Porphobilinogen synthase: An equilibrium of different assemblies in human health.

Abstract

Porphobilinogen synthase (PBGS) is an essential enzyme that catalyzes an early step in heme biosynthesis. An unexpected human PBGS quaternary structure dynamic drove the definition of morpheeins, which are protein multimers that dissociate, change shape, and re-assemble differently with functional consequences. Each PBGS monomer has two domains that can reposition through a hinge motion. Human PBGS exists in an equilibrium among high activity octamer, low activity hexamer, and low mole-fraction dimer in which the hinge motion occurs. The dimer conformation dictates the multimer architecture. An octamer-specific inter-subunit interaction responds to pH, resulting in a pH-dependence to the octamer-hexamer equilibrium. An inborn error of metabolism, ALAD porphyria, is caused by single amino acid substitutions that stabilize the hexamer relative to octamer. Drugs that stabilize the PBGS hexamer result in a drug side effect that can exacerbate porphyria. PBGS is essential for all organisms that require respiration, photosynthesis, or methanogenesis. Consequently, phylogenetic variation in PBGS multimerization equilibria provides insight into how Nature has harnessed oligomeric variation in the control of protein function. The dynamic multimerization of PBGS revealed the morpheein mechanism for allostery, a structural basis for inborn errors of metabolism, a quaternary structure focus for drug discovery and/or drug side effects, and a pathway toward new antibiotics or herbicides. The fortuitous discovery of PBGS quaternary structure dynamics arose from characterization of a low-activity single amino acid variant that dramatically stabilized the hexamer, whose existence had previously gone unnoticed.