adolescent↗
PubMed1978

Purification and properties of beta-hydroxybutyrate dehydrogenase from Mycobacterium phlei ATCC354.

beta-Hydroxybutyrate dehydrogenase (EC 1.1.1.30) was purified 145-fold from Mycobacterium phlei ATCC354 by ammonium sulphate fractionation and DEAE-cellulose chromatography. The pH optima for oxidation and reduction reactions were 8.4 and 6.8 respectively. The purified enzyme was specific for NAD, NADH, acetoacetate and D(-)-beta-hydroxybutyrate. Km values for DL-beta-hydroxybutyrate and NAD were 7.4 mM and 0.66 mM respectively. The enzyme was inactivated by mercurial thiol inhibitors and by heat, but could be protected by NADH, Ca2+ and partially by Mn2+. The enzyme did not require metal ions and was insensitive to EDTA, glutathione, dithiothreitol, beta-mercaptoethanol and cysteine.

Chloromercuribenzoates↗
PubMedDate not supplied

The effect of spontaneous diabetes mellitus on fatty acid oxidation, beta-hydroxybutyrate dehydrogenase activity and respiratory coupling of hepatic mitochondria in the guinea-pig (Cavia porcellus).

1. The purpose of this study was to determine whether hepatic mitochondria of guinea-pigs with spontaneous diabetes mellitus differ from those of non-diabetic guinea-pigs in the oxidation of fatty acids, the activity of beta-hydroxybutyrate dehydrogenase, or respiration-linked oxidative phosphorylation. During the course of the study, a third group of animals (referred to as the unclassified group) was discovered which, on the basis of the clinical chemistry and histological changes in the pancreas, appeared to be in a pre-diabetic or post-diabetic state. 2. No differences in the respiratory control ratios were found between any of the three groups. Fatty-acid oxidation in hepatic mitochondria was greater in both the unclassified and diabetic groups than in the non-diabetic group. Beta-Hydroxybutyrate dehydrogenase activity, however, was increased only in the diabetic group. These findings suggest that increased fatty acid oxidation is probably an intermediate change in the development of or the recovery from diabetes mellitus, whereas the activity of beta-hydroxybutyrate dehydrogenase is affected only in more advanced stages.

Animals↗
PubMed1985

A histochemical study of the distribution of beta-hydroxybutyrate dehydrogenase in developing rat cerebellum.

The distribution of beta-hydroxybutyrate dehydrogenase (3-hydroxybutyrate dehydrogenase, EC 1.1.1.30) in the developing rat cerebellum has been determined using a histochemical method. Staining of Purkinje cells, particularly the soma, was seen at all ages examined. Intense staining of the proximal portions of Purkinje dendrites was noted at 8-11 days postnatally, with less prominent staining of Purkinje dendrites and surrounding structures of the molecular layer seen at later times. Development of glomeruli in the granule cell layer could also be observed due to the intense staining of these structures. (Although noncerebellar structures were not the focus of this study, intense staining of the choroid plexus of the fourth ventricle was also noted.) the transient external germinal layer of the cerebellum did not show appreciable staining. Since beta-hydroxybutyrate dehydrogenase is required for ketone body metabolism, the apparent low level of this enzyme in the external germinal layer suggests that the cells of this layer are not particularly well adapted for utilization of ketone bodies. Thus these results do not provide support for the suggestion that ketone bodies may serve as major substrates for energy metabolism in the external germinal layer of the developing cerebellum. Indeed, the rather restricted distribution of this enzyme in both developing and mature cerebellum (and presumably elsewhere in brain) suggests that ketone body metabolism may be largely confined to relatively few specific cellular compartments.

Animals↗
PubMed1987

Regional distribution of high-affinity gamma-[3H]hydroxybutyrate binding sites as determined by quantitative autoradiography.

The distribution of high-affinity binding sites for gamma-[3H]hydroxybutyrate in coronal sections of rat brain was studied by quantitative autoradiographic techniques. Binding sites for this naturally occurring substance, which may possibly have a neurotransmitter role, are concentrated in some restricted areas of the brain, particularly in the limbic system. The hippocampus (especially field CA1 of Ammon's horn, at 292 fmol/mg of tissue), septum (72 fmol/mg of tissue), and cortex (frontal, 113 fmol/mg of tissue; parietal, 103 fmol/mg of tissue; cingulate, 114 fmol/mg of tissue; and entorhinal, 134 fmol/mg of tissue) show pronounced labeling with gamma-[3H]hydroxybutyrate. Binding is much lower in caudatus-putamen (50 fmol/mg of tissue), thalamus, and hypothalamus. Caudal parts of the brain (cerebellum, pons, and medulla) are practically devoid of binding sites. These results strongly support a functional role of endogenous gamma-hydroxybutyrate in particularly restricted areas of the rat brain.

Animals↗
PubMed1973

Inhibition by gamma-hydroxybutyrate of chlorpromazine-induced increase in homovanillic acid.

1. gamma-Hydroxybutyrate and its lactone precursor, gamma-butyrolactone, when administered in anaesthetic doses block the increase in the cerebral concentration of homovanillic acid normally observed after administration of chlorpromazine or haloperidol.2. Other hypnotics such as glutethimide, urethane, chloralose, chloral hydrate and thiopentone do not have this ability even when administered in anaesthetic doses.3. The ability of gamma-hydroxybutyrate to block the neuroleptic-induced increase in cerebral homovanillic acid is not due to a reduction in body temperature since a similar effect is observed in rats treated under conditions (32 degrees C) in which body temperature remains normal.4. Possible mechanisms for this action of gamma-hydroxybutyrate are discussed.

Animals↗
PubMed1982

The effect of gamma-hydroxybutyrate on mouse striatal tyramine, dopamine and homovanillic acid.

1 The concentrations of p- and m-tyramine, dopamine and homovanillic acid were measured in the mouse striatum following the subcutaneous injection of gamma-hydroxybutyrate; their control levels were 19.8, 6.3, 9600 and 1130 ng/g respectively. 2 The administration of 500-1000 mg/kg of gamma-hydroxybutyrate produced a reduction in p-tyramine that lasted at least 8 h. m-Tyramine and dopamine were significantly increased for at least 4 h. The levels of homovanillic acid were increased at 1 and 2 h after drug administration. 3 There experiments strongly suggest that the increases in dopamine turnover produced by gamma-hydroxybutyrate caused reciprocal changes in striatal tyramine that are similar to those produced by drug or treatment that increase dopamine turnover and tyrosine hydroxylase activity.

Animals↗
PubMed1998

In vitro synthesis of poly(3-hydroxybutyric acid) by using an enzymatic coenzyme A recycling system.

Purified recombinant poly(hydroxyalkanoic acid), PHA, synthase from Chromatium vinosum was used to examine in vitro poly(3-hydroxybutyric acid) (P(3HB)) formation. In combination with purified propionyl-coenzyme A transferase of Clostridium propionicum a two-enzyme in vitro P(3HB) biosynthesis system was established which allowed the synthesis of P(3HB) from free D-(-)-3-hydroxybutyric acid as substrate. The coenzyme A residue for the activation of this hydroxyacid was provided by acetyl-coenzyme A. By adding acetyl-coenzyme A synthetase to this system, a three-enzyme in vitro P(3HB) biosynthesis system was established. Coenzyme A that was released during the polymerization reaction was coupled to acetate which again served as the coenzyme A donor for the activation of 3-hydroxybutyric acid. The energy for the in vitro P(3HB) synthesis was provided by ATP hydrolyses resulting in acetyl-coenzyme A synthesis catalyzed by the acetyl coenzyme A synthetase. In this way the in vitro synthesis of P(3HB) became independent of the consumption of the expensive coenzyme A. By this procedure a handy system is available to produce in vitro PHA on a semipreparative scale.

3-Hydroxybutyric Acid↗
PubMed2001

Biosynthesis of poly-beta-hydroxybutyrate (PHB) is controlled by CydR (Fnr) in the obligate aerobe Azotobacter vinelandii.

CydR is an Fnr-like protein in the obligatory aerobic nitrogen-fixing bacterium Azotobacter vinelandii. The cydR mutant overproduces the cytochrome bd terminal oxidase. Using two-dimensional polyacrylamide gel electrophoresis, we showed that beta-ketothiolase and acetoacetyl-CoA reductase were also overexpressed in the cydR mutant. Fumarase C and a coenzyme A transferase, possibly succinyl-SCoA transferase, were decreased in this mutant. Enzyme assays confirmed the elevated beta-ketothiolase and acetoacetyl-CoA reductase activities in this mutant. The cydR mutant accumulated poly-beta-hydroxybutyrate throughout the exponential growth phase, unlike the wild-type strain that only accumulated poly-beta-hydroxybutyrate during stationary phase. The results demonstrate that CydR controls poly-beta-hydroxybutyrate synthesis in A. vinelandii.

Azotobacter vinelandii↗
PubMed2001

Isolation and characterization of a new poly(3-hydroxybutyrate)-degrading, denitrifying bacterium from activated sludge.

A new denitrifying chemoorganotrophic bacterium capable of aerobic and anaerobic degradation of poly(3-hydroxybutyrate) (PHB) and poly(3-hydroxybutyrate-co-hydroxyvalerate) (PHBV) was isolated from activated sludge. A phylogenetic analysis based on 16S rDNA sequences indicated that the new isolate is a member of the beta subclass of the Proteobacteria and represents a distinct line of descent within the family Comamonadaceae. During denitrifying growth with 3-hydroxybutyrate, PHB, or PHBV as the sole carbon source, the isolate reduced nitrate to N2 without appreciable accumulation of nitrite and nitrous oxide as intermediate products. Kinetic analyses of the denitrification with different grades of PHBV indicated that approximately 0.7 g of PHBV was required to reduce 1 g of NO3-. A high denitrification rate (19 mg N-NO3- removed h(-1) x g(-1) dry wt of cells) was found with PHBV as the electron donor.

Anaerobiosis↗
PubMed1982

Accumulation of poly-beta-hydroxybutyrate in Spirulina platensis.

Poly-beta-hydroxybutyrate has been identified in the cyanobacterium Spirulina platensis. The addition of reduced carbon compounds to the growth medium was not required for poly-beta-hydroxybutyrate accumulation. Poly-beta-hydroxybutyrate accumulated during exponential growth to 6% of the total dry weight and then decreased during the stationary phase.

Cyanobacteria↗
PubMed2001

Connection between poly-beta-hydroxybutyrate biosynthesis and growth on C(1) and C(2) compounds in the methylotroph Methylobacterium extorquens AM1.

Several DNA regions containing genes involved in poly-beta-hydroxybutyrate (PHB) biosynthesis and degradation and also in fatty acid degradation were identified from genomic sequence data and have been characterized in the serine cycle facultative methylotroph Methylobacterium extorquens AM1. Genes involved in PHB biosynthesis include those encoding beta-ketothiolase (phaA), NADPH-linked acetoacetyl coenzyme A (acetyl-CoA) reductase (phaB), and PHB synthase (phaC). phaA and phaB are closely linked on the chromosome together with a third gene with identity to a regulator of PHB granule-associated protein, referred to as orf3. phaC was unlinked to phaA and phaB. Genes involved in PHB degradation include two unlinked genes predicted to encode intracellular PHB depolymerases (depA and depB). These genes show a high level of identity with each other at both DNA and amino acid levels. In addition, a gene encoding beta-hydroxybutyrate dehydrogenase (hbd) was identified. Insertion mutations were introduced into depA, depB, phaA, phaB, phaC, and hbd and also in a gene predicted to encode crotonase (croA), which is involved in fatty acid degradation, to investigate their role in PHB cycling. Mutants in depA, depB, hbd, and croA all produced normal levels of PHB, and the only growth phenotype observed was the inability of the hbd mutant to grow on beta-hydroxybutyrate. However, the phaA, phaB, and phaC mutants all showed defects in PHB synthesis. Surprisingly, these mutants also showed defects in growth on C(1) and C(2) compounds and, for phaB, these defects were rescued by glyoxylate supplementation. These results suggest that beta-hydroxybutyryl-CoA is an intermediate in the unknown pathway that converts acetyl-CoA to glyoxylate in methylotrophs and Streptomyces spp.

Acetyl-CoA C-Acyltransferase↗
PubMed1979

Specific methods for the determination of radioactivity in D-(-)-3-hydroxybutyrate in blood plasma.

Two simple, high-yield rapid methods with good reproducibility are described, which permit the determination of radioactivity in plasma D-(-)-3-hydroxybutyrate. The compound is converted to acetoacetate, using a modified enzymatic method. In procedure 1, acetoacetate is reacted with 2,4-dinitrophenylhydrazine; the resulting hydrazone is oxidised by means of a sample oxidiser, and the product 14CO2 is collected in scintillation liquid and counted. In procedure 2, a Conway microdiffusion unit is applied. The acetoacetate is decarboxylated to acetone in the presence of o-phenylenediamine, and the acetone is then diffused into semicarbazide solution. This solution, containing the semicarbazone derivative of labelled acetone, is transferred to liquid scintillation and counted. In both procedures the radioactivity is measured simultaneously in a separate sample which was not subjected to the enzymatic conversion of D-(-)-3-hydroxybutyrate. The difference in radioactivity between the two samples is attributed to labelled (D-(-)-3-hydroxybutyrate.

Carbon Radioisotopes↗
PubMed2004

4-methylpyrazole decreases 1,4-butanediol toxicity by blocking its in vivo biotransformation to gamma-hydroxybutyric acid.

1,4-Butanediol (1,4-BD), a prodrug converted in vivo to gamma-hydroxybutyric acid by alcohol dehydrogenase, has resulted in life-threatening overdoses and deaths. We investigated whether 4-methylpyrazole (4-MP), an alcohol dehydrogenase antagonist, can be used as an antidote in a murine model of 1,4-BD overdose. CD-1 mice were overdosed with 1,4-BD, 600 mg/kg i.p. Mice then received 4-MP, 25 mg/kg i.p., or control injections after 1 min, 5 min, and symptom appearance. Mice were then evaluated for toxicity by the righting reflex and rotarod test every 10 min after intervention. When 4-MP was administered 1 and 5 min after 1,4-BD overdose, mice completely maintained their righting reflex. Conversely, control mice lost their righting reflex for 110 and 130 min, respectively (P < 0.05). When 4-MP was administered after symptomatic 1,4-BD overdose, mice lost their righting reflex but recovered it by 60 min. Conversely, control mice lost their righting reflex and recovered it by 140 min (P < 0.05). When 4-MP was administered at 1 min after 1,4-BD overdose, mice never failed the rotarod test. Conversely, control mice failed the rotarod test for 210 min (P < 0.05). When 4-MP was administered 5 min after 1,4-BD and after symptomatic 1,4-BD overdose, mice failed the rotarod test for 100 and 110 min, respectively. Conversely, control mice failed the rotarod test for 210 and 180 min, respectively (P < 0.05). In addition, treatment of mice with 4-MP significantly attenuated increases in blood gamma-hydroxybutyric acid concentrations and prevented loss of the righting reflex and failure of the rotarod test. In this murine model of 1,4-BD overdose, 4-MP conferred antidotal effects by inhibiting alcohol dehydrogenase-mediated biotransformation of 1,4-BD to gamma-hydroxybutyric acid.

Animals↗
PubMed1975

Patterns of free fatty acids, glycerol, D-beta-hydroxybutyrate and insulin in pregnant women and their newborn infants. Effects of a low and a high insulin response to glucose in the mothers.

Twenty-eight healthy women, 17 with high and 11 with low insulin response to glucose but with normal glucose tolerance, were followed throughout pregnancy. Plasma FFA, glycerol and D-beta-hydroxybutyrate as well as plasma insulin and glucose in blood were determined before and during a glucose infusion test (GIT) in each trimester and after pregnancy. In 13 infants of high insulin responders (IHR) and 10 infants of low responders (ILR) an intravenous glucose tolerance test (IVGTT) was performed, and the above lipid parameters were studied at birth and during the IVGTT. The low responder group was postulated to consist mainly of prediabetic individuals (8). Their infants have previously been shown to have an increased glucose assimilation rate at IVGTT (12, 13), as has been shown for infants of diabetic mothers. There was little difference between the two groups of mothers except for the insulin levels during the GIT in non-pregnant and early pregnant subjects, which were considerably lower in the low responders. They all had decreased fasting levels of FFA, glycerol, and D-beta-hydroxybutyrate in mid-pregnancy and normal values in late pregnancy. The ILR showed the same changes in FFA and glycerol as the IHR, but their D-beta-hydroxybutyrate levels were higher at birth than those of the IHR and lower after birth. Another difference found, was the correlation between birth weight and fasting insulin (and to some extent the insulin level at birth) in the ILR group, which was not found in the IHR. Apart from those differences the ILR and the IHR seemed to handle their fat metabolism in a similar way in the early neonatal perinatal period.

Adult↗