Allosteric regulation in Acetohydroxyacid Synthases (AHASs) – Different structures and kinetic behavior in isozymes in the same organisms

Acetohydroxyacid Synthases (AHASs) have separate small regulatory subunits which specifically activate the catalytic subunits with which they are associated. The binding sites for the inhibitory amino acid(s) (valine or leucine) are in the interface between two ACT (small ligand binding) domains, and are apparently found in all AHAS regulatory subunits. However, the structures and the kinetic mechanisms of the different enzymes are very heterogeneous. Among the three isozymes encoded in the enterobacteria, the regulatory patterns are different, and their different responses to the inhibitory end product valine can be rationalized, at least in part, on the basis of the regulatory subunit structures and differences in catalytic mechanisms. The regulatory subunits in “typical” single AHASs found in other bacteria are similar to that of Escherichia coli isozyme AHAS III. Eukaryotic AHASs have more complex regulatory mechanisms and larger regulatory subunits. Such AHASs have two separate ACT sequence domains on the same regulatory polypeptide and can simultaneously bind two amino acids with synergistic effects. Yeast and fungal AHASs have ATP-binding sequence inserts in their regulatory subunits and are activated by MgATP in addition to being inhibited by valine.

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► AHASs have separate regulatory subunits (RSUs) which bind valine or other inhibitory amino acids.
► All AHAS RSUs have one (or more) ACT domains with a β−α−β−β−α−β fold.
► The regulatory amino acid site is in the interface formed by a pair of ACT domains.
► The prototypical bacterial AHAS has a C-terminal domain which does not bind valine but is required for regulatory function.
► The overall structures of the RSUs and the kinetic pattern of their inhibition are widely varied.