5CKV

DAHP synthase from Mycobacterium tuberculosis, fully inhibited by tyrosine, phenylalanine, and tryptophan

Summary for 5CKV

• Entry DOI: 10.2210/pdb5ckv/pdb
• Related: 2B7O 2YPO 2YPP 2YPQ 3KGF 3NUD 3NUE 3NV8 3RZI
• Descriptor: Phospho-2-dehydro-3-deoxyheptonate aldolase AroG, CHLORIDE ION, SULFATE ION, ... (9 entities in total)
• Functional Keywords: tim-barrel, shikimate pathway, feedback inhibition, transferase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 105824.68

Authors

Munack, S.,Krengel, U. (deposition date: 2015-07-15, release date: 2016-01-27, Last modification date: 2024-01-10)

Primary citation

Munack, S.,Roderer, K.,Okvist, M.,Kamarauskaite, J.,Sasso, S.,van Eerde, A.,Kast, P.,Krengel, U.
Remote Control by Inter-Enzyme Allostery: A Novel Paradigm for Regulation of the Shikimate Pathway.
J.Mol.Biol., 428:1237-1255, 2016

PubMed 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, seems to be driven by dynamics and is likely a general strategy used by nature.

PubMed: 26776476
DOI: 10.1016/j.jmb.2016.01.001

Experimental method

X-RAY DIFFRACTION (2.787 Å)