The Daily Bulletin

Dr. Drew Barber from the Hauptman-Woodward Research Institute will give a research seminar on Thursday, March 14, 2025, from 12:15 PM to 1:30 PM in SAMC 151.

Seminar Title: Mechanistic Insights into OATP1B1: The Role of Bicarbonate in Transport

Abstract

The organic anion transporting polypeptide (OATP) 1B1 is a liver-specific transporter responsible for the uptake of numerous endogenous molecules and drugs before their metabolism and excretion by hepatocytes. Structurally, it belongs to the major facilitator superfamily and operates via an alternating access mechanism, facilitating solute movement between extracellular and intracellular compartments.

While most transporters function either passively—allowing solutes to move along concentration gradients—or actively, coupling transport to ATP hydrolysis or co-transported solutes, the exact mechanism of OATP1B1 remains unclear. Through mutagenesis, uptake assays, and kinetic analysis, we demonstrate that OATP1B1 uptake is regulated by bicarbonate. Interestingly, bicarbonate binds to a site distal to the ligand-binding domain rather than being co-transported. It is then broken down in an apparent enzymatic fashion, driving the transport cycle. This unique mechanism is highly dependent on a solvent-exposed, pH-sensitive histidine, which may explain OATP1B1’s pH-dependent activity. These findings provide new insights into the transport mechanism of OATP1B1 and its role in drug metabolism.