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The phosphoglycerate kinase 1 variants found in carcinoma cells display different catalytic activity and conformational stability compared to the native enzyme.

Fiorillo A, Petrosino M, Ilari A, Pasquo A, Cipollone A, Maggi M, Chiaraluce R, Consalvi V
PLoS One 13 e0199191 (2018)
Related entries: 5m3u, 5m6z, 5mxm, 5o7d

Cited: 14 times
EuropePMC logo PMID: 29995887

Abstract

Cancer cells are able to survive in difficult conditions, reprogramming their metabolism according to their requirements. Under hypoxic conditions they shift from oxidative phosphorylation to aerobic glycolysis, a behavior known as Warburg effect. In the last years, glycolytic enzymes have been identified as potential targets for alternative anticancer therapies. Recently, phosphoglycerate kinase 1 (PGK1), an ubiquitous enzyme expressed in all somatic cells that catalyzes the seventh step of glycolysis which consists of the reversible phosphotransfer reaction from 1,3-bisphosphoglycerate to ADP, has been discovered to be overexpressed in many cancer types. Moreover, several somatic variants of PGK1 have been identified in tumors. In this study we analyzed the effect of the single nucleotide variants found in cancer tissues on the PGK1 structure and function. Our results clearly show that the variants display a decreased catalytic efficiency and/or thermodynamic stability and an altered local tertiary structure, as shown by the solved X-ray structures. The changes in the catalytic properties and in the stability of the PGK1 variants, mainly due to the local changes evidenced by the X-ray structures, suggest also changes in the functional role of PGK to support the biosynthetic need of the growing and proliferating tumour cells.

Reviews citing this publication (7)

  1. Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK. Moldogazieva NT, Mokhosoev IM, Terentiev AA. Cancers (Basel) 12 E862 (2020)
  2. PGK1-mediated cancer progression and drug resistance. He Y, Luo Y, Zhang D, Wang X, Zhang P, Li H, Ejaz S, Liang S. Am J Cancer Res 9 2280-2302 (2019)
  3. Energy Metabolism in Cancer: The Roles of STAT3 and STAT5 in the Regulation of Metabolism-Related Genes. Valle-Mendiola A, Soto-Cruz I. Cancers (Basel) 12 E124 (2020)
  4. Analysis and Interpretation of the Impact of Missense Variants in Cancer. Petrosino M, Novak L, Pasquo A, Chiaraluce R, Turina P, Capriotti E, Consalvi V. Int J Mol Sci 22 5416 (2021)
  5. Metabolic Reprogramming in Cancer: Role of HPV 16 Variants. Arizmendi-Izazaga A, Navarro-Tito N, Jiménez-Wences H, Mendoza-Catalán MA, Martínez-Carrillo DN, Zacapala-Gómez AE, Olea-Flores M, Dircio-Maldonado R, Torres-Rojas FI, Soto-Flores DG, Illades-Aguiar B, Ortiz-Ortiz J. Pathogens 10 347 (2021)
  6. Phosphoglycerate kinase: structural aspects and functions, with special emphasis on the enzyme from Kinetoplastea. Rojas-Pirela M, Andrade-Alviárez D, Rojas V, Kemmerling U, Cáceres AJ, Michels PA, Concepción JL, Quiñones W. Open Biol 10 200302 (2020)
  7. Regulation of phosphoglycerate kinase 1 and its critical role in cancer. Zhang K, Sun L, Kang Y. Cell Commun Signal 21 240 (2023)

Articles citing this publication (7)

  1. Proton export alkalinizes intracellular pH and reprograms carbon metabolism to drive normal and malignant cell growth. Man CH, Mercier FE, Liu N, Dong W, Stephanopoulos G, Jiang L, Jung Y, Lin CP, Leung AYH, Scadden DT. Blood 139 502-522 (2022)
  2. Potent Anticancer Effect of the Natural Steroidal Saponin Gracillin Is Produced by Inhibiting Glycolysis and Oxidative Phosphorylation-Mediated Bioenergetics. Min HY, Pei H, Hyun SY, Boo HJ, Jang HJ, Cho J, Kim JH, Son J, Lee HY. Cancers (Basel) 12 E913 (2020)
  3. PGK1 : An Essential Player in Modulating Tumor Metabolism. Duncan L, Shay C, Teng Y. Methods Mol Biol 2343 57-70 (2022)
  4. Metabolic protein phosphoglycerate kinase 1 confers lung cancer migration by directly binding HIV Tat specific factor 1. Chang YC, Chan MH, Li CH, Yang CJ, Tseng YW, Tsai HF, Chiou J, Hsiao M. Cell Death Discov 7 135 (2021)
  5. Loss of stability and unfolding cooperativity in hPGK1 upon gradual structural perturbation of its N-terminal domain hydrophobic core. Pacheco-García JL, Loginov DS, Naganathan AN, Vankova P, Cano-Muñoz M, Man P, Pey AL. Sci Rep 12 17200 (2022)
  6. Extracellular Pgk1 interacts neural membrane protein enolase-2 to improve the neurite outgrowth of motor neurons. Fu CY, Chen HY, Lin CY, Chen SJ, Sheu JC, Tsai HJ. Commun Biol 6 849 (2023)
  7. The complex impact of cancer-related missense mutations on the stability and on the biophysical and biochemical properties of MAPK1 and MAPK3 somatic variants. Petrosino M, Novak L, Pasquo A, Turina P, Capriotti E, Minicozzi V, Consalvi V, Chiaraluce R. Hum Genomics 17 95 (2023)


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