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PubMed2005

Clinical, pathological, and biochemical studies in a patient with propionic acidemia and fatal cardiomyopathy.

A patient diagnosed at 9 months with a milder form of propionic acidemia was functioning at a near normal intellectual level and a normal neurological level at age 8. After 2-week history of feeling "poorly" but functioning normally, she became acutely ill and succumbed to heart failure and ventricular fibrillation in 12 h. At post-mortem the heart was hypertrophied and had low carnitine levels, despite carnitine supplementation and repeatedly normal plasma carnitine levels. The findings in this patient provide a possible mechanism for the cardiac complications that are becoming more apparent in propionic acidemia.

Amino Acid Metabolism, Inborn Errors↗
PubMed2001

Effects of methylmalonic and propionic acids on glutamate uptake by synaptosomes and synaptic vesicles and on glutamate release by synaptosomes from cerebral cortex of rats.

Neurological dysfunction is common in patients with methylmalonic and propionic acidemias. However, the mechanisms underlying the neuropathology of these disorders are far from understood. In the present study we investigated the in vitro effects of methylmalonic (MMA) and propionic (PA) acids at various concentrations (1 microM-5 mM) on three parameters of the glutamatergic system, namely the basal and potassium-induced release of L-[3H]glutamate by synaptosomes, Na+-dependent L-[3H]glutamate uptake by synaptosomes and Na+-independent L-[3H]glutamate uptake by synaptic vesicles from cerebral cortex of male adult Wistar rats. The results showed that MMA significantly increased potassium-induced but not basal L-[3H]glutamate release from synaptosomes with no alteration in synaptosomal L-[3H]glutamate uptake. A significant reduction of L-[3H]glutamate incorporation into vesicles caused by MMA was also detected. In contrast, PA had no effect on these parameters. These findings indicate that MMA alters the glutamatergic system. Although additional studies are necessary to evaluate the importance of these observations for the neuropathology of methylmalonic acidemia, it is possible that the effects elicited by MMA may lead to excessive glutamate concentrations at the synaptic cleft, a fact that may explain previous in vivo and in vitro findings associating MMA with excitotoxicity.

Animals↗
PubMed2000

Methylmalonic and propionic acids increase the in vitro incorporation of 32P into cytoskeletal proteins from cerebral cortex of young rats through NMDA glutamate receptors.

In this study we investigated the effects of methylmalonic acid (MMA) and propionic acid (PA) on the phosphorylation of cytoskeletal proteins of cerebral cortex of rats. Slices of tissue were incubated with 32P-orthophosphate in the presence or absence of glutamate, MMA, PA and ionotropic or metabotropic glutamate receptor agonists. The cytoskeletal fraction was isolated and the radioactivity incorporated into the cytoskeletal proteins was measured. Results demonstrated that the acids, glutamate and NMDA increased the phosphorylation of the proteins studied. However, this effect was not observed for non-NMDA ionotropic agonists or metabotropic agonists. Experiments using glutamate receptor antagonists confirmed that MMA and PA at the same concentrations as found in tissues from propionic or methylmalonic acidemic children increase the phosphorylation of cytoskeletal proteins, possibly via NMDA glutamate receptors. Therefore, it is feasible that these findings may be related to the neurological dysfunction characteristic of these disorders.

2-Amino-5-phosphonovalerate↗
PubMed1996

Primary treatment of propionic acidemia complicated by acute thiamine deficiency.

Propionic acidemia is often manifested during the neonatal period with vomiting, failure to thrive, lethargy, and hyperammonemic coma when catabolism is prolonged. Mild lactic acidosis frequently accompanies metabolic decompensation. We present two patients with propionic acidemia whose initial manifestation was complicated by severe lactic acidosis caused by thiamine deficiency, which resulted from an inadequate supply of, and an increased need for, thiamine during metabolic stress. To prevent acute thiamine deficiency, we propose early vitamin supplementation during treatment of any severe metabolic decompensation accompanied by insufficient food intake.

Acute Disease↗
PubMed1986

Carnitine reduces fasting ketogenesis in patients with disorders of propionate metabolism.

Patients with disorders of propionate metabolism have low plasma levels of free carnitine and excrete higher than normal quantities of esterified carnitine. The response to a 19 h fast was assessed as a physiological index of carnitine deficiency. In patients with propionic acidaemia and methylmalonic acidaemia a substantial ketogenesis developed in response to fasting. Supplementation with L-carnitine significantly reduced this ketogenic response.

Carnitine↗
PubMed1998

Propionic and methylmalonic acids inhibit the in vitro phosphorylation of a 85 kDa cytoskeletal protein from cerebral cortex of rats.

In this study we examine the action of methylmalonic (MMA) and propionic (PA) acids, metabolites which accumulate in methylmalonic and propionic acidemias respectively, on the endogenous phosphorylating system associated with the cytoskeletal fraction of cerebral cortex of young rats. Chronic treatment with PA and treatment of tissue slices with MMA or PA are effective in decreasing the in vitro phosphorylation into a 85 kDa cytoskeletal associated protein. We tested the effect of the acids on the endogenous kinase activities by using specific kinase activators and inhibitors. Results demonstrated that the acids interfere with the endogenous cAMP-dependent and Ca2+/calmodulin-dependent kinase activities. Furthermore, in vitro dephosphorylation of the 85 kDa protein was totally inhibited in brain slices treated with the acids. Considering the importance of protein phosphorylation to cellular function, we speculate that alteration in the phosphorylating level of cytoskeletal associated phosphoproteins induced by MMA and PA treatments may somehow be involved in steps leading to brain damage.

Animals↗
PubMed2002

Effect of thermal injury on relative anaplerosis and gluconeogenesis in the rat during infusion of [U-13C] propionate.

A new approach for the analysis of hepatic metabolism after burn injury is introduced. Relative anaplerotic, pyruvate recycling and gluconeogenic fluxes were measured by 13C NMR isotopomer analysis of blood glucose from rats with 40% body surface area injury, and from rats exposed to sham injury. A short chain fatty acid, [U-13C] propionate which is avidly extracted by the liver, was infused intravenously to deliver 13C into the citric acid cycle. There was no difference in the multiplets detected in the glucose carbon-2 (C-2) anomer from blood or liver after 45 or 60 min of infusion of propionate, indicating that steady-state isotopic conditions were achieved. Gluconeogenesis relative to citric acid cycle flux was not altered by burn injury; in both sham and burn groups the rate of glucose production was about equal to flux through citrate synthase. In the sham group of animals the rate of entry of carbon skeletons into the citric acid cycle was about four times citric acid cycle flux in animals after thermal injury. Similarly, flux through pyruvate kinase (again relative to citrate synthase) was significantly increased in burn injury.

Animals↗
PubMed1999

18Fluoro-2-deoxyglucose (18FDG) PET scan of the brain in propionic acidemia: clinical and MRI correlations.

The clinical data and the imaging findings of the positron emission tomography (PET) and the magnetic resonance imaging (MRI) studies in five patients, previously diagnosed to have propionic acidemia, were retrospectively reviewed. The patients were all normal at birth. The first clinical signs, typically hypotonia and failure to thrive, appeared during the first 2 years of life. With progression of the disease, the neurological findings consisted of variable degrees of dementia and extrapyramidal symptoms, notably dystonia, choreoathetosis and rigidity of variable degrees. Initial cerebral PET and MRI studies were normal. Follow-up MRI examinations showed progressive basal ganglia degeneration, with evidence of atrophy and signal abnormalities within the caudate nuclei and the putamina. The thalamic structures were normal. The PET studies demonstrated increased uptake in the basal ganglia and thalami, followed by decreased uptake in the basal ganglia at a later stage of the disease. The structural (MRI) and the functional (PET) studies of the brain were found to be complementary in the evaluation of propionic acidemia, and were in good correlation with the clinical findings.

Brain↗
PubMed2002

2-Amino-3-(3-hydroxy-1,2,5-thiadiazol-4-yl)propionic acid: resolution, absolute stereochemistry and enantiopharmacology at glutamate receptors.

In order to identify new subtype-selective (S)-glutamate (Glu) receptor ligands we have synthesized (RS)-2-amino-3-(3-hydroxy-1,2,5-thiadiazol-4-yl)propionic acid [(RS)-TDPA]. Resolution of (RS)-TDPA by chiral chromatography was performed using a Crownpac CR(+) column affording (R)- and (S)-TDPA of high enantiomeric purity (enantiomeric excess=99.9%). An X-ray crystallographic analysis revealed that the early eluting enantiomer has R-configuration. Both enantiomers showed high affinity as well as high agonist activity at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors, determined using a [(3)H]AMPA binding assay and an electrophysiological model, respectively. The affinities and agonist activities obtained for (R)-TDPA (IC(50)=0.265 microM and EC(50)=6.6 microM, respectively) and (S)-TDPA (IC(50)=0.065 microM and EC(50)=20 microM, respectively) revealed a remarkably low AMPA receptor stereoselectivity, (S)-TDPA showing the highest affinity and (R)-TDPA the most potent agonist activity. In addition, (S)-TDPA was shown to interact with synaptosomal Glu uptake sites displacing [(3)H](R)-aspartic acid (IC(50 ) approximately 390 microM). An enantiospecific and subtype-selective agonist activity was observed for (S)-TDPA at group I metabotropic Glu (mGlu) receptors (EC(50)=13 microM at mGlu(5) and EC(50)=95 microM at mGlu(1)).

Animals↗
PubMed1998

Synthesis of 1-[11C]methylpiperidin-4-yl propionate ([11C]PMP) for in vivo measurements of acetylcholinesterase activity.

Synthesis of 1-[11C]methylpiperidin-4-yl propionate ([11C]PMP), an in vivo substrate for acetylcholinesterase, is reported. An improved preparation of 4-piperidinyl propionate (PHP), the immediate precursor for radiolabeling, was accomplished in three steps from 4-hydroxypiperidine by (a) protection of the amine as the benzyl carbamate, (b) acylation with propionyl chloride, and (c) deprotection of the carbamate by catalytic hydrogenation. The final product was obtained in an overall 82% yield. Reaction of the free base form of PHP with [11C]methyl trifluoromethanesulfonate at room temperature in N,N-dimethylformamide, followed by high performance liquid chromatography (HPLC) purification, provided [11C]PMP in 57% radiochemical yield, > 99% radiochemical purity, and > 1500 Ci/mmol at the end of synthesis. The total synthesis time from end-of-bombardment was 35 min. [11C]PMP can thus be reliably prepared for routine clinical studies of acetylcholinesterase in human brain using positron emission tomography.

Acetylcholinesterase↗
PubMed2002

Rapid and sensitive method for prenatal diagnosis of propionic acidemia using stable isotope dilution gas chromatography-mass spectrometry and urease pretreatment.

Propionic acidemia is one of the most frequent inborn errors of metabolism caused by a deficiency of propionyl-CoA carboxylase. Methylcitric acid, a key indicator of this disorder, is increased in amniotic fluid when a fetus is affected. Therefore, the direct chemical analysis of cell-free amniotic fluid for methylcitric acid, using stable isotope dilution gas chromatography-mass spectrometry, was carried out for the prenatal diagnosis of propionic acidemia. We developed a simple, highly sensitive, and accurate method for quantitation of this polar methylcitric acid in amniotic fluids by applying a simplified urease pretreatment which we devised earlier for urine. As the recovery of methylcitric acid from amniotic fluid was as high as 91% with a coefficient of variation lower than 3% in this procedure, only 0.02 ml of sample was required for the analysis of the affected fetus. This new procedure takes 1 h for sample pretreatment, including derivatization, and 15 min for GC-MS measurement and provides final results within 1.5 h.

Amniotic Fluid↗
PubMed2005

The protonation state of a heme propionate controls electron transfer in cytochrome c oxidase.

In cytochrome c oxidase (CcO), exergonic electron transfer reactions from cytochrome c to oxygen drive proton pumping across the membrane. Elucidation of the proton pumping mechanism requires identification of the molecular components involved in the proton transfer reactions and investigation of the coupling between internal electron and proton transfer reactions in CcO. While the proton-input trajectory in CcO is relatively well characterized, the components of the output pathway have not been identified in detail. In this study, we have investigated the pH dependence of electron transfer reactions that are linked to proton translocation in a structural variant of CcO in which Arg481, which interacts with the heme D-ring propionates in a proposed proton output pathway, was replaced with Lys (RK481 CcO). The results show that in RK481 CcO the midpoint potentials of hemes a and a(3) were lowered by approximately 40 and approximately 15 mV, respectively, which stabilizes the reduced state of Cu(A) during reaction of the reduced CcO with O(2). In addition, while the pH dependence of the F --> O rate in wild-type CcO is determined by the protonation state of two protonatable groups with pK(a) values of 6.3 and 9.4, only the high-pK(a) group influences this rate in RK481 CcO. The results indicate that the protonation state of the Arg481 heme a(3) D-ring propionate cluster having a pK(a) of approximately 6.3 modulates the rate of internal electron transfer and may act as an acceptor of pumped protons.

Animals↗
PubMed2006

Functional implications of the propionate 7-arginine 220 interaction in the FixLH oxygen sensor from Bradyrhizobium japonicum.

BjFixL from Bradyrhizobium japonicum is a heme-based oxygen sensor implicated in the signaling cascade that enables the bacterium to adapt to fluctuating oxygen levels. Signal transduction is initiated by the binding of O(2) to the heme domain of BjFixL, resulting in protein conformational changes that are transmitted to a histidine kinase domain. We report structural changes of the heme and its binding pocket in the Fe(II) deoxy and Fe(III) met states of the wild-type BjFixLH oxygen sensor domain and four mutants of the highly conserved residue arginine 220. UV-visible, electron paramagnetic resonance, and resonance Raman spectroscopies all showed that the heme iron of the R220H mutant is unexpectedly six-coordinated at physiological pH in the Fe(III) state but undergoes pH- and redox-dependent coordination changes. This behavior is unprecedented for FixL proteins, but is reminiscent of another oxygen sensor from E. coli, EcDos. All mutants in their deoxy states are five-coordinated Fe(II), although we report rupture of the residue 220-propionate 7 interaction and structural modifications of the heme conformation as well as propionate geometry and flexibility. In this work, we conclude that part of the structural reorganization usually attributed to O(2) binding in the wild-type protein is in fact due to rupture of the Arg220-P7 interaction. Moreover, we correlate the structural modifications of the deoxy Fe(II) states with k(on) values and conclude that the Arg220-P7 interaction is responsible for the lower O(2) and CO k(on) values reported for the wild-type protein.

Arginine↗
PubMedDate not supplied

Study and mathematical modeling of the production of propionic acid by Propionibacterium acidipropionici immobilized in a stirred tank fermentor.

A mathematical model was developed that describes production of propionic acid by fermentation of sweet whey with Propionibacterium acidipropionici immobilized in calcium polygalacturonate beads in a fermentor-type stirred tank. This mathematical model is constituted by a partial differential equations system, which fits consumption, production, growth and internal diffusion rates in the support. Fermentation was experimentally studied with free cells and immobilized cells, effective diffusivities of lactose and propionic acid were estimated in the support, and typical parameters of the model were obtained by nonlinear regression of the experimental data. The variance analysis shows that the combination of micro(max) and K(d) parameters is the source of variation most significative, also they were found to be the most sensitive parameters of the model. Finally, an effectiveness factor was calculated in order to assess the effect of mass transfer on the overall reaction rate observed.

Cell Division↗
PubMedDate not supplied

Procedure for the parallel preparation of 3-imidazo[1,2-a]pyridin-3-yl-propionic acid derivatives involving Meldrum's acid.

We describe here an efficient and versatile method for the preparation of 3-imidazo[1,2-a]pyridin-3-yl-propionic acids involving, as a key step, a three-component Michael-type reaction. The extended and validated procedure allowed us to prepare various acids with three diversity points. The method was easily adaptable for parallel synthesis and an approximately 2000-membered 3-imidazo[1,2-a]pyridin-3-yl-propionic acid amide library was prepared in a semiautomated manner.

Combinatorial Chemistry Techniques↗
PubMed1995

Amphoteric drugs. 3. Synthesis and antiallergic activity of 3-[(5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11- ylidene)piperidino]propionic acid derivatives and related compounds.

An important approach to the design of antiallergic agents with reduced penetration into the central nervous system (CNS) is described. A series of 3-[(5,11- dihydro[1]benzoxepino[4,3-b]-pyridin-11-ylidene)piperidino]propion ic acid derivatives (31-47) and related compounds (48-54) were synthesized and evaluated for antiallergic activity and penetration of a compound into the CNS in comparison with the corresponding 6H-dibenz[b,e]oxepin derivative (3). Combination of zwitterionization and introduction of a pyridine component resulted in an increase in antiallergic activity and a great reduction of penetration into the CNS, which was evaluated by the selectivity (B/A) of antihistaminic activities in the central system [ID50 value (B) for ex vivo H1 binding to mouse brain membranes] and in the peripheral system [ED50 value (A) for inhibitory effect on histamine-induced increase in vascular permeability in mice]. This surprising reduction of penetration into the CNS could be considered on the basis of an increase in hydrophilicity caused by both of the zwitterionization and the introduction of a pyridine component. 3-[4-(8-Fluoro-5,11-dihydro[1]benzoxepino[4,3- b]pyridin-11-ylidene)piperidino]propionic acid (33) exhibited a strong antiallergic effect in various experimental models and very low penetration into the CNS. Compound 33 (HSR-609) is now under clinical trial as a promising antiallergic agent with greatly reduced penetration into the CNS.

Animals↗
PubMed1977

Dibenztroponeacetic and -propionic acids. Potent new antiinflammatory agents.

The syntheses and antiinflammatory assays of some dibenztroponeacetic and -propionic acids and derivatives are described. The most potent compound, d-2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, has a potency of ca, 70 times phenylbutazone in the rat carrageenan paw assay and two to three times indomethacin in long-term animal assays. Some beta-dialkylaminoethyl esters of this compound also show high antiinflammatory activity.

Acetates↗
PubMed1997

Synthesis of a series of potent and orally bioavailable thrombin inhibitors that utilize 3,3-disubstituted propionic acid derivatives in the P3 position.

As part of an effort to prepare efficacious and orally bioavailable analogs of the previously reported thrombin inhibitors 1a, b, we have synthesized a series of compounds that utilize 3,3-disubstituted propionic acid derivatives as P3 ligands. By removing the N-terminal amino group, the general oral bioavailability of this class of compounds was enhanced without excessively increasing the lipophilicity of the compounds. The overall properties of the molecules could be drastically altered depending on the nature of the groups substituted onto the 3-position of the P3 propionic acid moiety. A number of the compounds exhibited good oral bioavailability in rats and dogs, and numerous compounds were efficacious in a rat FeCl3-induced model of arterial thrombosis. Compound 7, the 3,3-diphenylpropionic acid derivative, showed the best overall profile of in vivo and in vitro activity. Molecular modeling studies suggest that these compounds bind in the thrombin active site in a manner essentially identical to that previously reported for compound 1a.

Administration, Oral↗