Muscle nucleotide synthesis

The enzymes of the pentose phosphate pathway are widely distributed in plants, animals, and microorganisms. Recently attempts have been made to evaluate the activity of this system in vivo. Isotope experiments, in which the rate of conversion of C-1 of glucose to CO2 is compared with the rate of CO2 formation from other atoms of glucose, indicate that a major part of the oxidation in liver may proceed by the pentose pathway. In contrast, glycolysis accounts for essentially all of muscle carbohydrate metabolism. The presence of Zwischenferment, however, does not imply that this cyclic mechanism is operative, since the first steps may be used for the production of pentose phosphate for nucleotide synthesis, polysaccharides, or other purposes. 

PEO [25] A myopathy with progressive muscle weakness and external ophthalmoplegia. Ataxia, episodic ke-toacidotic coma, and early death have been reported associated with single or multiple DNA deletions. Mutations in the gene encoding the muscle isoform of the adenylate carrier (ANTI) have been reported to cause PEO, presumably due to abnormal nucleotide availability for mtDNA synthesis. 

Additional information <1-7, 11, 14, 15, 17-19, 21, 30> (<7> cell-free synthesis in mRNA-dependent rabbit reticulocyte lysate system [40] <2,4,5> high activities in tissues where turnover of energy from adenine nucleotides is great, e. g. muscle [3] <1-6,11,14,15> tissue distribution [3,46] <2,5> rabbit and human carry a minimum of 2 sets of isozymes within an individual one set in muscle, erythrocytes, brain and another in liver, kidney and spleen [3]) [3, 40, 46]... 

C) Inhibition of cyclic nucleotide PDEs. Elevation in cellular cyclic nucleotides induces vascular smooth muscle relaxation [132]. The cellular accumulation of cAMP and cGMP depends upon the rate of their synthesis and their breakdown. The latter is achieved by cyclic nucleotide PDEs that have been classified into seven families [133]. Some flavonoids (apigenin, kaempferol, fisetin and quercetin) produce an inhibitory action on cyclic nucleotide PDEs [134,135] which may collaborate in the inhibitory effect on platelet aggregation [93] and vascular smooth muscle relaxation... 

Finally, muscle inosinic acid itself was synthesized by Levene and Tipson. This was the first (partial) synthesis of a naturally occurring nucleotide. Phosphorylation of 2,3-isopropylidene-inosine, the structure of which has already been discussed, gave the corresponding 5-phospho derivative, from which the isopropylidene group was cautiously hydrolyzed, yielding 5-phosphoinosine which proved to be identical with muscle inosinic acid. 

Adenylic Acid. Muscle adenylic acid ergaden -ylic acid t -adenylic acid adenosine S -monophosphate adenosine phosphate adenosine-5 -phosphoric add edeno-sine-5. monophosphoric acid A5MP AMP NSC-20264 Addiyl Cardiomone (Na salt) Lycedan My -B-Den My-oston Phosaden. C,0HhNjO7P mol wt 347.23, C 34.59%, H 4.06%, N 20.17%, O 32,25%, P 8,92%. Nucleotide widely distributed in nature. Prepn from tissues Embden, Zimmerman, Z. Physrot Chem. 167, 137 (1927) Embden, Schmidt, ibid. 181, 130 (1929) cf. Kalckar, J. B.ol Chem. 167, 445 (1947). Prepn by hydrolysis of ATP with barium hydroxide Kerr, 3. Biot Chem. 139, 13l (1941). Synthesis Baddiley, Todd. 3. Chem. Soc. 1947, 648. Commercial prepn by enzymatic phosphorylation of adenosine. Monograph on synthesis of nucleotides G. R. Pettit. Synthetic Nucleotides vol, 1 (Van Nostrand-Reinhold. New York, 1972) 252 pp. Crystal structure Kraut, lensen, Acta Cryst 16, 79 (1963). Reviews see Adenosine Nucleic Acids. 

Remarkable differences can also be found within a single species. For example, the glutamine synthetase from rat kidney acts on its substrate ten times faster than does the analogous enzyme from rat muscle (Iqbal and Ottaway, 1970). Again, cancer cells maintain a more rapid cell cycle than normal cells hence they are more sensitive to drugs which interfere with the synthesis of nucleotides. 

In continuing our studies on the rate of synthesis of nucleic acids as influenced by vitamin E deficiency, another precursor of the nucleotides was chosen. Control and vitamin E deficient rabbits were injected with P and nucleic acids were extracted at early time intervals following the injection (Dinning et al., 1956b). It was found that in vitamin E-deficient rabbits the specific activities of nucleic acids from skeletal muscle, spleen, kidney, liver, small intestines, and bone marrow were greatly increased as compared to control animals. The increased incorporation of P into... 

The results of all these experiments with rabbits may be explained as being due to an increased synthesis of DNA in skeletal muscle of the vitamin E-deficient animals with no appreciable change in the nucleic acid metabolism of other tissues. This increased rate of DNA synthesis in skeletal muscle from vitamin E-deficient animals would require an accelerated rate of synthesis of acid-soluble nucleotides, which in turn could result in higher specific activities of nucleic acids isolated from other tissues... 

The results with vitamin K-deficient monkeys would suggest that there is an increased rate of synthesis of DNA in both skeletal muscle and bone marrow. This conclusion is based on the observation that vitamin E deficiency in the monkey resulted in a greatly increased mcorporation of formate-C into marrow DNA with little effect on the incorporation into RNA. If the effects were due to an increased specific activity of the nucleotide pool the specific activities of both RNA and DNA should have been increased to approximately the same extent as was observed in rabbit bone marrow. Additional supporting evidence comes from the observation of many multicleated erythroid precursors in vitamin E-deficient monkey bone marrow (Porter et al., 1962). 

Matsuda et al. (27) showed that the adenylosuccinate synthetase basic isozyme has a lower Km for aspartate, is more sensitive to inhibition by fructose 1,6-bisphosphate, and less sensitive to inhibition by nucleotides than the acidic isozyme. These properties could indicate that the basic isozyme is regulated coordinately with glycolysis (or gluconeogenesis) as proposed for the operation of the purine nucleotide cycle in skeletal muscle. The enzyme could also be affected by the availability of aspartate, as was found in Ehrlich ascites cells. The increase in basic isozyme activity, under conditions used in this study where the animal must rely on protein for most of its energy, is consistent with the idea that it is involved in the purine nucleotide cycle. This probably is not as an alternative to glutamate dehydrogenase in urea synthesis but is simply in amino acid catabolism. The small... 

The few deficient patients examined thus far have shown, not the expected accumulation of AMP in exercised muscles, but rather a depletion of all adenine nucleotides and their loss from muscle as nucleosldes >. This suggests a compensatory dephosphorylation by nucleotidase when AMP deaminase is absent, in order to lower AMP levels. Since it is now known that muscle is a major site of de novo purine synthesis, exercise in affected patients might accelerate both purine synthesis and breakdown, and predispose them toward hyperuricemia and gout. It may be more than coincidental, therefore, that 1 of our patients has gout, 2 others have had elevated uric acid levels, and another case of the deficiency coexisting with gout has been reported. The evidence at present is too meager to justify other than a cautionary attitude. 

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