Molecular mechanisms whereby environmental contaminants cause physiological effects are often unknown.  Porphobilinogen synthase (PBGS) functions in heme biosynthesis and is a primary target for the toxin lead.  Unrelated to lead inhibition, PBGS activity is regulated allosterically via an equilibrium of inactive hexamers and active octamers.  Genetic variations that perturb this equilibrium result in inborn errors of metabolism.  Furthermore, small molecules inhibit PBGS in vitro by stabilizing the hexamer.   We screened the National Toxicology Program library of putative toxins for molecules that stabilize the PBGS hexamer and inhibit activity in vitro. Seventeen such compounds were identified, including the most potent PBGS inhibitor yet characterized (Mutagen X, IC50 = 1.4 �M), establishing that some toxins stabilize the inactive hexamer of PBGS and inhibit catalytic activity.  Allosteric regulation via an equilibrium of alternate oligomers may occur for other proteins; perturbation of these oligomeric equilibria by small molecules represents a novel mechanism of toxicity.

Environmental contaminants perturb fragile protein assemblies and inhibit normal protein function

244th National Meeting (2012)

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