Oncotarget

Research Papers:

Pyruvate kinase is a dosage-dependent regulator of cellular amino acid homeostasis

Katharina Bluemlein, Matthias Glueckmann, Nana-Maria Grüning, René Feichtinger, Antje Krüger, Mirjam MC. Wamelink, Hans Lehrach, Stephen Tate, Daniel Neureiter, Kofler Barbara and Markus Ralser _

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Oncotarget. 2012; 3:1356-1369. https://doi.org/10.18632/oncotarget.730

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Abstract

Katharina Bluemlein1,*, Matthias Glückmann2,*, Nana-Maria Grüning1, René Feichtinger4, Antje Krüger3, Mirjam Wamelink6, Hans Lehrach3, Stephen Tate5, Daniel Neureiter7, Barbara Kofler4, and Markus Ralser1,3,*

1 Department of Biochemistry & Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom

2 AB SCIEX, Landwehrstrasse, Darmstadt, Germany

3 Max Planck Institute for Molecular Genetics, Berlin, Germany

4 Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, University Hospital Salzburg, Salzburg, Austria

5 AB SCIEX, Concord, Ontario, Canada

6 VU University Medical Center Amsterdam , Amsterdam, The Netherlands

7 Institute of Pathology, Paracelsus Medical University, University Hospital Salzburg, Salzburg, Austria

* denotes equal contribution

Correspondence:

Markus Ralser, email:

Keywords: cancer metabolism, pyruvate kinase, proteomics, amino acid profile

Received: October 29, 2012, Accepted: October 30, 2012, Published: November 01, 2012

Abstract

The glycolytic enzyme pyruvate kinase (PK) is required for cancer development, and has been implicated in the metabolic transition from oxidative to fermentative metabolism, the Warburg effect. However, the global metabolic response that follows changes in PK activity is not yet fully understood. Using shotgun proteomics, we identified 31 yeast proteins that were regulated in a PK-dependent manner. Selective reaction monitoring confirmed that their expression was dependent on PK isoform, level and activity. Most of the PK targets were amino acid metabolizing enzymes or factors of protein translation, indicating that PK plays a global regulatory role in biosynthethic amino acid metabolism. Indeed, we found strongly altered amino acid profiles when PK levels were changed. Low PK levels increased the cellular glutamine and glutamate concentrations, but decreased the levels of seven amino acids including serine and histidine. To test for evolutionary conservation of this PK function, we quantified orthologues of the identified PK targets in thyroid follicular adenoma, a tumor characterized by high PK levels and low respiratory activity. Aminopeptidase AAP-1 and serine hydroxymethyltransferase SHMT1 both showed PKM2- concentration dependence, and were upregulated in the tumor. Thus, PK expression levels and activity were important for maintaining cellular amino acid homeostasis. Mediating between energy production, ROS clearance and amino acid biosynthesis, PK thus plays a central regulatory role in the metabolism of proliferating cells.


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