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Reexamination of serum from a child thought to have died of ethylene glycol poisoning showed that the child had methylmalonic acidemia. The gas chromatographic peak identified as ethylene glycol by a clinical laboratory was actually due to propionic acid. Proof of a metabolic basis for the child's symptoms eventually exonerated his mother of the charge of murder.
Although propionic acidemia and methylmalonic acidemia, two disorders of branched-chain amino acid metabolism often complicated by chronic anorexia and vomiting, are not usually treated with parenteral nutrition for fear of amino acid overload and exacerbation of biochemical derangements, we gave long-term parenteral nutrition to two critically ill patients with these disorders. Health and growth were restored, and there was minimal production of abnormal metabolites. The dramatic clinical and biochemical improvement of these patients bolsters the concept that most of the toxic metabolites produced in these diseases are not related to the administered load of nutrient precursors, but rather to endogenous turnover of amino acids, particularly during a chronic catabolic state. Suppression of catabolism can produce striking biochemical and clinical improvement. With appropriate monitoring, parenteral nutrition can be used safely in the management of patients with these disorders.
Cypha, propionic acid, 2-(4-methoxyphenol) salt, is a commercially available sweet taste inhibitor used in food products. The present study examined whether or not Cypha blocked the sweet taste response of rats. This was accomplished by measuring the consummatory response of rats to sucrose solutions during short-term taste tests. Nondeprived female rats were given 2-bottle choice tests (10 min) with different sucrose solutions. When given the choice between 10% sucrose and 10% sucrose containing Cypha at concentrations of 0.0125% to 0.10%, the rats showed no reliable preference for one or the other solution. In other tests, they reliably preferred 10% sucrose to 8%, 6%, and 4% sucrose, demonstrating the sensitivity of the behavioral test. To confirm the activity of the Cypha sample, a second experiment was conducted with human subjects. Using a visual analogue scale, the subjects rated the sweetness of various sucrose solutions (0% to 10%) and 10% sucrose solutions containing Cypha at concentrations of 0.0125% or 0.025%. Cypha reliably reduced the sweetness ratings of the sucrose solution. The 10% sucrose + 0.0125% Cypha solution was judged isosweet to 2.3-2.9% sucrose, and the 10% sucrose + 0.025% Cypha solution was rated as isosweet to a 1.2% sucrose solution. Taken together, these data confirm prior reports on the sweetness-inhibitory effect of Cypha in humans and demonstrate its ineffectiveness in rats. These findings are consistent with other reported differences between rats and humans in their response to other sweetness inhibitors, as well as to artificial sweeteners.
The characteristics of different types of MnO(2) catalytic ozonation of sulfosalicylic acid (SSal) and propionic acid (PPA) have been investigated in this paper. The experimental results show the dependence of catalytic activity of MnO(2) on organic compounds and the pH of solutions, but it is independent on the type of MnO(2). For example, three types of MnO(2) have not any catalytic activity when ozonation of PPA under the condition of this experiment. All MnO(2) catalytic ozonation of SSal at pH=1.0 have a greater total organic carbon removal than ozonation alone has, however, at pH=6.8 and 8.5, catalytic efficiency is not observed. Furthermore, the batch experimental results indicate that there are no direct relationship between the activity of metal oxide catalytic decomposition of ozone and that of its catalytic degradation of organic compounds.
140 strains of anaerobic, Gram-negative, propionate-negative, non-pigmented rods (Bacteroides oralis group) were isolated from normal flora and from clinical specimens. They were characterized by physiological tests, gas chromatography of the acid end products, and determination of the G + C content of their DNA. In addition, their distribution in the various biotopes of the human body (oropharyngeal tract, genitourinary tract, and gut) and in clinical specimens was investigated. The strains could be assigned to the recently described species Bacteroides denticola, B. buccae, B. buccalis, and B. oris, or to B. bivius, B. disiens and B. oralis. In the investigated group, especially B. bivius exhibits an antibiotic resistance--particularly against the beta-lactam antibiotics--comparable to that of B. fragilis.
A new, p-carborane containing analog of tyrosine, namely 3-[1-hydroxy-1,12-dicarba-closo-dodecaboran(12)-12-yl]propionic acid was prepared from p-carborane in five steps involving hydroxypropylation of O-protected 1-hydroxy-p-carborane as the key transformation. The simple tyrosine mimetic can function as a hydrophobic surrogate for an N-terminal tyrosine residue in insect and mammalian neuropeptides to enhance the lipophilicity, and therefore, the cuticle and/or tissue permeability properties of mimetic analogs.
A toxicologic and dermatologic review of linalyl propionate when used as a fragrance ingredient is presented.
The cyclobutylglycine (+/-)-2-amino-2-(3-cis and trans-carboxycyclobutyl-3-(9-thioxanthyl)propionic acid) (LY393053) has been identified as a functionally potent metabotropic glutamate receptor antagonist. It is most potent on the two group I metabotropic glutamate receptors, 1alpha and 5alpha, with IC50 values of 1.0+/-0.4 microM and 1.6+/-1.4 microM, respectively. In this study, LY393053 has also been evaluated electrophysiologically on native group I metabotropic glutamate receptors in an in vitro spinal cord preparation as well as behaviourally, in a mouse model of visceral pain. LY393053 dose-dependently antagonised group I agonist, (RS)-3, 5-dihydroxyphenylglycine, or a broad-spectrum agonist (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid-induced depolarisation of spinal motoneurons. The apparent Kd values were estimated to be 0.3 microM against (RS)-3, 5-dihydroxyphenylglycine-induced depolarisation and 0.5 microM against (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid-induced depolarisation, respectively. On the other hand, the dorsal root-ventral root potential elicited at 8 x threshold was depressed by LY393053 with IC50 values of 9.0+/-0.7 microM and 12.7+/-1.7 microM on monosynaptic and polysynaptic responses, respectively. When investigated using the mouse acetic acid writhing test, LY393053 showed significant analgesic effects at doses of 1-10 mg/kg intraperitoneally. An ED50 value of 6.0 mg/kg was obtained in this test. By revealing a potent effect of LY393053 in antagonising the native group I metabotropic receptor-mediated responses in the spinal cord in rodents, and an antinociceptive efficacy in a mouse visceral pain model, these results, therefore, provide additional evidence in support of the analgesic potential of metabotropic glutamate receptor antagonists.
Propionyl CoA carboxylase (PCC) is a mitochondrial, biotin-dependent enzyme involved in the catabolism of amino acids, odd-chained fatty acids and other metabolites. PCC is composed of two equal subunits, alpha and beta, which are encoded by two separate genes at two distinct human loci. Mutations of either gene in humans results in propionic acidemia (PA). To identify the mouse cDNA for the propionyl CoA carboxylase beta-subunit (pccb), we have screened the mouse EST database using the human sequence. The murine mRNA transcript is approximately 2.3 kb, nearly 500 bps larger than the human approximately 1.8 kb transcript. A PAC genomic DNA clone from the mouse was also isolated and used to generate probes and PCR primers for mapping the pccb locus in the mouse. Both the C57Bl/6JEi and Spret/Ei alleles for regions flanking the pccb gene were sequenced to identify RFLPs. The Jackson Laboratory BSS and BSB backcross panel DNAs were then analyzed using a DdeI polymorphism placing the pccb locus on mouse chromosome 9. Northern blots of adult tissue show that the pccb gene is broadly expressed in the mouse. The approximately 2.3 kb transcript is most abundantly expressed in the kidney, liver, small intestine and stomach tissues.
Previous studies have shown that the short-chain fatty acids acetate (Ac) and propionate (Pr) enhance the absorption of calcium (Ca) in the rectum and distal colon of humans, with Pr being more effective than Ac. To investigate the effect of Ac and Pr on the kinetics of Ca absorption from the human rectum and distal colon, six healthy subjects were studied. Solutions containing various concentrations of CaCl2.H2O with 56.3 mmol/L Ac, Pr, or NaCl were rectally infused to each subject. Rectal fluid was sampled at the end of the infusion (0 min), and 30 min later colonic contents were collected. Ca absorption for all treatments increased linearly with Ca concentration. For Ca + NaCl, the slope of regression line was 62 mumol.mmol-1.L Ca. With Ac + Ca, the slope of Ca absorption increased significantly to 113 mumol.mmol-1.L Ca, and with Pr + Ca, the slope increased to 159 mumol.mmol-1.L (P = 0.043 versus Ac + Ca) Ac and Pr absorption were increased by Ca. The data suggest that, over a physiologic range of Ca concentration, in the absence or presence of Ac and Pr, Ca is absorbed in the human rectum and distal colon by a non-saturable diffusion process, and that Ca absorption is enhanced by Ac and Pr. The data also suggest that both Ac and Pr absorption is stimulated by Ca.
Propionic acidemia (PA, MIM 232000 and 232050) is caused by a deficiency of mitochondrial biotin-dependent propionyl-CoA carboxylase (PCC, EC 6.4.1.3), a heteropolymeric enzyme composed of alpha and beta subunits, which are encoded by the PCCA and PCCB genes, respectively. The PCCA protein (alpha subunit) is responsible for the formation of carboxybiotin upon hydrolysis of ATP and contains a C-terminal biotin-binding domain and a biotin carboxylase domain, defined by homology with other biotin-dependent carboxylases, some of them characterized structurally. More than 24 mutations have been found in the PCCA gene in patients with PA, among them 14 missense mutations and one in-frame deletion, for which the precise molecular effect is unknown. In this study, we have established the pathogenicity of 11 PCCA mutations (10 missense and an in-frame deletion) by expression studies in deficient fibroblasts and in a cell-free in vitro system, and analyzed the effect of each mutation on PCC activity, protein stability and domain structure. The results show that most mutant proteins show an increased turnover and are functionally deficient, suggesting that the structural alterations they cause are incompatible with normal assembly to produce a stable, functional PCC oligomer. These results are discussed in the context of the genotype-phenotype correlations in PCCA-deficient PA patients.
Propionic acidemia (PA) is a recessive disorder caused by a deficiency of propionyl-CoA carboxylase (PCC), a dodecameric enzyme composed of two different proteins alpha-PCC and beta-PCC, nuclear encoded by the PCCA and PCCB genes, respectively. Mutations in either gene cause PA and to date, up to 47 different allelic variations in the PCCB gene have been identified in different populations. In this work, we describe the expression studies of 18 PCCB sequence changes in order to elucidate their functional consequences. We have used a PCCB-deficient transformed fibroblast cell line to target the wild-type and mutant proteins to their physiological situation, analysing the effect of the mutations on PCC activity and protein stability. Of the 18 mutant proteins tested for activity, those carrying the L17M and A497V substitutions showed an activity similar to the wild-type one, which proves that these changes do not have any effect on protein activity. The other 16 mutant proteins exhibited two different functional behaviours, 3 retained substantial activity (K218R, R410W and N536D), and the remaining 13 proteins showed null or very low activity. Western blot analysis demonstrated instability only for the L519P, R512C and G112D mutant proteins. We have proved the pathogenicity of R67S, R165Q and G112D mutation in PCCB gene, expressed for the first time in this work. The information derived from the expression analysis is discussed in the phenotype and genotype context in order to improve the knowledge of this complex disease.
The inherited metabolic disease propionic acidemia (PA) can result from mutations in either of the genes PCCA or PCCB, which encode the alpha and beta subunits, respectively, of the mitochondrial enzyme propionyl CoA-carboxylase. In this work we have analyzed the molecular basis of PCCA gene defects, studying mRNA levels and identifying putative disease causing mutations. A total of 10 different mutations, none predominant, are present in a sample of 24 mutant alleles studied. Five novel mutations are reported here for the first time. A neutral polymorphism and a variant allele present in the general population were also detected. To examine the effect of a point mutation (M348K) involving a highly conserved residue, we have carried out in vitro expression of normal and mutant PCCA cDNA and analyzed the mitochondrial import and stability of the resulting proteins. Both wild-type and mutant proteins were imported into mitochondria and processed into the mature form with similar efficiency, but the mature mutant M348K protein decayed more rapidly than did the wild-type, indicating a reduced stability, which is probably the disease-causing mechanism.
The purpose of this study was to investigate the comparative efficacy and safety of equal doses of inhaled fluticasone propionate (FP) and inhaled budesonide (BUD) using their respective dry powder inhalers in a population of severe asthmatics requiring high doses of inhaled corticosteroid. This double-blind double-dummy parallel-group study compared the effects of 24 weeks of treatment with FP (2000 micrograms daily via a Diskhaler inhaler; Glaxo Wellcome, Evreux, France) and BUD (2000 micrograms daily via a Turbuhaler inhaler; Astra Pharmaceuticals, Rijswijka, Netherlands) on lung function and asthma exacerbations in 395 patients with asthma. FP was statistically significantly superior to BUD with respect to the percentage of symptom-free days (P = 0.02), the incidence of days free from rescue bronchodilator usage (P = 0.02) and the distribution of change in peak expiratory flow (PEF) expressed as a percentage of the predicted PEF (P = 0.04). During the treatment period FP was statistically significantly superior to BUD for change in forced expiratory volume in 1 sec (FEV1) at 8, 16 and 24 weeks, change in the median daytime symptom score during weeks 5-16, for incidence of symptom-free days and incidence of days free from rescue bronchodilator usage during weeks 17-24. There was no significant difference between FP and BUD with respect to the number of patients experiencing one or more asthma exacerbation (33.8 and 28.4% of patients, respectively). There was, however, evidence that the exacerbations were clinically less severe in patients treated with FP, in that the time to resolution was quicker (11.0 vs. 14.7 days; P = 0.035), mean duration of all exacerbations (for an individual patient) tended to be shorter (18.5 vs. 23.6 days; P = 0.12), the time off work was reduced (4.2 vs. 7.6 days; P = 0.012) and the lowest PEF recorded during the exacerbation was higher (301 vs. 263 l min-1; P = 0.07). There were no clinically relevant differences in the safety (serum cortisol levels, markers of bone turnover, adverse events) of FP and BUD at these microgram equivalent doses. The patients recruited into this study, in retrospect, probably had no need for such high doses of inhaled corticosteroid but, irrespective of this, FP at microgram equivalent doses showed evidence of superior efficacy to BUD with respect to lung function and severity of asthma exacerbations without producing any greater adverse systemic effect.
Modulations of alpha and aryl substitutions on 3-aryloxy propionic acid hydroxamates led to novel and potent inhibitors of MMP-2,3,9 and 13, and selectivity versus MMP-1.
To examine the effect of replacing the N-terminal amino group in opioid peptides with a methyl group on biological activity, a stereospecific synthesis of the tyrosine analogue (2S)-2-methyl-3-(2',6'-dimethyl-4'-hydroxyphenyl)-propionic acid (Mdp) was performed. The enkephalin analogue (2S)-Mdp-D-Ala-Gly-Phe-Leu-NH2 turned out to be a quite potent delta opioid antagonist and a somewhat less potent mu antagonist, indicating that a positively charged N-terminal amino group is not a conditio sine qua non for the binding of opioid peptides to delta and mu receptors but may be required for signal transduction.
Propionic acidemia (PA) is an autosomal recessive inborn error in the catabolism of methionine, isoleucine, threonine, and valine, odd-numbered chain length fatty acids and cholesterol. Clinical symptoms are very heterogeneous and present as a severe neonatal-onset or a late-onset form. It is caused by a deficiency of propionyl-CoA carboxylase (PCC, EC 6.4.1.3), a biotin-dependent enzyme that catalyzes the carboxylation of propionyl-CoA to D-methylmalonyl-CoA. PCC is a heteropolymeric enzyme composed of alpha- and beta-subunits. A greater heterogeneity is observed in the PCCA gene, while for the PCCB gene, a limited number of mutations is responsible for the majority of the alleles characterized in both Caucasian and Oriental populations. We identified eight Korean patients with PA by organic acid analysis confirmed in five patients by the PCC enzyme assay in the lymphoblasts. Two neonatal-onset patients showed undetectable PCC activities while three cases with residual enzyme activities had relatively late manifestations. In the molecular analysis, we identified five novel mutations, Y439C, 1527del3, 1357insT, IVS12-8T-->A, and 31del10, and one known mutation, T428I in PCCB gene. Alleleic frequency of T428I in Korean patients with PA was 56.3% in this study. Two neonatal-onset patients with null enzyme activities were homozygotes with 1527del3 and T428I, respectively. This finding implies that T428I and 1527del3 mutation could be responsible for their severe clinical courses and null enzyme activities. The mRNA of PCCB gene in T428I and 1527del3 homozygotes were normal but in Western blot analysis, the betaPCC-subunit was only absent in 1527del3 homozygote patient suggesting different molecular pathology.
The H-bonds in dimethylol propionic acid (DMPA) are investigated through the spectra changes between -150 and 180 degrees C, the spectra comparison before and after the pendent carboxylic group was neutralized as well as after DMPA was partly deuterated. Vibrational bands assignment is proposed based on the group frequency, band shape, intensity and the crystal structure. It was found that the highly crystallized DMPA is also highly H-bonded with the obvious crystal relating bands besides the typical H-bonded characteristic bands of both alcohols and carboxylic acids. The packing mode of carboxylic acid is similar to long-chain polymers to some extent but possesses the dimer spectra characteristic, especially still showing the prominent out-of-plane bending vibrational band gammaOH. The three hydroxyls, including the carboxylic hydroxyl, are all in the different H-bond states, showing three H-bonded hydroxyl bands with different frequencies. The frequency, intensity and shape of nuOH relates not only to OH bond length, but also to H-bond length as well as the bond angle. The H-bond in carboxylic hydroxyl is more sensitive to temperature changes and deuteration whereas the two primary hydroxyls form another H-bond pattern after DMPA was neutralized. It was also found that the possible overtone of gammaOH appears at lower temperature.