A critique of the alternating access transporter model of uniport glucose transport

Abstract

The alternating access transporter model (AATM) was initially constructed to rationalize and explain a few readily quantifiable and reproducible experimental findings. The AATM, as originally conceived, consists of single specific binding site centrally situated within the cell membrane. The site alternately faces inwards and outwards. During the inversion process, the site can transport sugar across the membrane, and dissociation into the alternate bathing solution results in net transport. Return of the empty site reinitiates the transport cycle as illustrated in Fig. 1A. Glucose transport, which was demonstrated first in human red cells (Le Fevre and Le Fevre 1952) and sheep placenta (Widdas 1951), has high stereospecificity for D-pyranose sugars, like d-glucose and d-xylose in preference to l-sugars, e.g. l-fructose or non-transported l-glucose. This transport process has similarities to enzyme kinetics: both have saturation kinetics, the Km being the concentration at which half maximal transport velocity, Vmax obtained, is a measure of apparent affinity of ligand for the transporter (Fig. 1B). The process is passive in the human red cell, since at equilibrium the glucose concentrations in the extra and intracellular solutions are the same; i.e. net uphill accumulation does not occur. Open in a separate window Fig. 1 A Conventional representation of the symmetrical carrier model with the KDin = KDout = 3 mmol/L and kCout–in = kCin–out. The thicker arrows represent higher flow rates of liganded carrier than those of the empty carrier. The blue arrows represent the influx pathway and the red arrows the efflux pathway. The symmetrical rates of ligand carrier transit kGCout–in, kGCout–in are 10× faster than the fast rate of empty carrier movement kCout–in, the second-order rates of ligand association with the external and internal carrier forms, Goutkout and Ginkin are assigned to be 1000× faster than kCout–in. B Conventional representation of the asymmetric alternating transporter model with parameters as illustrated in D. The simulation shows that Vm = 1.6 nmol/(L·s) for zero-trans- net influx with the parameters as in D is approximately 33% of the Vm for exchange uptake = 4.8 nmol/(L·s) and the Km for net influx = 1.0 mmol/(L·s) is approximately 20% of the Km for exchange influx = 5.0 mmol/L. The Vm for net efflux = 6.3 nmol/(L·s), i.e. 3.9× faster than net influx. C Jardetzky adaptation of gated asymmetric transporter. D Asymmetric single-cycle alternating carrier model. The lengths of the vertical lines represent the relative rates of association and dissociation. The relative lengths and widths of the horizontal lines represent the relative transit rates of loaded and unloaded carrier forms. The angular displacements of the horizontal rates represent the Gibbs free energy differences between the states. The free energy differences between liganded and unliganded states are not displayed. E Equations showing how asymmetric affinities of a single-cycle carrier enforce asymmetric rates of empty carrier distribution