An allostatic mechanism for M2 pyruvate kinase as an amino-acid sensor

The Biochemical Journal
Meng YuanMalcolm D Walkinshaw

Abstract

We have tested the effect of all 20 proteinogenic amino acids on the activity of the M2 isoenzyme of pyruvate kinase (M2PYK) and show that, within physiologically relevant concentrations, phenylalanine, alanine, tryptophan, methionine, valine, and proline act as inhibitors, while histidine and serine act as activators. Size exclusion chromatography has been used to show that all amino acids, whether activators or inhibitors, stabilise the tetrameric form of M2PYK. In the absence of amino-acid ligands an apparent tetramer-monomer dissociation Kd is estimated to be ∼0.9 µM with a slow dissociation rate (t1/2 ∼ 15 min). X-ray structures of M2PYK complexes with alanine, phenylalanine, and tryptophan show the M2PYK locked in an inactive T-state conformation, while activators lock the M2PYK tetramer in the active R-state conformation. Amino-acid binding in the allosteric pocket triggers rigid body rotations (11°) stabilising either T or R states. The opposing inhibitory and activating effects of the non-essential amino acids serine and alanine suggest that M2PYK could act as a rapid-response nutrient sensor to rebalance cellular metabolism. This competition at a single allosteric site between activators and inhibitors provides a nove...Continue Reading

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Citations

Sep 27, 2018·The Biochemical Journal·Alice Rose MitchellMalcolm D Walkinshaw
Oct 28, 2019·Bioscience Reports·Ting TaoXiaoping Yang
Feb 1, 2020·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Sabih RashidLesley T MacNeil
Oct 24, 2019·FEBS Letters·Vivian M LiuMatthew G Vander Heiden
Mar 8, 2020·The Journal of Biological Chemistry·Suparno Nandi, Mishtu Dey
Aug 12, 2019·Free Radical Biology & Medicine·Mohammed AlquraishiAhmed Bettaieb
Jan 30, 2021·The Journal of Biological Chemistry·Suparno Nandi, Mishtu Dey
Jul 27, 2021·Journal of Cellular Physiology·Yoon-Beom LeeJae-Bong Park
Nov 3, 2021·Journal of Medicinal Chemistry·Sahil AroraRaj Kumar

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Methods Mentioned

BETA
acetylation
ELISA
X-ray
ELISAs
Gel filtration
gel-filtration

Software Mentioned

REFMAC
PHASER
COOT
Berkley Madonna

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