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PubMed2003

[Characterization of Amycolatopsis meditteranei U32 chromosome by pulse-field gel electrophoresis].

Amycolatopsis meditteranei U32 is an industrial strain with high yield of rifamycin SV. Its chromosome structure was characterized by pulse-field gel electrophoresis. The topological structure of U32 chromosome was linear and its genome size was about 10 Mb. There was no internal plasmid found. Gene encoding several enzymes involved in rifamycin bio-synthesis and relevant primary metabolism as well as protein related to metabolic regulation were localized by Southern blot. The results revealed that there were at least five copies of rrn operon in U32. The rifamycin bio-synthesis gene cluster was located on one about 700 kb PshBI fragement where several other important genes related to primary and secondary metabolism were also situated. They were the nasD gene, the mcm gene encoding methylmalonyl CoA mutase, the accA gene encoding acethyl CoA carboxylase biotin carrier protein and one copy of the rrn operons.

Actinomycetales↗

PubMed2005

Two newborns with nutritional vitamin B12 deficiency: challenges in newborn screening for vitamin B12 deficiency.

Vitamin B12 deficiency causes decreased Methionine Synthase and L-Methylmalonyl-CoA Mutase activity and results in accumulation of Homocysteine, Methylmalonic acid and Propionylcarnitine. Propionylcarnitine is included in tandem mass spectrometry-based newborn screening programs for detection of certain inborn errors of metabolism. We report two asymptomatic newborns with Vitamin B12 deficiency due to maternal deficiencies. One was detected incidentally at 3 weeks of age; the second on supplemental newborn screening based on elevated Propionylcarnitine at 2 days of age. This illustrates the potential for false negative results for Vitamin B12 deficiency screening by acylcarnitine profiling in newborn screening. Homocysteine and Methylmalonic acid may be better markers of Vitamin B12 deficiency. In conclusion, we suggest measuring Methylmalonic acid, Propionylcarnitine and Homocysteine levels in blood spots in expanded newborn screening in order to detect asymptomatic newborns with Vitamin B12 deficiency. Further studies are needed to establish the sensitivity of these three markers in screening for Vitamin B12 deficiency.

Acyl-CoA Dehydrogenase, Long-Chain↗

PubMed2006

Proteomic analysis of secreted proteins of non-small cell lung cancer.

BACKGROUND & OBJECTIVE: Secreted proteins from cancer cells may be potential serologic biomarkers of cancer. It's important to globally identify secreted proteins of cancer cells. This study was to identify secreted proteins of lung cancer cells. METHODS: Proteins in the conditioned medium of non-small cell lung cancer (NSCLC) cell line A549 was collected and the proteome analysis was subsequently performed. Specific protein spots in A549 cells were identified by peptide mass fingerprints using mass spectrometry and through searching database. The expression of identified secreted proteins was detected by reverse transcription-polymerase chain reaction (RT-PCR) in 15 specimens of NSCLC tissue and paired distant lung tissue. Manganese superoxide dismutase (Mn-SOD) activity in serum and conditioned medium was detected by spectrophotometry. RESULTS: Fourteen secreted proteins were identified, which included peptidyl-prolyl cis-trans isomerase A (PPIA), Mn-SOD, peroxiredoxin 1 (PDX1), phosphatidylethanolamine binding protein (PEBP), glutathione S-transferase P (GSTP1-1), glucose-dependent insulinotropic protein receptor (GIPR), ubiquitin carboxyl-terminal hydrolase isozyme L1 (PGP9.5), alpha enolase (ENO1), dihydrodiol dehydrogenase (DDH), phosphoglycerate mutase 1 (PGAM1), galectin-1 (GAL1). PPIA, DDH, PGAM1, PDX1, PGP9.5, ENO1, and PEBP were overexpressed in cancer tissues. Higher level of Mn-SOD activity was detected in conditioned medium than in control. Serum Mn-SOD activity was significantly higher in NSCLC patients than in healthy controls (P<0.01). CONCLUSIONS: Multiple secreted proteins of A549 cells were identified in this study and the overexpression of ENO1 and PEBP in NSCLC was revealed for the first time. Mn-SOD is secreted serologic marker of NSCLC. The results presented here would provide clues to identify new serologic biomarkers of NSCLC.

Adult↗

PubMedDate not supplied

[The nutritional importance and pharmacologic effects of cobalt and vitamin B 12 in man].

Cobalt is an unique trace element for man as it can only reveal its essential properties if provided directly as its biological active form, cobalamin or vitamin B12, the daily requirement of which is 1 to 2 micrograms in adults. This vitamin takes part in the activity of the enzyme methylmalonyl coenzyme A mutase, involved in the conversion of propionyl CoA to succinyl CoA, an intermediary product of the citrate cycle, and of the 5-methyltetrahydrofolate: homocystein methyltransferase, working in the metabolism of methionin and in DNA synthesis. Vitamin B12 deficiency is responsible for a megaloblastic anemia called pernicious anemia and for specific neurological disorders that can be corrected by adequate supplementation. Inorganic cobalt salts can therefore not be considered as essential micronutrients for man, but being able to induce polycythemia, they have a pharmacological property that was recommended in the treatment of various anemias, and they are also used in the management of cyanide poisoning.

Cobalt↗

PubMed1991

Antibody catalysis of carbon-carbon bond formation.

We have used rationally designed transition state analogues to generate antibodies that catalyse two important carbon-carbon bond forming reactions: a bimolecular Diels-Alder cycloaddition and a unimolecular Claisen rearrangement. Our tailored immunoglobulin catalysts (abzymes) exhibit all the properties of naturally occurring enzymes, including substantial rate accelerations, substrate specificity, and high regio- and stereoselectivity. As first generation abzymes are generally inferior to naturally occurring enzymes, we are also employing classical genetic selection strategies to augment their chemical efficiency. We have expressed the antibody that catalyses the Claisen rearrangement of chorismate in yeast cells that lack natural chorismate mutase activity. Improved versions of the abzyme will be identified, following random mutagenesis, by their ability to repair this metabolic defect. The development and study of highly efficient catalytic antibodies promises to advance our understanding of how enzymes work and evolve, how protein function correlates with structure, and how entirely new enzymic activities can be created for use in research, industry and medicine.

Antibodies↗

PubMed1990

Effect of hydroxycobalamin[c-lactam] on propionate and carnitine metabolism in the rat.

The administration in vivo of the cobalamin analogue hydroxycobalamin[c-lactam] inhibits hepatic L-methylmalonyl-CoA mutase activity. The current studies characterize in vivo and in vitro the hydroxycobalamin[c-lactam]-treated rat as a model of disordered propionate and methylmalonic acid metabolism. Treatment of rats with hydroxycobalamin[c-lactam] (2 micrograms/h by osmotic minipump) increased urinary methylmalonic acid excretion from 0.55 mumol/day to 390 mumol/day after 2 weeks. Hydroxycobalamin[c-lactam] treatment was associated with increased urinary propionylcarnitine excretion and increased short-chain acylcarnitine concentrations in plasma and liver. Hepatocytes isolated from cobalamin-analogue-treated rats metabolized propionate (1.0 mM) to CO2 and glucose at rates which were only 18% and 1% respectively of those observed in hepatocytes from control (saline-treated) rats. In contrast, rates of pyruvate and palmitate oxidation were higher than control in hepatocytes from the hydroxycobalamin[c-lactam]-treated rats. In hepatocytes from hydroxycobalamin[c-lactam]-treated rats, propionylcarnitine was the dominant product generated from propionate when carnitine (10 mM) was present. The addition of carnitine thus resulted in a 4-fold increase in total propionate utilization under these conditions. Hepatocytes from hydroxycobalamin[c-lactam]-treated rats were more sensitive than control hepatocytes to inhibition of palmitate oxidation by propionate. This inhibition of palmitate oxidation was partially reversed by addition of carnitine. Thus hydroxycobalamin[c-lactam] treatment in vivo rapidly causes a severe defect in propionate metabolism. The consequences of this metabolic defect in vivo and in vitro are those predicted on the basis of propionyl-CoA and methylmalonyl-CoA accumulation. The cobalamin-analogue-treated rat provides a useful model for studying metabolism under conditions of a metabolic defect causing acyl-CoA accretion.

Acyl Coenzyme A↗

PubMed1975

A specific enzyme for glucose 1,6-bisphosphate synthesis.

The reaction: glycerate-1,3-P2 PLUS GLUCOSE-1-P YIELDS TO GLUCOSE-1,6-P2 plus glycerate-P is catalyzed by a distinct enzyme of mouse brain. A divalent metal requirement was shown when the enzyme was treated with imidazole and EDTA. Mg2+, Mn2+, Ca2+, Zn2+, Ni2+, Co2+, and Cd2+ were quite effective cofactors. The enzyme, in better than 50 percent yield, has been purified away from 99 percent of the phosphoglucomutase, phosphoglycrate mutase, and phosphofructokinase. Acetyl-P, ATP, enolpyruvate-P, creatine-P, and fructose-1,6-P2 are not phosphoryl donors. Glucose-6-P and mannose-1-P are good alternate acceptors. Mannose-6-P, galactose-Ps, and fructose-Ps have little or no acceptor activity. Strong inhibition was found with fructose-1,6-P2, glycerate-2,3-P2, enolpyruvate-P, and acetyl CoA. From the amount of activity and the kinetic constants of the purified enzyme it seems likely that this enzyme is responsible for the glucose-1,6-P2 synthesis of brain.

Acetyl Coenzyme A↗

PubMed1990

Both valine and isoleucine supplementation delay the development of neurological impairment in vitamin B12 deficient bats.

Supplementation of the diet with valine or isoleucine protects the fruit bat from neurological impairment associated with experimentally induced vitamin B12 deficiency. Valine and isoleucine are precursors in the vitamin B12 dependent propionic acid pathway and it is proposed that they exert their protective effect through stimulation of this pathway. This suggests that the previously observed protective effect of methionine may be mediated also through this pathway, since methionine may be metabolised via the transsulfuration pathway to propionyl CoA. The results of this study refocus attention on the propionic acid pathway, and specifically on the methylmalonyl CoA mutase reaction, as central to the biochemical basis of the vitamin B12 neuropathy.

Animals↗

PubMed1989

Vitamins and inherited human errors of metabolism.

Vitamin therapy for inborn errors of metabolism has been used in thiamin-responsive maple syrup urine disease, homocystinuria (pyridoxine-responsive cystathionine synthetase deficiency), disorders of vitamin B12 metabolism and defective methylmalonyl-CoA mutase, biotinidase and holocarboxylase synthetase deficiency, multiple acyl-CoA dehydrogenase deficiency, defective methylene tetrahydrofolate reductase and complex III deficiency (respiratory chain). The inherited defects lead either to alterations of the apoenzymes or to deficiencies of enzymes involved in the processing or reutilization of the vitamins. The application of pharmacological doses of vitamins can be useful in these disorders in order to overcome diminished apoenzyme binding, to saturate residual activities of defective processing enzymes, to compensate for pathological losses, or for acting as electron carriers.

Humans↗

PubMed1989

Disorders of glycogen metabolism of muscle.

Glycogen is a crucial source of energy in the initial stages of muscle activity and during exercise of high intensity. There are 10 well-defined biochemical defects of glycogen metabolism expressed in muscle and affecting the following enzymes: alpha 1,4 glucosidase (glycogenesis type II), debrancher enzyme (III), brancher enzyme (IV), phosphorylase (V), phosphofructokinase (VII), phosphorylase b kinase (VIII), phosphoglycerate kinase (IX), phosphoglycerate mutase (X), lactate dehydrogenase (XI). These disorders cause two main syndromes: one characterized by exercise intolerance with cramps and myoglobinuria, the other by fixed weakness. However, there are examples of clinical and biochemical heterogeneity for each disease, and molecular genetic analysis is already showing evidence of genetic heterogeneity. Although our understanding of the biochemical errors has progressed considerably, the pathogenesis of symptoms and signs remains incomplete.

Enzymes↗

PubMed1989

[The modifying influence of adenosylcobalamin on the transplacental carcinogenic effect of N-nitroso-N-ethylurea in organ cultures of the kidneys of DBA/2 mice].

Transplacental effect of cobalamin coenzyme, adenosylcobalamin (Adocbl), on the carcinogenic action of N-nitroso-N-ethylurea (ENU) was studied in culture of the mouse embryonic kidney tissue by histoautoradiography. Coenzyme methylmalonyl-CoA-mutase, Adocbl, injected into DBA/2 mice in the prenatal period did not stimulate the proliferative activity of epithelial cells of the embryonic kidney. The treatment with Adocbl did not intensify hyperplastic changes common for the early stages of carcinogenesis. The frequency of hyperplastic changes mainly of focal proliferation in kidney explants with the combined administration was considerably lower than with the isolated action of the carcinogen and amounted to 8.7% and 21.5%, respectively (P less than 0.001).

Animals↗

PubMed1988

The enzymes of the glycolytic pathway in erythrocytes infected with Plasmodium falciparum malaria parasites.

Enzymes of the glycolytic pathway as well as some ancillary enzymes were studied in normal red cells parasitized with Plasmodium falciparum in culture at varying parasitemias as well as in isolated parasites. The levels of all enzymes except diphosphoglycerate mutase, glucose-6-phosphate dehydrogenase, and adenylate kinase were elevated. Extreme elevations of hexokinase, aldolase, enolase, pyruvate kinase, and adenosine deaminase concentrations were noted. In most cases, electrophoretically distinct bands of enzyme activity were also seen. These findings partly explain the previously noted 50- to 100-fold increase in glucose consumption of infected red cells and suggest that further knowledge of these parasite enzymes and their genetic basis may aid both in designing new chemotherapy and in understanding the evolution of these parasites.

Animals↗

PubMed1988

The use of carba(dethia)-coenzyme A (CH2CoA) derivatives for mechanistic investigations.

A novel class of acyl-coenzyme A analogues has been synthesized in which the sulphur atom is replaced by methylene. In contrast to their natural thiolester counterparts these acyl-CH2CoA analogues are stable to hydrolysis. They are good substrates for several enzymes that do not attack the thiolester group (carboxylases, mutases, dehydrogenases, epimerases, etc.) and potent inhibitors for most enzymes that do so. Some of the new insights gained by the use of acyl-CH2CoA are discussed in terms of enzymatic mechanisms.

Coenzyme A↗

PubMed1988

Protein diffusivities in skinned frog skeletal muscle fibers.

In this preliminary report, we investigate the problem of why proteins appear to diffuse much more slowly in muscle cytoplasm than in aqueous solutions. Microvolumetric sampling methods were used to partition the cytoplasm of freshly skinned muscle fibers into diffusible (cytosol) and nondiffusible (cytomatrix) fractions. Some of the diffusible proteins that were identified tentatively on the basis of electrophoretic mobility are: glyceraldehyde-3-phosphate dehydrogenase, triose-P-isomerase, phosphoglycerate mutase and parvalbumin. The latter was most abundant. The apparent (radial) diffusion coefficients of these proteins in the skinned fiber were about a tenth (or less) of their value in aqueous solution. Tortuosity and viscosity factors are probably responsible for their reduced diffusivity, but binding to cytomatrix proteins or sarcoplasmic reticular structures may also contribute. The apparent diffusion coefficient of parvalbumin, a strong chelator of Ca2+, was similar to that reported for trace amounts of Ca2+ injected into skinned frog fibers under oil1), thus supporting the notion that the low apparent diffusion coefficient of Ca2+ is actually that of a Ca2+-parvalbumin complex.

Animals↗

PubMed1978

Analysis of pH-induced changes of the glycolysis of human erythrocytes.

The full time courses of some important metabolites of the glycolysis of human erythrocytes are reported following pH-shifts from pH 7.4 to 8.1 and from 8.1 to 6.9. The regulatory enzymes which are affected by the pH-transitions have been identified by computer simulation using a mathematical model of the erythrocyte glycolysis. It is concluded that in the transition to pH 8.1 the hexokinase-phosphofructokinase system is activated and the pyruvate kinase is inhibited. At pH 6.9 the hexokinase-phosphofructokinase system and the bisphosphoglycerate mutase are inhibited whereas the non-glycolytic ATP-consuming processes seem to be activated.

Adenosine Diphosphate↗

PubMedDate not supplied

[Directed synthesis of macrotetrolides].

The composition of the macrotetrolide complex was found to be strongly dependent on the conditions of the Streptomyces chrysomallus v. macrotetrolidi cultivation and could be varied by including in the medium 0.2% of organic acids, precursors of macrotetrolides, such as acetic, propionic and succinic. Acetate caused an increase of the nonactin/monactin ratio, and no other homologues were detected. On the contrary, propionate and succinate produced a drop in the nonactin synthesis, which was accompanied by a rise in the amount of the higher homologues. The composition of the macrtetrolide mixture can also be changed by introducing in the cultivation medium specific inhibitors (100-200 micrograms/ml) such as malonate, cobalamin analogue, sulfadimesin. Malonate, an inhibitor of succinate dehydrogenase, increased the biosynthesis of higher ethylated homologues. Inhibition of methylmalonate mutase resulted in an increased yield of the methylated nonactin homologue and in a decreased yield of dinactin. In this case no other homologues were produced. The inhibitor of transmethylation, sulfadimesin, had no effect on the biosynthesis and composition of the macrotetralide mixture.

Anti-Bacterial Agents↗

PubMed1987

Cobalamin derivatives in subcellular fractions of porcine ileal enterocytes.

The distribution of cobalamin derivatives in porcine enterocytes was studied using thin-layer chromatography and bioautography. Compared with the original homogenate, adenosyl-cobalamin (Ado-Cbl) was concentrated 5-10 times in the mitochondrial fraction. Cyanocobalamin was found in the lysosomal fraction, but was not detected in the mitochondria. Methyl-cobalamin (Me-Cbl) was found only in the sap fraction and could not be detected in the total homogenate. Hydroxocobalamin was the main form of Cbl in the lysosomal fraction. These results provide indirect evidence that in enterocytes methylmalonyl-CoA mutase, the coenzyme of which is Ado-Cbl, is located in the mitochondrial fraction and that methionine synthetase, the coenzyme of which is Me-Cbl, is located in the sap fraction. These enzymes thus appear to be distributed in the same way as in liver cells.

Animals↗

PubMed1986

Changes in glycolytic intermediates in rat erythrocytes during exposure to simulated high altitude.

Regulatory mechanisms of erythrocyte glycolysis and 2,3-diphosphoglycerate (2,3DPG) metabolism under hypoxia were studied in rats exposed to a simulated altitude of 18,000 ft (5,486 m) for 5 d. Changes in erythrocyte glycolytic intermediates were determined by enzymatic analysis. Marked alterations of glycolytic intermediates were found during 1 d of exposure which were quite different from those observed during exposure for 2, 3, and 5 d. Alterations of intermediates seem to be highly correlated with blood pH changes; however, pH alone cannot explain the overall changes in intermediates. Results suggested that overall intermediate changes are the results of the combined effect of alterations of cellular pH and hemoglobin desaturation. Increased 2,3DPG at initial stages of exposure (within 1 d) may be caused mainly by the increased cellular pH; sustained elevation of 2,3DPG at later stages could be attributed to the relief of product inhibition of diphosphoglycerate mutase by deoxygenation.

2,3-Diphosphoglycerate↗