Deactivation by S-Glutathionylation overrules activation by PRMT1-dependent asymmetrical di-methylation in PFKFB3
Main Article Content
Abstract
To understand PFKFB3 control by covalent modifications, the structure/function effect of protein arginine methyl transferase 1-dependent asymmetric di-methylations at Arg131 and Arg134 (N-CH3) and its relationship to S-glutathionylation at Cys206 (S-Gsh) was investigated. Distinctly from the report that N-CH3 is for protection of PFKFB3 from the APC/C-Cdh-mediated polyubiquitination and proteolysis, an increase in the activity for Fru-2,6-P2 production was shown from a molecular simulation and in-vitro tests. The simulation suggested that N-CH3 would uncouple the Fru-6-P entry turn (-130TRERRH-) from its coupling to the p-helix (-204DKCDRD-) by disabling the interaction between Arg131/134 and Asp207. The uncoupling consequently is likely to facilitate the Fru-6-P binding by enhancing the conformational flexibility.
Confirming the simulation, N-CH3 was shown to cause a 5-fold increase in the specific activity (kcat/Km) mostly through a 4-fold decrease in Kms for Fru-6-P. A similar extent of activation was induced by Asp207àA mutagenesis, which disables the coupling, while the activation by N-CH3 was almost abolished by Arg131àA mutagenesis. More interestingly, PFKFB3 with N-CH3 could be additionally S-glutathionylated at Cys206, when oxidative stress is elevated. When modified by both N-CH3 and S-Gsh, the activity was decreased, as if there was no N-CH3 at all, suggesting that the deactivation completely overrules the activation.
When HeLa cells were treated for the dual modifications of PFKFB3, the overruling deactivation effect of S-Gsh was prevalent, causing decreases in Fru-2,6-P2 levels and increases in glycolytic flux redirected to the pentose phosphate pathway. As a result, the levels of NADPH and reduced glutathione were markedly elevated, enhancing cell viability under the conditions of elevated oxidative stress. Altogether, it is suggested that the functional effect of S-Gsh, which represents a mechanism for survival under detrimental oxidative stress, dominates over the effect of N-CH3, which has been suggested as a mechanism for growth.
Keywords:
PFKFB3, N-methylation, S-glutathionylation, glycolysis, pentose phosphate pathway, Oxidative stress, Covalent control
Article Details
How to Cite
KIM, Jeong-Do et al.
Deactivation by S-Glutathionylation overrules activation by PRMT1-dependent asymmetrical di-methylation in PFKFB3.
Medical Research Archives, [S.l.], v. 10, n. 1, jan. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2654>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v10i1.2654.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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7. Minchenko A, Leshchinsky I, Opentanova I, et al. Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) gene. Its possible role in the Warburg effect. J Biol Chem. Feb 22 2002;277(8):6183-7.
8. Atsumi T, Chesney J, Metz C, et al. High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res. Oct 15 2002;62(20):5881-7.
9. Depre C, Veitch K, Hue L. Role of fructose 2,6-bisphosphate in the control of glycolysis. Stimulation of glycogen synthesis by lactate in the isolated working rat heart. Acta Cardiol. 1993;48(1):147-64.
10. Pilkis SJ, Granner, D.K. . Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis. Ann Rev Physiol. 1992;54:885-909.
11. Ogush S, Lawson JW, Dobson GP, Veech RL, Uyeda K. A new transient activator of phosphofructokinase during initiation of rapid glycolysis in brain. J Biol Chem. Jul 5 1990;265(19):10943-9.
12. Pilkis SJ, El-Maghrabi MR, Claus TH. Hormonal regulation of hepatic gluconeogenesis and glycolysis. . Ann Rev Biochem. 1988;55:755-783.
13. Rousseau GG, Hue L. Mammalian 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase: a bifunctional enzyme that controls glycolysis. . Prog Nucl Acid Res Mol Biol. 1993;45:99-127.
14. Pilkis SJ, Claus TH, Kurland IJ, Lange AJ. 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase: A metabolic signaling enzyme. Annu Rev Biochem. 1995;64:799-835.
15. El-Maghrabi MR, Noto F, Wu N, Manes N. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: suiting structure to need, in a family of tissue-specific enzymes. Curr Opin Clin Nutr Metab Care. Sep 2001;4(5):411-8.
16. Yalcin A, Clem BF, Imbert-Fernandez Y, et al. 6-Phosphofructo-2-kinase (PFKFB3) promotes cell cycle progression and suppresses apoptosis via Cdk1-mediated phosphorylation of p27. Cell Death Dis. 2014;5:e1337. doi:10.1038/cddis.2014.292
17. Verbon EH, Post JA, Boonstra J. The influence of reactive oxygen species on cell cycle progression in mammalian cells. Review. Gene. Dec 10 2012;511(1):1-6. doi:10.1016/j.gene.2012.08.038
18. Boonstra J, Post JA. Molecular events associated with reactive oxygen species and cell cycle progression in mammalian cells. Review. Gene. Aug 4 2004;337:1-13. doi:10.1016/j.gene.2004.04.032
19. Perez JX, Roig T, Manzano A, et al. Over expression of fructose-2,6-bisphosphatase decreases glycolysis and cell cycle progression. Am J Physiol Cell Physiol. 2000;279:C1359-C1364.
20. Cantelmo AR, Conradi LC, Brajic A, et al. Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy. Cancer Cell. Dec 12 2016;30(6):968-985. doi:10.1016/j.ccell.2016.10.006
21. De Bock K, Georgiadou M, Schoors S, et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell. Aug 1 2013;154(3):651-63. doi:10.1016/j.cell.2013.06.037
22. Garber K. Energy boost: the Warburg effect returns in a new theory of cancer. J Natl Cancer Inst. Dec 15 2004;96(24):1805-6.
23. Zhu W, Ye L, Zhang J, et al. PFK15, a Small Molecule Inhibitor of PFKFB3, Induces Cell Cycle Arrest, Apoptosis and Inhibits Invasion in Gastric Cancer. PLoS One. 2016;11(9):e0163768. doi:10.1371/journal.pone.0163768
24. Xu Y, An X, Guo X, et al. Endothelial PFKFB3 plays a critical role in angiogenesis. Arterioscler Thromb Vasc Biol. Jun 2014;34(6):1231-9. doi:10.1161/ATVBAHA.113.303041
25. Boyd S, Brookfield JL, Critchlow SE, et al. Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3. J Med Chem. Apr 23 2015;58(8):3611-25. doi:10.1021/acs.jmedchem.5b00352
26. Clem BF, O'Neal J, Tapolsky G, et al. Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol Cancer Ther. Aug 2013;12(8):1461-70. doi:10.1158/1535-7163.MCT-13-0097
27. Seo M, Kim JD, Neau D, Sehgal I, Lee YH. Structure-based development of small molecule PFKFB3 inhibitors: a framework for potential cancer therapeutic agents targeting the Warburg effect. PLoS One. 2011;6(9):e24179. doi:10.1371/journal.pone.0024179
28. Crochet RB, Cavalier MC, Seo M, et al. Investigating combinatorial approaches in virtual screening on human inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3): a case study for small molecule kinases. Analytical biochemistry. Nov 1 2011;418(1):143-8. doi:10.1016/j.ab.2011.06.035
29. Reid MA, Lowman XH, Pan M, et al. IKKbeta promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3. Genes Dev. Aug 15 2016;30(16):1837-51. doi:10.1101/gad.287235.116
30. Bando H, Atsumi T, Nishio T, et al. Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer. Comparative Study. Clinical cancer research. Aug 15 2005;11(16):5784-92. doi:10.1158/1078-0432.CCR-05-0149
31. Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG, Hue L. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis. Biochem J. Aug 1 2004;381(Pt 3):561-79.
32. Seo M, Lee YH. PFKFB3 regulates oxidative stress homeostasis via its S-glutathionylation in cancer. J Mol Biol. Feb 20 2014;426(4):830-42. doi:10.1016/j.jmb.2013.11.021
33. Tudzarova S, Colombo SL, Stoeber K, Carcamo S, Williams GH, Moncada S. Two ubiquitin ligases, APC/C-Cdh1 and SKP1-CUL1-F (SCF)-beta-TrCP, sequentially regulate glycolysis during the cell cycle. Research Support, Non-U.S. Gov't. Proceedings of the National Academy of Sciences of the United States of America. Mar 29 2011;108(13):5278-83. doi:10.1073/pnas.1102247108
34. Vizan P, Alcarraz-Vizan G, Diaz-Moralli S, Solovjeva ON, Frederiks WM, Cascante M. Modulation of pentose phosphate pathway during cell cycle progression in human colon adenocarcinoma cell line HT29. Research Support, Non-U.S. Gov't. International journal of cancer Journal international du cancer. Jun 15 2009;124(12):2789-96. doi:10.1002/ijc.24262
35. Kim SG, Cavalier M, El-Maghrabi MR, Lee YH. A direct substrate-substrate interaction found in the kinase domain of the bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Research Support, Non-U.S. Gov't. Journal of molecular biology. Jun 29 2007;370(1):14-26. doi:10.1016/j.jmb.2007.03.038
36. Kim SG, Manes NP, El-Maghrabi MR, Lee YH. Crystal structure of the hypoxia-inducible form of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3): a possible new target for cancer therapy. Research Support, Non-U.S. Gov't. The Journal of biological chemistry. Feb 3 2006;281(5):2939-44. doi:10.1074/jbc.M511019200
37. Boada J, Roig T, Perez X, et al. Cells overexpressing fructose-2,6-bisphosphatase showed enhanced pentose phosphate pathway flux and resistance to oxidative stress. Research Support, Non-U.S. Gov't. FEBS letters. Sep 1 2000;480(2-3):261-4.
38. Urner F, Sakkas D. Characterization of glycolysis and pentose phosphate pathway activity during sperm entry into the mouse oocyte. Research Support, Non-U.S. Gov't. Biology of reproduction. Apr 1999;60(4):973-8.
39. Israelsen WJ, Dayton TL, Davidson SM, et al. PKM2 Isoform-Specific Deletion Reveals a Differential Requirement for Pyruvate Kinase in Tumor Cells. Cell. Oct 10 2013;155(2):397-409. doi:10.1016/j.cell.2013.09.025
40. Anastasiou D, Poulogiannis G, Asara JM, et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science. Dec 2 2011;334(6060):1278-83. doi:10.1126/science.1211485
41. Yi W, Clark PM, Mason DE, et al. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science. Aug 24 2012;337(6097):975-80. doi:10.1126/science.1222278
42. Yamamoto T, Takano N, Ishiwata K, et al. Reduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway. Nat Commun. Mar 17 2014;5:3480. doi:10.1038/ncomms4480
43. Morales Y, Nitzel DV, Price OM, et al. Redox Control of Protein Arginine Methyltransferase 1 (PRMT1) Activity. J Biol Chem. Jun 12 2015;290(24):14915-26. doi:10.1074/jbc.M115.651380
44. Lee YH, Li Y, Uyeda K, Hasemann CA. Tissue-specific structure/function differentiation of the liver isoform of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. J Biol Chem. Jan 3 2003;278(1):523-30.
45. Moritz B, Striegel K, de Graaf AA, Sahm H. Changes of Pentose Phosphate Pathway Flux in Vivo in Corynebacterium glutamicum during Leucine-Limited Batch Cultivation as Determined from Intracellular Metabolite Concentration Measurements. Metabolic Engineering. 2002;4(4):295-305. doi:10.1006/mben.2002.0233
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