Serine is a natural ligand and allosteric activator of pyruvate kinase M2.
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.
Cancer Research UK, The Beatson Institute for Cancer Research, Switchback Road, Glasgow, G61 1BD, Scotland, United Kingdom.
Barbara
B
Chaneton
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
Petra
P
Hillmann
Cancer Research UK, The Beatson Institute for Cancer Research, Switchback Road, Glasgow, G61 1BD, Scotland, United Kingdom.
Liang
L
Zheng
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
Agnès C L
ACL
Martin
Cancer Research UK, The Beatson Institute for Cancer Research, Switchback Road, Glasgow, G61 1BD, Scotland, United Kingdom.
Oliver D K
ODK
Maddocks
Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, Joseph Black Building, B3.09, University of Glasgow, Glasgow, G12 8QQ, Scotland, United Kingdom.
Achuthanunni
A
Chokkathukalam
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
Joseph E
JE
Coyle
Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, Joseph Black Building, B3.09, University of Glasgow, Glasgow, G12 8QQ, Scotland, United Kingdom.|Groningen Bioinformatics Centre, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.
Andris
A
Jankevics
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
Finn P
FP
Holding
Cancer Research UK, The Beatson Institute for Cancer Research, Switchback Road, Glasgow, G61 1BD, Scotland, United Kingdom.
Karen H
KH
Vousden
Cancer Research UK, The Beatson Institute for Cancer Research, Switchback Road, Glasgow, G61 1BD, Scotland, United Kingdom.
Christian
C
Frezza
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
Marc
M
O'Reilly
Cancer Research UK, The Beatson Institute for Cancer Research, Switchback Road, Glasgow, G61 1BD, Scotland, United Kingdom.
Eyal
E
Gottlieb
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D005998:Glycine / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism* / Q000494:pharmacology
D020536:Enzyme Activators; D008024:Ligands; D011994:Recombinant Proteins; D012694:Serine; D019289:Pyruvic Acid; D011770:Pyruvate Kinase; D005947:Glucose; D005998:Glycine