Binding and sequestration of poison frog alkaloids by a plasma globulin

Alkaloids are important bioactive molecules throughout the natural world,
and in many animals, they serve as a source of chemical defense against
predation. Dendrobatid poison frogs bioaccumulate alkaloids from their
diet to make themselves toxic or unpalatable to predators. Despite the
proposed roles of plasma proteins as mediators of alkaloid trafficking and
bioavailability, the responsible proteins have not been identified. We use
chemical approaches to show that a ~50 kDa plasma protein is the principal
alkaloid binding molecule in blood from poison frogs. Proteomic and
biochemical studies establish this plasma protein to be liver-derived
alkaloid-binding globulin (ABG) that is a member of the serine-protease
inhibitor (serpin) family. In addition to alkaloid binding activity, ABG
sequesters and regulates the bioavailability of “free” plasma alkaloids in
vitro. Unexpectedly, ABG is not related to saxiphilin or albumin but
instead exhibits sequence and structural homology to mammalian hormone
carriers and amphibian biliverdin binding proteins. Alkaloid-binding
globulin (ABG) represents a new small molecule binding functionality in
serpin proteins, a novel mechanism of plasma alkaloid transport in poison
frogs, and more broadly points towards serpins acting as tunable scaffolds
for small molecule binding and transport across different organisms.