Pyruvate cycling

Pyruvate cycling commonly refers to an intracellular loop of spatial movements and chemical transformations involving pyruvate. Spatial movements occur between mitochondria and cytosol and chemical transformations create various Krebs cycle intermediates. In all variants, pyruvate is imported into the mitochondrion for processing through part of the Krebs cycle. In addition to pyruvate, alpha-ketoglutarate may also be imported. At various points, the intermediate product is exported to the cytosol for additional transformations and then re-imported. Three specific pyruvate cycles are generally considered,^[1] each named for the principal molecule exported from the mitochondrion: malate, citrate, and isocitrate. Other variants may exist, such as dissipative or "futile" pyruvate cycles.^[2]^[3]

This cycle is usually studied in relation to Glucose Stimulated Insulin Secretion ( or GSIS ) and there is thought to be a relationship between the insulin response and NADPH produced from this cycle^[4]^[5] but the specifics are not clear and particular confusion exists about the role of malic enzymes.^[6]^[7] It has been observed in various cell types including islet cells.

The pyruvate-malate cycle was described in liver and kidney preparations as early as 1971.^[8]

References[edit]

^ Ronnebaum SM, Ilkayeva O, Burgess SC, et al. (October 2006). "A pyruvate cycling pathway involving cytosolic NADP-dependent isocitrate dehydrogenase regulates glucose-stimulated insulin secretion". The Journal of Biological Chemistry. 281 (41): 30593–602. doi:10.1074/jbc.M511908200. PMID 16912049.
^ Gregory RB, Berry MN (May 1992). "Stimulation by thyroid hormone of coupled respiration and of respiration apparently not coupled to the synthesis of ATP in rat hepatocytes". The Journal of Biological Chemistry. 267 (13): 8903–8. doi:10.1016/S0021-9258(19)50365-9. PMID 1577728.
^ Agius L, Tosh D, Peak M (January 1993). "The contribution of pyruvate cycling to loss of 6-3Hglucose during conversion of glucose to glycogen in hepatocytes: effects of insulin, glucose and acinar origin of hepatocytes". The Biochemical Journal. 289 (Pt 1): 255–62. doi:10.1042/bj2890255. PMC 1132158. PMID 8380985.
^ Pongratz RL, Kibbey RG, Cline GW (2009). "Chapter 24 Investigating the Roles of Mitochondrial and Cytosolic Malic Enzyme in Insulin Secretion". Mitochondrial Function, Part B: Mitochondrial Protein Kinases, Protein Phosphatases and Mitochondrial Diseases. Methods in Enzymology. Vol. 457. pp. 425–50. doi:10.1016/S0076-6879(09)05024-1. ISBN 978-0-12-374622-1. PMC 4422111. PMID 19426882.
^ Guay C, Madiraju SR, Aumais A, Joly E, Prentki M (December 2007). "A role for ATP-citrate lyase, malic enzyme, and pyruvate/citrate cycling in glucose-induced insulin secretion". The Journal of Biological Chemistry. 282 (49): 35657–65. doi:10.1074/jbc.M707294200. PMID 17928289.
^ Ronnebaum SM, Jensen MV, Hohmeier HE, et al. (October 2008). "Silencing of Cytosolic or Mitochondrial Isoforms of Malic Enzyme Has No Effect on Glucose-stimulated Insulin Secretion from Rodent Islets". The Journal of Biological Chemistry. 283 (43): 28909–17. doi:10.1074/jbc.M804665200. PMC 2570884. PMID 18755687.
^ Heart E, Cline GW, Collis LP, Pongratz RL, Gray JP, Smith PJ (June 2009). "Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion". American Journal of Physiology. Endocrinology and Metabolism. 296 (6): E1354–62. doi:10.1152/ajpendo.90836.2008. PMC 2692397. PMID 19293334.
^ Scaduto RC, Davis EJ (August 1986). "The involvement of pyruvate cycling in the metabolism of aspartate and glycerate by the perfused rat kidney". The Biochemical Journal. 237 (3): 691–8. doi:10.1042/bj2370691. PMC 1147046. PMID 3800911.

Further reading[edit]

Kley S, Hoenig M, Glushka J, et al. (April 2009). "The impact of obesity, sex, and diet on hepatic glucose production in cats". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 296 (4): R936–43. doi:10.1152/ajpregu.90771.2008. PMC 2698604. PMID 19193946.
Li C, Nissim I, Chen P, et al. (June 2008). "Elimination of KATP Channels in Mouse Islets Results in Elevated U-13CGlucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt". The Journal of Biological Chemistry. 283 (25): 17238–49. doi:10.1074/jbc.M709235200. PMC 2427330. PMID 18445600.
Ronnebaum SM, Joseph JW, Ilkayeva O, et al. (May 2008). "Chronic Suppression of Acetyl-CoA Carboxylase 1 in β-Cells Impairs Insulin Secretion via Inhibition of Glucose Rather Than Lipid Metabolism". The Journal of Biological Chemistry. 283 (21): 14248–56. doi:10.1074/jbc.M800119200. PMC 2386941. PMID 18381287.
Burgess SC, Iizuka K, Jeoung NH, et al. (January 2008). "Carbohydrate-response element-binding protein deletion alters substrate utilization producing an energy-deficient liver". The Journal of Biological Chemistry. 283 (3): 1670–8. doi:10.1074/jbc.M706540200. PMID 18042547.
Jin ES, Park BH, Sherry AD, Malloy CR (March 2007). "Role of excess glycogenolysis in fasting hyperglycemia among pre-diabetic and diabetic Zucker (fa/fa) rats". Diabetes. 56 (3): 777–85. doi:10.2337/db06-0717. PMID 17327448.
Rajas F, Jourdan-Pineau H, Stefanutti A, Mrad EA, Iynedjian PB, Mithieux G (May 2007). "Immunocytochemical localization of glucose 6-phosphatase and cytosolic phosphoenolpyruvate carboxykinase in gluconeogenic tissues reveals unsuspected metabolic zonation". Histochemistry and Cell Biology. 127 (5): 555–65. doi:10.1007/s00418-006-0263-5. PMID 17211624. S2CID 20621391.
Fransson U, Rosengren AH, Schuit FC, Renström E, Mulder H (July 2006). "Anaplerosis via pyruvate carboxylase is required for the fuel-induced rise in the ATP:ADP ratio in rat pancreatic islets". Diabetologia. 49 (7): 1578–86. doi:10.1007/s00125-006-0263-y. PMID 16752176.
Jensen MV, Joseph JW, Ilkayeva O, et al. (August 2006). "Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion". The Journal of Biological Chemistry. 281 (31): 22342–51. doi:10.1074/jbc.M604350200. PMID 16740637.
Jin ES, Burgess SC, Merritt ME, Sherry AD, Malloy CR (April 2005). "Differing mechanisms of hepatic glucose overproduction in triiodothyronine-treated rats vs. Zucker diabetic fatty rats by NMR analysis of plasma glucose". American Journal of Physiology. Endocrinology and Metabolism. 288 (4): E654–62. doi:10.1152/ajpendo.00365.2004. PMID 15562253. S2CID 5870945.
Burgess SC, Hausler N, Merritt M, et al. (November 2004). "Impaired tricarboxylic acid cycle activity in mouse livers lacking cytosolic phosphoenolpyruvate carboxykinase". The Journal of Biological Chemistry. 279 (47): 48941–9. doi:10.1074/jbc.M407120200. PMID 15347677.
Thompson SN (August 2004). "Dietary fat mediates hyperglycemia and the glucogenic response to increased protein consumption in an insect, Manduca sexta L". Biochimica et Biophysica Acta (BBA) - General Subjects. 1673 (3): 208–16. doi:10.1016/j.bbagen.2004.05.002. PMID 15279893.
Boucher A, Lu D, Burgess SC, et al. (June 2004). "Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue". The Journal of Biological Chemistry. 279 (26): 27263–71. doi:10.1074/jbc.M401167200. PMID 15073188.
Jin ES, Jones JG, Merritt M, Burgess SC, Malloy CR, Sherry AD (April 2004). "Glucose production, gluconeogenesis, and hepatic tricarboxylic acid cycle fluxes measured by nuclear magnetic resonance analysis of a single glucose derivative". Analytical Biochemistry. 327 (2): 149–55. doi:10.1016/j.ab.2003.12.036. hdl:10316/3869. PMID 15051530.
She P, Burgess SC, Shiota M, et al. (July 2003). "Mechanisms by which liver-specific PEPCK knockout mice preserve euglycemia during starvation". Diabetes. 52 (7): 1649–54. doi:10.2337/diabetes.52.7.1649. PMID 12829628.
Thompson SN, Borchardt DB, Wang LW (March 2003). "Dietary nutrient levels regulate protein and carbohydrate intake, gluconeogenic/glycolytic flux and blood trehalose level in the insect Manduca sexta L". Journal of Comparative Physiology B. 173 (2): 149–63. doi:10.1007/s00360-002-0322-8. PMID 12624653. S2CID 21527819.
Newgard CB, Lu D, Jensen MV, et al. (December 2002). "Stimulus/secretion coupling factors in glucose-stimulated insulin secretion: insights gained from a multidisciplinary approach". Diabetes. 51 Suppl 3 (90003): S389–93. doi:10.2337/diabetes.51.2007.S389. PMID 12475781.
Thompson SN, Redak RA, Borchardt DB (June 2002). "The glucogenic response of a parasitized insect Manduca sexta L. is partially mediated by differential nutrient intake". Biochimica et Biophysica Acta (BBA) - General Subjects. 1571 (2): 138–50. doi:10.1016/S0304-4165(02)00208-8. PMID 12049794.
Lu D, Mulder H, Zhao P, et al. (March 2002). "13C NMR isotopomer analysis reveals a connection between pyruvate cycling and glucose-stimulated insulin secretion (GSIS)". Proceedings of the National Academy of Sciences of the United States of America. 99 (5): 2708–13. doi:10.1073/pnas.052005699. PMC 122412. PMID 11880625.
Thompson SN (February 2001). "Parasitism enhances the induction of glucogenesis by the insect, Manduca sexta L". The International Journal of Biochemistry & Cell Biology. 33 (2): 163–73. doi:10.1016/S1357-2725(00)00079-0. PMID 11240373.
Thompson SN (August 2000). "Pyruvate cycling and implications for regulation of gluconeogenesis in the insect, Manduca sexta L". Biochemical and Biophysical Research Communications. 274 (3): 787–93. doi:10.1006/bbrc.2000.3238. PMID 10924355.
Landau BR, Chandramouli V, Schumann WC, et al. (July 1995). "Estimates of Krebs cycle activity and contributions of gluconeogenesis to hepatic glucose production in fasting healthy subjects and IDDM patients". Diabetologia. 38 (7): 831–8. doi:10.1007/s001250050360. PMID 7556986.
Tosh D, Beresford G, Agius L (November 1994). "Glycogen synthesis from glucose by direct and indirect pathways in hepatocyte cultures from different nutritional states". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1224 (2): 205–12. doi:10.1016/0167-4889(94)90192-9. PMID 7981234.
Kunz WS, Davis EJ (January 1991). "Control of reversible intracellular transfer of reducing potential". Archives of Biochemistry and Biophysics. 284 (1): 40–6. doi:10.1016/0003-9861(91)90260-P. PMID 1824912.
Rognstad R (August 1979). "Pyruvate cycling involving possible oxaloacetate decarboxylase activity". Biochimica et Biophysica Acta (BBA) - General Subjects. 586 (2): 242–9. doi:10.1016/0304-4165(79)90096-5. PMID 476141.

External links[edit]

"FIGURE 2: Biochemical mechanisms of glucose-stimulated insulin secretion, including roles of the pyruvate cycling pathways of the β-cell". from Muoio, Deborah M.; Newgard, Christopher B. (2008). "Mechanisms of disease: Molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes". Nature Reviews Molecular Cell Biology. 9 (3): 193–205. doi:10.1038/nrm2327. PMID 18200017. S2CID 3335727.

[1] Ronnebaum SM, Ilkayeva O, Burgess SC, et al. (October 2006). "A pyruvate cycling pathway involving cytosolic NADP-dependent isocitrate dehydrogenase regulates glucose-stimulated insulin secretion". The Journal of Biological Chemistry. 281 (41): 30593–602. doi:10.1074/jbc.M511908200. PMID 16912049.

[2] Gregory RB, Berry MN (May 1992). "Stimulation by thyroid hormone of coupled respiration and of respiration apparently not coupled to the synthesis of ATP in rat hepatocytes". The Journal of Biological Chemistry. 267 (13): 8903–8. doi:10.1016/S0021-9258(19)50365-9. PMID 1577728.

[3] Agius L, Tosh D, Peak M (January 1993). "The contribution of pyruvate cycling to loss of 6-3Hglucose during conversion of glucose to glycogen in hepatocytes: effects of insulin, glucose and acinar origin of hepatocytes". The Biochemical Journal. 289 (Pt 1): 255–62. doi:10.1042/bj2890255. PMC 1132158. PMID 8380985.

[4] Pongratz RL, Kibbey RG, Cline GW (2009). "Chapter 24 Investigating the Roles of Mitochondrial and Cytosolic Malic Enzyme in Insulin Secretion". Mitochondrial Function, Part B: Mitochondrial Protein Kinases, Protein Phosphatases and Mitochondrial Diseases. Methods in Enzymology. Vol. 457. pp. 425–50. doi:10.1016/S0076-6879(09)05024-1. ISBN 978-0-12-374622-1. PMC 4422111. PMID 19426882.

[5] Guay C, Madiraju SR, Aumais A, Joly E, Prentki M (December 2007). "A role for ATP-citrate lyase, malic enzyme, and pyruvate/citrate cycling in glucose-induced insulin secretion". The Journal of Biological Chemistry. 282 (49): 35657–65. doi:10.1074/jbc.M707294200. PMID 17928289.

[6] Ronnebaum SM, Jensen MV, Hohmeier HE, et al. (October 2008). "Silencing of Cytosolic or Mitochondrial Isoforms of Malic Enzyme Has No Effect on Glucose-stimulated Insulin Secretion from Rodent Islets". The Journal of Biological Chemistry. 283 (43): 28909–17. doi:10.1074/jbc.M804665200. PMC 2570884. PMID 18755687.

[7] Heart E, Cline GW, Collis LP, Pongratz RL, Gray JP, Smith PJ (June 2009). "Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion". American Journal of Physiology. Endocrinology and Metabolism. 296 (6): E1354–62. doi:10.1152/ajpendo.90836.2008. PMC 2692397. PMID 19293334.

[8] Scaduto RC, Davis EJ (August 1986). "The involvement of pyruvate cycling in the metabolism of aspartate and glycerate by the perfused rat kidney". The Biochemical Journal. 237 (3): 691–8. doi:10.1042/bj2370691. PMC 1147046. PMID 3800911.

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