Remote Control by Inter-Enzyme Allostery: A Novel Paradigm for Regulation of the Shikimate Pathway

Journal of Molecular Biology
Steffi MunackUte Krengel

Abstract

DAHP synthase and chorismate mutase catalyze key steps in the shikimate biosynthetic pathway en route to aromatic amino acids. In Mycobacterium tuberculosis, chorismate mutase (MtCM; Rv0948c), located at the branch point toward phenylalanine and tyrosine, has poor activity on its own. However, it is efficiently activated by the first enzyme of the pathway, DAHP synthase (MtDS; Rv2178c), through formation of a non-covalent MtCM-MtDS complex. Here, we show how MtDS serves as an allosteric platform for feedback regulation of both enzymes, using X-ray crystallography, small-angle X-ray scattering, size-exclusion chromatography, and multi-angle light scattering. Crystal structures of the fully inhibited MtDS and the allosterically down-regulated MtCM-MtDS complex, solved at 2.8 and 2.7Å, respectively, reveal how effector binding at the internal MtDS subunit interfaces regulates the activity of MtDS and MtCM. While binding of all three metabolic end products to MtDS shuts down the entire pathway, the binding of phenylalanine jointly with tyrosine releases MtCM from the MtCM-MtDS complex, hence suppressing MtCM activation by 'inter-enzyme allostery'. This elegant regulatory principle, invoking a transient allosteric enzyme interaction...Continue Reading

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Citations

Feb 17, 2017·Bioorganic & Medicinal Chemistry·Manjulatha KhanapurManojit Pal
Jun 6, 2017·Biochemistry·Danielle L Schmitt, Songon An
May 3, 2018·Acta Crystallographica. Section F, Structural Biology Communications·Oluwatoyin A AsojoPeter J Myler
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Oct 12, 2020·The Journal of Biological Chemistry·Jūratė Fahrig-KamarauskaitėPeter Kast
Aug 3, 2020·Current Opinion in Structural Biology·Wanting JiaoEmily J Parker
Feb 11, 2021·Applied Microbiology and Biotechnology·Yi JiangTengfei Wang
Feb 20, 2021·Chemical Communications : Chem Comm·Florian HubrichJennifer N Andexer
Jan 18, 2021·The Journal of Biological Chemistry·Jūrate Fahrig-KamarauskaitPeter Kast
May 31, 2017·Chemical Reviews·Steve P MeisburgerNozomi Ando

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