Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.1.1.41 (propionyl-CoA carboxylase)
344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The efficient microscale synthesis of [1-14C]propionyl-CoA from commercially available sodium [1-14C]-propionate using 1,1'-carbonyldiimidazole in yields of nearly 70% is reported for the first time. A substantial improvement in the process for making [1-14C]acetyl-CoA from sodium [1-14C]acetate was also achieved. Yields of greater than 90% were consistently obtained for the latter synthesis. The salt-free CoA-thioesters were obtained in homogenous form by reverse-phase HPLC. The products were judged to be pure by 1H NMR analysis: neither iso-CoA analogs nor contaminants frequently found in commercial samples could be detected. The samples of acetyl- and propionyl-CoA were shown to be radiochemically pure by HPLC and by analysis of the products of incubations with acetyl- and propionyl-CoA carboxylase. This highly efficient synthesis is a cost-effective method for the preparation of radiolabeled CoA thioesters and can easily be adapted to the production of other acyl-CoA analogs.
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PMID:Efficient synthesis of radiolabeled propionyl-coenzyme A and acetyl-coenzyme A. 771 64

Aerobic, glucose-limited chemostat of Saccharomyces cerevisiae CBS 8066 co-metabolized propionate when this compound was added to the reservoir medium. Co-metabolism of propionate led to an increase of the biomass and protein yields. Attempts to grow S. cerevisiae on propionate as a sole source of carbon and energy were not successful. Activities of propionyl-CoA synthetase in cell-free extracts were sufficient to account for the rates of propionate consumption observed in the chemostat cultures. Activities of propionyl-CoA carboxylase, a key enzyme of the methylmalonyl-CoA pathway of propionate metabolism, were negligible. In contrast, activities of 2-methylcitrate synthase, a key enzyme activity of the 2-methylcitrate pathway of propionate metabolism, increased substantially with increasing propionate-to-glucose ratios in the reservoir media, and were sufficient to account for the propionate consumption rates observed in the chemostat cultures. This suggested that the 2-methylcitrate pathway is the major pathway of propionate metabolism in S. cerevisiae. In the literature, labelling patterns observed after incubation of this yeast with [3-13C]propionate have been interpreted as evidence for channelling of tricarboxylic acid (TCA) cycle intermediates, possibly as a consequence of the organization of TCA cycle enzymes in a metabolon. However, this interpretation of 13C-labelling patterns rested on the assumption that propionate metabolism in S. cerevisiae occurs via the methylmalonyl-CoA pathway. Since the distribution of 13C in alanine reported in the literature is fully compatible with a major role of the 2-methylcitrate pathway in propionate metabolism, it cannot be interpreted as evidence for the existence of a TCA cycle metabolon in S. cerevisiae.
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PMID:Propionate metabolism in Saccharomyces cerevisiae: implications for the metabolon hypothesis. 791 43

Steady-state kinetics of the 220-kDa form of acetyl-CoA carboxylase (ACC220), as purified from mature pea seeds, have been investigated with respect to the substrate specificity and inhibition by quizalofop, a herbicide of the aryloxyphenoxypropionate type. The enzyme showed a dual specificity, being able to carboxylate propionyl-CoA at a maximal rate approximately 20% that measured in the presence of the acetyl-CoA substrate. These two reactions occur at separate sites on the enzyme. One site binds either acetyl-CoA (Km = 226 microM) or propionyl-CoA (Km = 38 microM) and is strongly inhibited by quizalofop (Ki = 25 microM and 9.3 microM for the acetyl-CoA and propionyl-CoA substrates, respectively). The other is specific for acetyl-CoA (Km = 11 microM) and is much less inhibited by quizalofop (Ki = 256 microM). Owing to the existence of these two catalytically different sites, the enzyme obeyed Michaelis-Menten kinetics with propionyl-CoA, but exhibited kinetic co-operativity in the presence of acetyl-CoA. Also, kinetics of propionyl-CoA carboxylase activity of ACC220 exhibited hyperbolic inhibition in the presence of quizalofop, but co-operative inhibition when following the ACC activity of the enzyme. The results suggest that the higher the substrate specificity, the lower the quizalofop sensitivity of the active site. Similar kinetic behaviour was observed with ACC220 purified from pea leaves. Also, the apparent correlation between the substrate specificity and the sensitivity of ACC towards quizalofop was confirmed by kinetic analyses of the low-molecular-mass form of ACC present in chloroplasts of young pea leaves. This enzyme was insensitive to quizalofop inhibition and was not able to carboxylate propionyl-CoA. No other propionyl-CoA carboxylase activity, different from that catalysed by ACC220, could be detected from either reproductive or vegetative organs of pea plants at any stage of development.
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PMID:Kinetics of the two forms of acetyl-CoA carboxylase from Pisum sativum. Correlation of the substrate specificity of the enzymes and sensitivity towards aryloxyphenoxypropionate herbicides. 795 2

We present a new case of holocarboxylase synthetase (HCS) deficiency, a rare autosomal recessive metabolic disorder, causing the "early-onset" form of multiple carboxylase deficiency. The patient was born at term of healthy consanguineous parents after an uncomplicated pregnancy. On the 2nd day of life she refused oral feeding, became tachydyspnoeic and showed excessive weight loss. Laboratory studies showed metabolic acidosis, marked lactic acidaemia, hyperammonaemia and increased urinary excretion of 3-hydroxyisovaleric acid, 3-methylcrotonylglycine, 3-hydroxpropionic acid and methylcitric acid. Peritoneal dialysis combined with oral supplementation of biotin (10 mg/day) started on the 3rd day of life resulted in rapid clinical recovery and normalisation of biochemical parameters. HCS deficiency was established in lymphocytes and skin fibroblasts. The activities of all biotin-dependent carboxylases were severely decreased in fibroblasts grown in medium with moderate biotin concentration (10(-8) mol/l) but normal in a high biotin medium (10(-5) mol/l). Mitochondrial carboxylase activities in lymphocytes were 23%-29% of mean normal during therapy with 20 mg of biotin/day, with the higher dose of 40 mg/day they were within (3-methylcrotoryl-CoA carboxylase, pyruvate carboxylase) or slightly below (propionyl-CoA carboxylase) the normal range. At the age of 3 years the patient's physical and psychomotor development are normal. Early biotin supplementation should be considered in newborns with lactic acidosis and organoaciduria until a final diagnosis has been established. Furthermore, the required individual dose of biotin has to be carefully evaluated biochemically for the individual patient.
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PMID:Holocarboxylase synthetase deficiency: early diagnosis and management of a new case. 831 16

Using an oligonucleotide corresponding to the consensus sequence for the biotin-binding motif, two unlinked genetic loci, bpl1 and bpl2, were cloned from the erythromycin producer Saccharopolyspora erythraea and the nucleotide sequences of a c. 4 kb segment from each determined. The two loci share a virtually identical segment of 1746 nucleotides, coinciding with most of the genes designated bcpA1 and bcpA2 present in bpl1 and bpl2, respectively. The deduced sequences of these genes are highly similar to that of the alpha-chain of mammalian propionyl-CoA carboxylase. Upstream of bcpA2 lies pccB, the gene encoding the beta-chain of this enzyme. Mutant strains carrying frameshift mutations in bcpA1 and pccB were constructed, but we failed to isolate insertional mutants in bcpA2. Propionyl-CoA carboxylase activity was undetectable in the pccB mutant, but was unaffected in the bcpA1-defective strain. These results indicate that pccB encodes the beta-chain of propionyl-CoA carboxylases, and suggest that the alpha-chain of this enzyme, which is likely to be encoded by bcpA2, is shared with some other essential biotin-dependent enzyme. The pccB mutation had no impact on erythromycin production in complex medium.
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PMID:Erythromycin production in Saccharopolyspora erythraea does not require a functional propionyl-CoA carboxylase. 883 Feb 78

Methylmalonyl-CoA decarboxylase catalyses the only energy-conserving step during succinate fermentation by Propionigenium modestum: the decarboxylation of (S)-methylmalonyl-CoA to propionyl-CoA is coupled to the vectorial transport of Na+ across the cytoplasmic membrane, thereby creating a sodium ion motive force that is used for ATP synthesis. By taking advantage of the sequence similarity between the beta-subunits of other Na+-transport decarboxylases, a portion of the P. modestum beta-subunit gene was amplified by PCR with degenerated primers. The cloned PCR product then served as homologous probe for cloning suitable fragments from genomic DNA. Sequence analysis of a 3.7-kb region identified four genes which probably form a transcriptional unit, mmdADCB. Remarkably, a mmdE gene which is present in the homologous mmdADECB cluster from Veillonella parvula and encodes the 6-kDa epsilon-subunit, is missing in P. modestum. By sequence comparisons, the following functions could be assigned to the P. modestum proteins: MmdA (56.1 kDa; alpha-subunit), carboxyltransferase; MmdB (41.2 kDa; beta-subunit), carboxybiotin-carrier-protein decarboxylase; MmdC (13.1 kDa; gamma-subunit), biotin carrier protein. MmdD (14.2 kDa; delta-subunit) presumably is essential for the assembly of the complex, as shown for the corresponding V. parvula protein. Methylmalonyl-CoA decarboxylase was solubilized from membranes of P. modestum with n-dodecylmaltoside and enriched 15-fold by affinity chromatography on monomeric avidin resin. The purified protein was composed of four subunits, three of which were identified by N-terminal sequence analysis as MmdA, MmdD, and MmdC. The purified enzyme exhibited a specific activity of up to 25 U/mg protein and an apparent Km value for (S)-methylmalonyl-CoA of approximately 12 microM. Compared to the five-subunit complex of V. parvula, the four-subunit enzyme of P. modestum appeared to be more labile, presumably a consequence of the lack of the epsilon-subunit.
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PMID:Methylmalonyl-CoA decarboxylase from Propionigenium modestum--cloning and sequencing of the structural genes and purification of the enzyme complex. 942 14

An acyl-coenzyme A carboxylase that carboxylates acetyl-CoA, butyryl-CoA, propionyl-CoA, and succinyl-CoA was purified from Myxococcus xanthus. Since the enzyme showed maximal rates of carboxylation with propionyl-CoA, the enzyme is thought to be propionyl-CoA carboxylase. The apparent Km values for acetyl-CoA, butyryl-CoA, propionyl-CoA, and succinyl-CoA were found to be 0.2, 0. 2, 0.03, and 1.0 mM, respectively. The native enzyme has a molecular mass of 605-615 kDa and is composed of nonidentical subunits (alpha and beta) with molecular masses of 53 and 56 kDa, respectively. The enzyme showed maximal activity at pH 7.0-7.5 and at 25-30 degrees C, and was affected by variation in concentrations of ATP and Mg2+. During development of M. xanthus, the propionyl-CoA carboxylase activity increased gradually, with maximum activity observed during the sporulation stage. Previous work has shown that a propionyl-CoA-carboxylase-deficient mutant of M. xanthus reduces levels of long-chain fatty acids. These results suggest that the propionyl-CoA carboxylase is also responsible for the carboxylation of acetyl-CoA to malonyl-CoA used for the synthesis of long-chain fatty acids during development.
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PMID:Propionyl-CoA carboxylase of Myxococcus xanthus: catalytic properties and function in developing cells. 968 57

The pathway of autotrophic CO2 fixation was studied in the phototrophic bacterium Chloroflexus aurantiacus and in the aerobic thermoacidophilic archaeon Metallosphaera sedula. In both organisms, none of the key enzymes of the reductive pentose phosphate cycle, the reductive citric acid cycle, and the reductive acetyl coenzyme A (acetyl-CoA) pathway were detectable. However, cells contained the biotin-dependent acetyl-CoA carboxylase and propionyl-CoA carboxylase as well as phosphoenolpyruvate carboxylase. The specific enzyme activities of the carboxylases were high enough to explain the autotrophic growth rate via the 3-hydroxypropionate cycle. Extracts catalyzed the CO2-, MgATP-, and NADPH-dependent conversion of acetyl-CoA to 3-hydroxypropionate via malonyl-CoA and the conversion of this intermediate to succinate via propionyl-CoA. The labelled intermediates were detected in vitro with either 14CO2 or [14C]acetyl-CoA as precursor. These reactions are part of the 3-hydroxypropionate cycle, the autotrophic pathway proposed for C. aurantiacus. The investigation was extended to the autotrophic archaea Sulfolobus metallicus and Acidianus infernus, which showed acetyl-CoA and propionyl-CoA carboxylase activities in extracts of autotrophically grown cells. Acetyl-CoA carboxylase activity is unexpected in archaea since they do not contain fatty acids in their membranes. These aerobic archaea, as well as C. aurantiacus, were screened for biotin-containing proteins by the avidin-peroxidase test. They contained large amounts of a small biotin-carrying protein, which is most likely part of the acetyl-CoA and propionyl-CoA carboxylases. Other archaea reported to use one of the other known autotrophic pathways lacked such small biotin-containing proteins. These findings suggest that the aerobic autotrophic archaea M. sedula, S. metallicus, and A. infernus use a yet-to-be-defined 3-hydroxypropionate cycle for their autotrophic growth. Acetyl-CoA carboxylase and propionyl-CoA carboxylase are proposed to be the main CO2 fixation enzymes, and phosphoenolpyruvate carboxylase may have an anaplerotic function. The results also provide further support for the occurrence of the 3-hydroxypropionate cycle in C. aurantiacus.
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PMID:Presence of acetyl coenzyme A (CoA) carboxylase and propionyl-CoA carboxylase in autotrophic Crenarchaeota and indication for operation of a 3-hydroxypropionate cycle in autotrophic carbon fixation. 997 33

Glutaconyl-CoA decarboxylase from Acidaminococcus fermentans (clostridal cluster IX), a strict anaerobic inhabitant of animal intestines, uses the free energy of decarboxylation (delta G(o) approximately -30 kJ mol-1) in order to translocate Na+ from the inside through the cytoplasmic membrane. The proton, which is required for decarboxylation, most probably comes from the outside. The enzyme consists of four different subunits. The largest subunit, alpha or GcdA (65 kDa), catalyses the transfer of CO2 from glutaconyl-CoA to biotin covalently attached to the gamma-subunit, GcdC. The beta-subunit, GcdB, is responsible for the decarboxylation of carboxybiotin, which drives the Na+ translocation (approximate K(m) for Na+ 1 mM), whereas the function of the smallest subunit, delta or GcdD, is unclear. The gene gcdA is part of the 'hydroxyglutarate operon', which does not contain genes coding for the other three subunits. This paper describes that the genes, gcdDCB, are transcribed in this order from a distinct operon. The delta-subunit (GcdD, 12 kDa), with one potential transmembrane helix, probably serves as an anchor for GcdA. The biotin carrier (GcdC, 14 kDa) contains a flexible stretch of 50 amino acid residues (A26-A75), which consists of 34 alanines, 14 prolines, one valine and one lysine. The beta-subunit (GcdB, 39 kDa) comprising 11 putative transmembrane helices shares high amino acid sequence identities with corresponding deduced gene products from Veillonella parvula (80%, clostridial cluster IX), Archaeoglobus fulgidus (61%, Euryarchaeota), Propionigenium modestum (60%, clostridial cluster XIX), Salmonella typhimurium (51%, enterobacteria) and Klebsiella pneumoniae (50%, enterobacteria). Directly upstream of the promoter region of the gcdDCB operon, the 3' end of gctM was detected. It encodes a protein fragment with 73% sequence identity to the C-terminus of the alpha-subunit of methylmalonyl-CoA decarboxylase from V. parvula (MmdA). Hence, it appears that A. fermentans should be able to synthesize this enzyme by expression of gctM together with gdcDCB, but methylmalonyl-CoA decarboxylase activity could not be detected in cell-free extracts. Earlier observations of a second, lower affinity binding site for Na+ of glutaconyl-CoA decarboxylase (apparent K(m) 30 mM) were confirmed by identification of the cysteine residue 243 of GcdB between the putative hellces VII and VIII, which could be specifically protected from alkylation by Na+. The alpha-subunit was purified from an overproducing Escherichia coli strain and was characterized as a putative homotrimer able to catalyse the carboxylation of free biotin.
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PMID:The sodium ion translocating glutaconyl-CoA decarboxylase from Acidaminococcus fermentans: cloning and function of the genes forming a second operon. 1002 65

Biotin is a water soluble enzyme cofactor that belongs to the vitamin B complex. In humans, biotin is involved in important metabolic pathways such as gluconeogenesis, fatty acid synthesis, and amino acid catabolism by acting a as prosthetic group for pyruvate carboxylase, propionyl-CoA carboxylase, beta-methylcrotinyl-CoA carboxylase, and acetyl-CoA carboxylase. Carboxylases are synthesized as apo-carboxylases without biotin and the active form is produced by their covalent binding of biotin to the epsilon-amino group of a lysine residue of the apocarboxylases. This reaction is catalyzed by the holo-carboxylase synthetase. The last step in the degradation of carboxylases, the cleavage of the biotinyl moiety from the epsilon-amino group lysine residues, is catalyzed by biotinidase and results in the release of free biotin, which can be recycled. Biotin regulates the catabolic enzyme propionyl-CoA carboxylase at the posttranscriptional level whereas the holo-carboxylase synthetase is regulated at the transcriptional level. Aside from its role in the regulation of gene expression of carboxylases, biotin has been implicated in the induction of the receptor for the asialoglycoprotein, glycolytic enzymes and of egg yolk biotin binding proteins. Biotin deficiency in humans is extremely rare and is generally associated with prolonged parenteral nutrition, the consumption of large quantities of avidin, usually in the form of raw eggs, severe malnutrition and, inherited metabolic disorders. In humans, there are autosomal recessive disorders of biotin metabolism that result from the disruption of the activity of biotinidase or holo-carboxylase synthetase.
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PMID:[Importance of biotin metabolism]. 1084 44


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