May 5, 2020

A dual-purpose metabolic switch

John York and colleagues have demonstrated that the protein Vip1 is a rare type of bifunctional enzyme: it can both synthesize and destroy key cellular signaling molecules.

Compounds called inositol diphosphates are cellular signaling “codes” involved in multiple processes ranging from phosphate sensing to DNA metabolism. 

John York, PhD, and colleagues have demonstrated that the evolutionarily conserved gene product Vip1 is capable of both synthesizing and destroying inositol diphosphates.

The researchers showed that Vip1 has two independent catalytic domains tethered together: a kinase domain that adds phosphate groups and a pyrophosphatase domain that removes them.

They provided atomic resolution structures of inositol diphosphate products to define the selective site of Vip1 action. Perturbation of kinase or pyrophosphatase activities had differential effects on vacuolar morphology and osmotic responses. 

The findings, reported in the Proceedings of the National Academy of Sciences, demonstrate that Vip1 represents a rare class of bifunctional enzyme. This single gene product is a key metabolic switch critical for nutrient and regulatory responses, the authors conclude.

This research was supported by funds from the Howard Hughes Medical Institute and from National Institutes of Health grants HL055672 and GM124404. York is an alumni investigator of the Howard Hughes Medical Institute.