Interactions of human reduced folate carrier SLC19A1 with folates and antifolates.

Abstract

The human reduced folate carrier (hRFC, also known as SLC19A1) is a major importer of folates and chemotherapeutic agents such as methotrexate (MTX). As an anion exchanger, hRFC imports folates/antifolates and exports anions across the cell membrane and it is a major determinant in MTX (antifolate) sensitivity as genetic variants and its depletion exhibit drug resistance. However, the molecular basis of substrate specificity by hRFC remains unclear. This study aims to determine possible exit pathways of folates/antifolates through hRFC and investigate important interactions during the dissociation process. Using an equilibrated hRFC-MTX structure as the initial state, we performed multiple steered molecular dynamics (SMD) simulations of folates and antifolates. Various behaviors and possible crucial interactions for the binding-unbinding process were observed. Our findings will provide a better understanding of the dissociation mechanism and substrate specificity of folates and antifolate drugs from hRFC.