Chemical chaperones are conserved cellular modulators that developed early in evolution. These small molecules allow cells to maintain homeostasis under changing environmental conditions. Numerous organisms including bacteria, archaea, plants, and animals, synthesize or accumulate small molecules to protect macromolecules from stress-induced alterations. While previous studies clearly show the key roles of these chaperones in maintaining proteostasis, it has recently shown that their influence extends beyond proteins and that they can also affect the homeostasis of metabolites. These insights position chemical chaperones at the interface of proteostasis and metabolostasis, two quality-control mechanisms. Evolution might have selected these small molecules as natural guardians of intracellular stability to buffer protein folding and metabolite aggregation, thereby maintaining a functional chemical environment under stress. • Chemical chaperones are small molecules involved in macromolecular stability. • Their modulation of proteostasis led to the concept of ‘pharmacological chaperones’. • It has recently been discovered that they could control the assembly of metabolites. • Chemical chaperones may serve as master regulators of cellular homeostasis. • They could be explored for the treatment of inborn errors of metabolism.
Bar-Yosef et al. (Tue,) studied this question.