Differentiating a ligand's chemical requirements for allosteric interactions from those for protein binding. Phenylalanine inhibition of pyruvate kinase

Biochemistry
Rachel WilliamsAron W Fenton

Abstract

The isoform of pyruvate kinase from brain and muscle of mammals (M(1)-PYK) is allosterically inhibited by phenylalanine. Initial observations in this model allosteric system indicate that Ala binds competitively with Phe, but elicits a minimal allosteric response. Thus, the allosteric ligand of this system must have requirements for eliciting an allosteric response in addition to the requirements for binding. Phe analogues have been used to dissect what chemical properties of Phe are responsible for eliciting the allosteric response. We first demonstrate that the l-2-aminopropanaldehyde substructure of the amino acid ligand is primarily responsible for binding to M(1)-PYK. Since the allosteric response to Ala is minimal and linear addition of methyl groups beyond the beta-carbon increase the magnitude of the allosteric response, we conclude that moieties beyond the beta-carbon are primarily responsible for allostery. Instead of an all-or-none mechanism of allostery, these findings support the idea that the bulk of the hydrophobic side chain, but not the aromatic nature, is the primary determinant of the magnitude of the observed allosteric inhibition. The use of these results to direct structural studies has resulted in a 1.65 ...Continue Reading

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Citations

Jun 28, 2011·Analytical and Bioanalytical Chemistry·Charulata B PrasannanAron W Fenton
Mar 27, 2013·Proceedings of the National Academy of Sciences of the United States of America·Hugh P MorganMalcolm D Walkinshaw
Sep 4, 2013·Acta Crystallographica. Section D, Biological Crystallography·Wenhe ZhongMalcolm D Walkinshaw
May 23, 2014·Journal of Molecular Modeling·Natércia F BrásMaria J Ramos
Dec 5, 2014·International Journal of Molecular Sciences·Leticia Ramírez-SilvaNallely Cabrera
May 4, 2010·International Journal of Biological Macromolecules·Yan OuShaoning Yu
May 27, 2009·Archives of Biochemistry and Biophysics·Aron W Fenton, Myra Hutchinson
Aug 19, 2008·Trends in Biochemical Sciences·Aron W Fenton
Sep 9, 2008·Journal of Molecular Biology·Lindsay B TullochMalcolm D Walkinshaw
Jul 21, 2015·General and Comparative Endocrinology·Jinyoung ChoiDaniel R Buchholz
Jul 16, 2010·Protein Science : a Publication of the Protein Society·Aron W FentonTodd Holyoak
Aug 19, 2015·Seminars in Cell & Developmental Biology·William J Israelsen, Matthew G Vander Heiden
Jun 12, 2013·International Journal of Biological Macromolecules·Feng LiShaoning Yu
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