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PubMed1983

Further characterization of the heat-stable factor in the alpha-hydroxylation and oxidation of lignoceric acid in brain: effect of acidic amino acids and hexose-phosphates on brain fatty acid metabolism.

Lignoceric acid and other very long-chain fatty acids are converted to alpha-hydroxy fatty acids and ceramide in brain. These fatty acids are also oxidized and produce glutamic acid and other water-soluble products. All of these metabolic conversions are catalyzed by a rat brain particulate fraction and require NADPH, heat-labile factor, and heat-stable factor. The heat-stable factor was prepared from calf cerebellum. Glucose 6-phosphate and N-acetylaspartic acid have previously been identified as active components of the heat-stable factor. We report in this manuscript that glutamic acid, glutamine, aspartic acid, and gamma-aminobutyric acid as well as inorganic phosphate and adenosine nucleotides are also active components of the heat-stable factor. When the amino acids, glucose 6-phosphate, AMP, and phosphoric acid were combined, full activity of the heat-stable factor for the formation of cerebronate (by alpha-hydroxylation) and glutamate (presumably by beta-oxidation) from lignoceric acid was recovered. The role of the acidic amino acids in the metabolic conversion of lignoceric acid in brain appears to be their conversion to the corresponding alpha-keto acids and then incorporation into the TCA cycle. Glucose 6-phosphate is also likely to be involved in the TCA cycle through the Emden-Meyerhof pathway. Inorganic phosphate and AMP seemingly are used to produce ATP. However, the addition of up to 20 mM ATP alone did not replace the heat-stable factor.

Amino Acids↗
PubMed1984

Oligosaccharides on cathepsin D from porcine spleen.

Cathepsin D from porcine spleen contained mannose (3.3%), glucosamine (1.4%), and mannose 6-phosphate (0.08%). Essentially all of the oligosaccharides of cathepsin D could be released by endo-beta-N-acetylglucosaminidase H, pointing to oligomannoside types of structures. Three neutral oligosaccharide fractions, containing 5, 6, and 7 mannose residues, respectively, were isolated by gel permeation chromatography on Bio-Gel P-2. Studies using exoglycosidase digestions and 500-MHz 1H NMR spectroscopy revealed that their structures are [Man alpha 1 leads to 2]0 or 1 Man alpha 1 leads to 6[Man alpha 1 leads to 3]Man alpha 1 leads to 6[Man alpha 1 leads to 2)0 or 1 Man alpha 1 leads to 3]Man beta 1 leads to 4GlcNAc beta 1 leads to 4 GlcNAc. These structures are identical to what have recently been proposed by Takahashi et al. for the major oligosaccharide units of cathepsin D from the same source (T. Takahashi, P. G. Schimidt, and J. Tang (1983) J. Biol. Chem. 258, 2819-2930), except for the occurrence of two isomeric oligosaccharides containing six mannoses. Only a part (3.4%) of the oligosaccharides were acidic, containing phosphates in monoester linkage. The phosphorylated oligosaccharides also consisted of oligomannoside-type chains which were analogous to, but more heterogeneous in size than the neutral oligosaccharides. Cathepsin D was bound to a mannose- and N-acetylglucosamine-specific lectin (mannan-binding protein) isolated from rabbit liver with the Ki value of 5.4 X 10(-6) M.

Acetylglucosaminidase↗
PubMed1985

Hexose monophosphate shunt-stimulated reduction of methemoglobin by divicine.

Reduced divicine (2,6-diamino-4,5-dihydroxypyrimidine), an aglycone implicated in the pathogenesis of favism, reduces methemoglobin efficiently in intact erythrocytes and in hemolysates. Oxidized divicine produces the same effect when glucose or an NADPH-generating system is added to intact erythrocytes or to hemolysates. Although NADPH, NADH, and GSH have no direct methemoglobin-reducing activity in vitro, they convert oxidized divicine to the reduced hydroquinone species, which is responsible for the electron transfer to methemoglobin. Reduction of methemoglobin is optimally observed under nitrogen since, in the presence of oxygen, reduced divicine undergoes autoxidation. Several lines of evidence rule out the reduction of methemoglobin by divicine through an enzyme-catalyzed process, although it is certainly sustained by the hexose monophosphate shunt activity of erythrocytes through the generation of both NADPH and GSH. Thus, the strong enhancing effect that glucose produces on the divicine-dependent methemoglobin reduction within intact normal erythrocytes is completely absent in erythrocytes from glucose-6-phosphate dehydrogenase-deficient subjects. This distinctive behavior might account for the enhanced methemoglobin levels that are found both in vitro in glucose-6-phosphate dehydrogenase-deficient erythrocytes exposed to divicine and in vivo as a typical feature of the acute hemolytic crisis of favic patients.

Catalase↗
PubMed1985

The synthesis of mannose 1-phosphate in brain.

The interconversion of mannose-6-P and mannose-1-P in brain has been shown to be catalyzed by a distinct enzyme. The enzyme has been separated from most of the phosphoglucomutase activity of the brain. The residual phosphoglucomutase activity (less than 1%) may be associated with phosphomannomutase itself. Mannose-1,6-P2 or glucose-1,6-P2 is required for the reaction as well as a divalent cation (Mg2+ greater than Co2+ greater than Ni2+ greater than Mn2+). Glucose-1-P, glucose-6-P, and 2-deoxyglucose-6-P are also substrates or inhibitors. Other phosphorylated sugars tested, glucosamine-6-P, N-acetylglucosamine-6-P, galactose-6-P, fructose-6-P, ribose-5-P, and arabinose-5-P, do not affect the rate of the reaction when assayed in the presence of mannose-6-32P.

Animals↗
PubMed1987

Inhibition of hexokinase activity by a fructose 2,6-bisphosphate-dependent cytosolic protein from liver.

Mammalian and yeast hexokinases were found to be reversibly inhibited by fructose 2,6-bisphosphate, an effect requiring the presence of a cytosolic protein factor. Experimental evidence suggests that this factor (inhibitor) is a regulatory protein, the interactions of which with hexokinases are modulated by fructose 2,6-bisphosphate. The Vmax of hexokinase D was decreased, and no changes on other kinetic parameters were observed. The inhibitor was present in fresh liver cytosol filtered through Sephadex G-25 and was partially isolated by negative absorption on DEAE-cellulose followed by ammonium sulfate fractionation. The inhibitor was also present in brain and kidney, but not in muscle. A molecular mass of 200,000 was determined by gel filtration. The inhibition was dependent on the concentrations of both the inhibitory protein and fructose 2,6-bisphosphate. No delay in fructose 2,6-bisphosphate inhibition was observed. Several other hexose phosphates were tested and were not effective. In the presence of amounts of inhibitor sufficient to produce complete inhibition of hexokinase D, the concentration of fructose 2,6-bisphosphate required to produce 50% inhibition was about 0.5 microM. The inhibitor was unstable and was stabilized by the presence of fructose 2,6-bisphosphate.

Animals↗
PubMed1987

Factors underlying significant underestimations of glucokinase activity in crude liver extracts: physiological implications of higher cellular activity.

M. Kuwajima, C. B. Newgard, D. W. Foster, and J. D. McGarry (1986, J. Biol. Chem. 261, 8849-8853) have concluded that the reason postprandial hepatic glycogenesis occurs primarily from gluconeogenic precursors rather than glucose is because glucokinase activity is insufficient to support the observed rates of glycogen synthesis. F. L. Alvares and R. C. Nordlie (1977, J. Biol. Chem. 252, 8404-8414) have concluded that the combined activities of glucokinase and hexokinase are less than the apparent rates of hepatic glucose uptake. We have identified several factors in the assays used in these studies which lead to substantial underestimations of glucokinase activity. Glucokinase was assayed either by allowing glucose 6-phosphate to accumulate over 10 min (discontinuous assay) or by coupling the formation of glucose 6-phosphate with its oxidation by Leuconostoc mesenteroides glucose 6-phosphate dehydrogenase and NAD (continuous assay). Accurate determinations of glucokinase at 37 degrees C with subsaturating glucose require both 100 mM KCl and 2.5 mM dithioerythritol in the assay medium; 2-mercaptoethanol will not substitute for dithioerythritol. When both KCl and dithioerythritol are absent (Kuwajima et al.) glucokinase activity is underestimated by 3- to 5-fold. The discontinuous assay as used previously (Alvares and Nordlie) underestimates glucokinase activity in crude extracts by 2- to 2.5-fold, due in part to the hydrolysis of glucose 6-phosphate and its transformation to other hexose monophosphates. Under optimized conditions at 37 degrees C both assays yield similar results in extracts from fed rats, i.e., 2-3 and 4-5 units/g liver at 10 and 100 mM glucose, respectively. Some implications of the finding that total hepatic glucose phosphorylating capacity at physiological concentrations significantly exceeds the observed rates of postprandial glycogen synthesis are discussed.

Animals↗
PubMed1989

Rat brain hexokinase: further studies on the specificity of the hexose and hexose 6-phosphate binding sites.

Based on the lack of correlation between the ability of various hexoses to serve as substrate and the ability of the corresponding hexose 6-phosphates to inhibit brain hexokinase (ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1), R. K. Crane and A. Sols (1954, J. Biol. Chem. 210, 597-606) proposed that this enzyme possesses two discrete sites capable of binding hexose moieties, one serving as the substrate binding site and a second, regulatory in function, to which inhibitory 6-phosphates bind. Subsequent work has provided further experimental support for this proposal. The pioneering work by Crane and Sols focused primarily on the specificity of these sites with respect to requirements for orientation of hydroxyl substituents at the various positions of the pyranose ring. The present study explores additional aspects of the specificity of these sites, namely, the effect of substitution of a sulfur atom in place of the oxygen in the pyranose ring on ability to serve as substrate or inhibitor, and the effect of modification in charge of the substituent at the 6-position on inhibitory effectiveness. 5-Thioglucose is a linear competitive (versus glucose) inhibitor of rat brain hexokinase, with a Ki of about 0.2 mM, and is a linear mixed inhibitor (versus ATP), with Ki values in this same range. 5-Thioglucose is not, however, readily phosphorylated by brain hexokinase. Thus, although 5-thioglucose binds with moderate affinity to the glucose binding site, it is not effectively used as a substrate of the enzyme. Inhibition of brain hexokinase by glucose 6-phosphate or its analogs has been found to require a dianionic substituent at the 6-position. The 6-fluorophosphate derivative and glucose 6-sulfate are poor inhibitors of the enzyme, and the Ki for inhibition by 1,5-anhydroglucitol 6-phosphate increases markedly at pH values below the pK of the 6-phosphate group, indicating that the monoanionic form is ineffective as an inhibitor. In contrast to the detrimental effect that substitution of the oxygen atom in the pyranose ring with a sulfur has on ability to serve as substrate, 5-thio analogs are considerably more effective as inhibitors, the Ki for inhibition by 5-thioglucose 6-phosphate being 10-fold lower than that seen with glucose 6-phosphate. This effect of the heteroatom substitution can partially offset the decreased inhibition resulting from monoanionic character at the 6-position, but the 6-fluorophosphate derivative of 5-thioglucose 6-phosphate still inhibits with a Ki about 1000-fold greater than that seen with 5-thioglucose 6-phosphate.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗