Serine is a natural ligand and allosteric activator of pyruvate kinase M2

By B. Chaneton, Petra Hillmann, Liang Zheng, Agnés C. L. Martin, O. Maddocks, Achuthanunni Chokkathukalam, J. Coyle, A. Jankevics, F. Holding, Karen H. Vousden and 3 more. Nature, 2012

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Cancer cells exhibit several unique metabolic phenotypes that are critical for cell growth and proliferation. Specifically, they overexpress the M2 isoform of the tightly regulated enzyme pyruvate kinase (PKM2), which controls glycolytic flux, and are highly dependent on de novo biosynthesis of serine and glycine. Here we describe a new rheostat-like mechanistic relationship between PKM2 activity and serine biosynthesis. We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation. This reduction in PKM2 activity shifts cells to a fuel-efficient mode in which more pyruvate is diverted to the mitochondria and more glucose-derived carbon is channelled into serine biosynthesis to support cell proliferation.

Subfields: Biochemistry, Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/5719faa3af2f5241f9b49cbb5fc81692304897da

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Citations in the corpus

HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. (2013, neutral): “First and foremost, PKM2 functions as a pyruvate kinase in glycolysis (Figure 3) but, in contrast to PKM1, its activity is regulated by allosteric interactions with phosphopeptides (67) and intermediary metabolites (68, 69) as well as by phosphorylation, acetylation, and oxidation (70–72).”
Regulation of glycolysis by the hypoxia‐inducible factor (HIF): implications for cellular physiology (2020, background): “These enzymes; hexokinase, phosphofructokinase and pyruvate kinase, are allosterically regulated and are understood to have important roles in the regulation of glycolytic flux (Jurica et al. 1998; Kemp & Gunasekera, 2002; Chaneton et al. 2012).”
MYC, metabolism, cell growth, and tumorigenesis. (2013, background): “The glycolytic intermediate 3- phosphoglycerate is a substrate for the synthesis of lipids, as well as a precursor of serine and glycine (Chaneton et al. 2012).”
Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages (2015, positive): “, 1998), serine (Chaneton et al., 2012), as well as by a multitude of post-translational modifications (Wu and Le, 2013) including tyrosine phosphorylation.”
The return of metabolism: biochemistry and physiology of the pentose phosphate pathway (2014, background): “Allosteric activation of PKM2 can be achieved by interaction with fructose 1,6-bisphosphate, succinylaminoimidazolecarboxamide ribose 5′-phosphate (SAICAR) and serine (Chaneton et al., 2012; Keller, Tan & Lee, 2012).”
Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013, background): “The expression of SBP enzymes is LDHA Citrate α-Ketoglutarate Fumarate Malate Oxaloacetate Ac-CoA Pyruvate Glutamate Glutamine Lactate TCA cycle SDH GLS PDH PKM2 Succinate Ac-CoA Lipids Aspartate Amino acids Glutaminolysis Glycolysis PEP 3PG Glucose 6-”