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GLUOCXEOGENIC ENZYMES* Neogenic Processes. The 96 BIOCHEMISTRY: WEBER ET AL. PROC. N. A. S. tion yielded products which competitively inhibited the aminoacylation of native sRNA. The inhibition was specific for a given amino acid acceptor. Periodate oxidation of preparations enriched in tyrosyl-sRNA and poor in valyl-sRNA yielded an inhibitor effective in the tyrosine system and ineffective in the valine system. Similar specificity was observed with a periodate-treated fraction which had been enriched in valine acceptor activity. * USPHS postdoctoral International Fellow; Fellow del Instituto Nacional de la Investigacion Cientifica de Mexico. 1 Chapeville, F., F. Lipmann, G. von Ehrenstein, B. Weisblum, W. J. Ray, Jr., and S. Benzer, these PROCEEDINGS, 48, 1086 (1962). 2 Bergmann, F. H., P. Berg, and M. Dieckmann, J. Biol. Chem., 236, 1735 (1961). 3 Apgar, J., R. W. Holley, and S. H. Merrill, J. Biol. Chem., 237, 796 (1962). 4 Berg, P., F. H. Bergmann, E. J. Ofengand, and M. Dieckmann, J. Biol. Chem., 236, 1726 (1961). 6 Zubay, G., and M. Takanami, Biochem. Biophys. Res. Commun., 15, 207 (1964). 6Nihei, T., and G. L. Cantoni, J. Biol. Chem., 238, 3991 (1963). 7 Holley, R. W., J. Apgar, B. P. Doctor, J. Farrow, M. A. Marini, and S. H. Merrill, J. Biol. Chem., 236, 200 (1961). 8 Preiss, J., P. Berg, E. J. Ofengand, F. H. Bergmann, and M. Dieckmann, these PROCEEDINGS, 45, 319 (1959). 9 Whitfeld, P. R., and R. Markham, Nature, 171, 1151 (1953). 10 Lineweaver, H., and D. Burk, J. Am. Chem. Soc., 56, 658 (1934). 11 A comparison of the products of a 4% digestion with snake venom by the two procedures showed that the capacity to accept valine was reduced to about 1% by the technique of Zubay and Takanami (ref. 5), whereas digestion at pH 8.9 resulted in retention of 33% of valine acceptor activity. 12 The quantity of periodate-oxidized sRNA required to achieve a 50% inhibition in the tyro- sine test system using fraction Tyr (Fig. 5) was about l/2o of that necessary for a 50% inhibition in the valine test system using fraction Val, (Fig. 4). This disparity can largely be accounted for by the facts that: (a) compared to crude sRNA, tyrosine acceptor sRNA was 6-fold enriched in fraction Tyr, while valine acceptor sRNA was enriched only 1.4-fold in fraction Val, (Table 2); and (b) the level of untreated sRNA used in the valine experiment contained three times more valine acceptor sRNA than the amount of tyrosine acceptor sRNA used in the tyrosine experi- ment and therefore would require a larger quantity of periodate-oxidized sRNA to achieve an equivalent inhibition. 13 Hecht, L. I., M. L. Stephenson, and P. C. Zamenenik, these PROCEEDINGS, 45, 505 (1959). INSULIN: SUPPRESSOR OF BIOSYNTHESIS OF HEPATIC GLUOCXEOGENIC ENZYMES* BY GEORGE WEBER, R. L. SINGHAL, AND S. K. SRIVASTAVA DEPARTMENT OF PHARMACOLOGY, INDIANA UNIVERSITY SCHOOL OF MEDICINE, INDIANAPOLIS, INDIANA Communicated by Charles Huggins, October 30, 1964 The homeostatic control of blood sugar depends in part on regulation of gluco- neogenic processes. The "final common path of gluconeogenesis,"l the series of steps converting pyruvate into glucose, involves a number of reversible and 4 one- way reactions. From the point of view of metabolic control our attention is Downloaded by guest on September 28, 2021 VOL. 53, 1965 BIOCHEMISTRY: WEBER ET AL. 97 focused on the one-way reactions catalyzed by the key enzymes of gluconeogenesis, glucose 6-phosphatase, fructose 1,6-diphosphatase, phosphoenolpyruvate carboxy- kinase, and pyruvate carboxylase. The limiting role of these enzymes is em- phasized by the following properties relevant to regulation. The enzymes are in- volved in circumventing thermodynamic barriers,2 they are all one-way reactions, their activities are the lowest in the gluconeogenic sequence,' and they are organ- specific since they occur only in liver and kidney where gluconeogenesis can take place. The genetic code of the key gluconeogenic enzymes probably is in the same region or on the same genetic chain, since these are the only enzymes of carbo- hydrate metabolism which are progressively deleted with increasing growth rate in hepatomas and are completely absent in rapidly growing liver tumors.3 4 In searching for regulatory influences that could selectively and differentially control the enzymatic processes of gluconeogenesis, we investigated the action of glucocorticoid hormone and insulin. Evidence will be presented indicating that the genic expression of the key gluconeogenic enzymes is regulated by the action of glucocorticoid as an inducer and insulin as a suppressor of the biosynthesis of these hepatic enzymes. Methods.-Male Wistar rats of 90-110 gm were kept in separate cages, with Purina laboratory chow and water ad libitum unless otherwise specified. The tech- niques for preparation of tissue homogenate, supernatant fluid, counting of cell nuclei, assaying glucose 6-phosphatase and fructose 1,6-diphosphatase were described previously.5' 6 The determination of RNA amount and specific activity was cited elsewhere.7 Orotic acid-6-C14 (New England Nuclear Corp.) had a specific activity of 6.5 mc/mM, and 3 jAC/100 gm rat was injected intraperitoneally 2 hr before animals were killed. Triamcinolone (Lederle) was purchased as a commercial preparation. Actinomycin D was a gift from Merck, Sharp & Dohme. Enzyme activities were expressed per cell as micromoles of substrate X 107 metabolized per hr at 370C. The RNA specific activity was calculated as cpm per mg RNA. The data were given for convenient comparison as percentages of values found in normal untreated rats. Alloxan diabetes was induced, in animals starved for 30 hr, by intraperitoneal injection of 12 mg per 100 gm rat alloxan monohydrate (Eastman). Blood sugar was determined according to Nelson's adaptation of the Somogyi method for glucose.8 Results and Discussion. -Evidence for the action of glucocorticoid hormone as inducer of biosynthesis of key gluconeogenic enzymes: For the definition of an inducer, the one recommended in the "Report of the Commission on Enzymes" is used.9 "A relative increase in the rate of synthesis of a specific apoenzyme resulting from ex- posure to a chemical substance will be called enzyme induction. The substance in- ducing such a synthesis is an enzyme inducer." The following evidence has ac- cumulated to show that this concept applies to the action of glucocorticoid hor- nmones on hepatic gluconeogenic enzymes. Glucocorticoid hormones increased the activities of rat liver glucose 6-phospha- tase,5' 10. "fructose 1,6-diphosphatase," 12phosphoenolpyruvate carboxykinase,3 14 and pyruvate carboxylase. 1" A more marked response for the specific phosphatases was obtained with triamcinolonel which was also more effective in promoting glu- coneogenesis."6 Graded effects occurred with increasing hormone dosage." 13, 17 The enzyme increases were detectable in a few hours. 1, 17. 18 The increases are Downloaded by guest on September 28, 2021 98 BIOCHEMISTRY: WEBER ET AL. PROC. N. A. S. thought to represent de novo enzyme synthesis because the rise can be blocked or prevented by inhibitors of protein synthesis such as actinomycin," 7, 18-20 puro- mycin," 13 or ethionine." 12, 13, 21 The blockers of protein synthesis were capable of interrupting the glucocorticoid-induced synthesis and then enzyme activities de- creased to normal in 24 hr." 18, 22 In acute starvation these enzymes were preferentially maintained near normal range.'3' 23-25 However, when hypophysectomized rats were fasted, the enzyme activities rapidly declined.6' 25 The preferential maintenance of specific phos- phatases in starvation also can be interrupted by actinomycin or ethionine and then activities rapidly decrease.22 Adrenalectomy returned the highly increased enzyme activities to normal in diabetic rats." 11 13 In rats carrying ACTH-secreting pituitary tumors the glucose 6-phosphatase and fructose 1,6-diphosphatase activities increased and upon adrenalectomy they re- turned to normal range.26 Thus, endogenous hormones exert biosynthetic effects similar to those observed with exogenous synthetic glucocorticoid derivatives. The role of RNA metabolism in glucocorticoid-induced metabolic responses was shown by the stimulation in the rates of incorporation of radioactive precursors into RNA.27-29 Since it was observed that actinomycin, a selective inhibitor of DNA- directed RNA synthesis,30 inhibited the cortisone-induced elevation of certain en- zymes, it was suggested that the stimulation of precursor incorporation into RNA is an integral part of the hormone action.3' Similar concepts were formed by in- vestigators who brought evidence that the early effects of corticosteroid hormones involve stimulation of RNA polymerase activity and messenger RNA synthesis in rat liver nucleus.32-36 The role of RNA metabolism in glucocorticoid action is further emphasized by the graded dose response of an increase in hepatic RNA amount and by the rise in specific activity with orotate or uracil as precursors in response to increasing doses of triamcinolone.20 22 A correlation of the glucocorticoid-induced rise in liver enzyme biosynthesis, RNA metabolism, and amino acid levels was shown and the increases found with triamcinolone were more marked than those obtained with cortisone.7' 20 This accords with the higher gluconeogenic potency of the fluori- nated steroid.'6 The involvement of DNA-directed RNA synthesis in gluconeo- genic events is indicated by the complete blocking of the triamcinolone or cortisone- induced rise in the biosynthesis of hepatic gluconeogenic enzymes'7' 18-20 and in the increase of RNA metabolism by actinomycin.7 20 The enumerated evidence favors the concept that the glucocorticoid hormones act as inducers of biosynthesis of the key gluconeogenic enzymes. Thus, gluco- corticoids act positively on the transcription of structural genes into specific cata- lytic proteins, namely, key enzymes in the gluconeogenic sequence. Evidence for the action of insulin as suppressor of biosynthesis of key gluconeogenic enzymes: In contrast to the function of an inducer, a suppressor acts negatively o11 the transcription of structural genes into enzyme proteins.
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