“…Another strategy to avoid toxic solute levels is by introduction of a transmembrane leak pathway that permits efflux when the intracellular concentration becomes too high [49]. Indeed, a reduction in steady-state accumulation ratio ([solute] in /[solute] out ) with increasing extracellular substrate concentration is well-documented, including for E. coli transport of thiogalactosides [50,51] and arabinose [52], hexose uptake in the eukaryotic Chlorella vulgaris [53], sugar transport in Streptococcus thermophilus [54], for maltose in yeast membrane vesicles [55], and for some amino acids in yeast [49] and cancerous mouse cells [56,57]. We distinguish between two types of leak pathways: those mediated by the transporter in question, termed 'internal leaks', and those that are not, or 'external leaks'.…”