Interdomain conformational changes provide allosteric regulation en route to chorismate

Ali Reza Nazmi, Eric J.M. Lang, Yu Bai, Timothy M. Allison, Mohamad H. Othman, Santosh Panjikar, Vickery L. Arcus, Emily J. Parker

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Multifunctional proteins play a variety of roles in metabolism. Here, we examine the catalytic function of the combined 3-deoxy-D-arabino heptulosonate-7-phosphate synthase (DAH7PS) and chorismate mutase (CM) from Geobacillus sp. DAH7PS operates at the start of the biosynthetic pathway for aromatic metabolites, whereas CM operates in a dedicated branch of the pathway for the biosynthesis of amino acids tyrosine and phenylalanine. In line with sequence predictions, the two catalytic functions are located in distinct domains, and these two activities can be separated and retain functionality. For the full-length protein, prephenate, the product of the CM reaction, acts as an allosteric inhibitor for the DAH7PS. The crystal structure of the full-length protein with prephenate bound and the accompanying small angle x-ray scattering data reveal the molecular mechanism of the allostery. Prephenate binding results in the tighter association between the dimeric CM domains and the tetrameric DAH7PS, occluding the active site and therefore disrupting DAH7PS function. Acquisition of a physical gating mechanism to control catalytic function through gene fusion appears to be a general mechanism for providing allostery for this enzyme.

Original languageEnglish
Pages (from-to)21836-21847
Number of pages12
JournalJournal of Biological Chemistry
Volume291
Issue number42
DOIs
Publication statusPublished - 14 Oct 2016

Cite this

Nazmi, A. R., Lang, E. J. M., Bai, Y., Allison, T. M., Othman, M. H., Panjikar, S., ... Parker, E. J. (2016). Interdomain conformational changes provide allosteric regulation en route to chorismate. Journal of Biological Chemistry, 291(42), 21836-21847. https://doi.org/10.1074/jbc.M116.741637
Nazmi, Ali Reza ; Lang, Eric J.M. ; Bai, Yu ; Allison, Timothy M. ; Othman, Mohamad H. ; Panjikar, Santosh ; Arcus, Vickery L. ; Parker, Emily J. / Interdomain conformational changes provide allosteric regulation en route to chorismate. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 42. pp. 21836-21847.
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abstract = "Multifunctional proteins play a variety of roles in metabolism. Here, we examine the catalytic function of the combined 3-deoxy-D-arabino heptulosonate-7-phosphate synthase (DAH7PS) and chorismate mutase (CM) from Geobacillus sp. DAH7PS operates at the start of the biosynthetic pathway for aromatic metabolites, whereas CM operates in a dedicated branch of the pathway for the biosynthesis of amino acids tyrosine and phenylalanine. In line with sequence predictions, the two catalytic functions are located in distinct domains, and these two activities can be separated and retain functionality. For the full-length protein, prephenate, the product of the CM reaction, acts as an allosteric inhibitor for the DAH7PS. The crystal structure of the full-length protein with prephenate bound and the accompanying small angle x-ray scattering data reveal the molecular mechanism of the allostery. Prephenate binding results in the tighter association between the dimeric CM domains and the tetrameric DAH7PS, occluding the active site and therefore disrupting DAH7PS function. Acquisition of a physical gating mechanism to control catalytic function through gene fusion appears to be a general mechanism for providing allostery for this enzyme.",
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Nazmi, AR, Lang, EJM, Bai, Y, Allison, TM, Othman, MH, Panjikar, S, Arcus, VL & Parker, EJ 2016, 'Interdomain conformational changes provide allosteric regulation en route to chorismate' Journal of Biological Chemistry, vol. 291, no. 42, pp. 21836-21847. https://doi.org/10.1074/jbc.M116.741637

Interdomain conformational changes provide allosteric regulation en route to chorismate. / Nazmi, Ali Reza; Lang, Eric J.M.; Bai, Yu; Allison, Timothy M.; Othman, Mohamad H.; Panjikar, Santosh; Arcus, Vickery L.; Parker, Emily J.

In: Journal of Biological Chemistry, Vol. 291, No. 42, 14.10.2016, p. 21836-21847.

Research output: Contribution to journalArticleResearchpeer-review

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