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The first enzyme of the shikimate pathway, 3-deoxy-D- arabino -heptulosonate 7-phosphate synthase (DAH7PS), adopts a range of distinct allosteric regulation mechanisms in different organisms, related to different quaternary assemblies. DAH7PS from  Mycobacterium tuberculosis  ( Mtu DAH7PS) is a homotetramer, with the allosteric sites in close proximity to the interfaces. Here we examine the importance of the quaternary structure on catalysis and regulation, by amino acid substitution targeting the tetramer interface of  Mtu DAH7PS. Using only single amino acid substitutions either in, or remote from the interface, two dimeric variants of  Mtu DAH7PS ( Mtu DAH7PS F227D  and  Mtu DAH7PS G232P ) were successfully generated. Both dimeric variants maintained activity due to the distance between the sites of amino acid substitution and the active sites, but attenuated catalytic efficiency was observed. Both dimeric variants showed significantly disrupted allosteric regulation with greatly impaired binding affinity for one of the allosteric ligands. Molecular dynamics simulations revealed changes in protein dynamics and average conformations in the dimeric variant caused by amino acid substitution remote to the tetramer interface ( Mtu DAH7PS G232P ), which are consistent with the observed reduction in catalytic efficiency and loss of allosteric response.

plos one

Quaternary structure is an essential component that contributes to the sophisticated allosteric regulation mechanism in a key enzyme from Mycobacterium tuberculosis