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. 2018;4(6):287-299.
doi: 10.1007/s41048-018-0076-9. Epub 2018 Nov 16.

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

Richard J Naftalin  1
Affiliations

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

Richard J Naftalin. Biophys Rep. 2018.
No abstract available

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Conflict of interest statement

Richard Naftalin declares that he has no conflict of interest.This article does not contain any studies with human or animal subjects performed by the author.

Figures

Fig. 1
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
Fig. 2
Fig. 2
A Multisite model of glucose transport, the squares represent external and internal binding sites for net glucose influx and efflux. The inner site has a 10 × lower affinity 30 mmol/L than the outside site 3.0 mmol/L. The circles represent voids between binding sites through which glucose diffuses and equilibrates. During net efflux, the central void contains higher glucose concentrations than during net influx because the dissociation rate of glucose from the inside site is faster than the dissociation rate from the outside site. During equilibrium exchange, the void at the midpoint has similar amounts of both labelled sugars, so exchange is most favourable at the midpoint, although it is possible that there are other exchange sites. B Simulations of net glucose influx and efflux and equilibrium exchange flux with high-affinity external and low-affinity internal sites. An intermediate sink allows sugars to diffuse passively between the sites without net energy transference at equilibrium
Fig. 3
Fig. 3
A Branched network model of glucose transport illustrating the effects of the T295M mutation on net influx and efflux at 37 °C. The square and circle symbols represent the same as in Fig. 2A. The right branch to the external vestibule is blocked by the M295 mutation in GLUT1DS and reduces net influx by 50% but without greatly affecting Km net influx. However, the M295 mutation has a much larger effect on net efflux as slowing efflux leads to an accumulation of glucose within the external vestibule with a tailback that retarded glucose efflux and a reduces the Km net efflux. B Simulations of the comparative effects of control and mutant glucose net influx and efflux (Cunningham and Naftalin 2013). C Docking studies of GLUT1 showing docking positions of glucose. The effect of the T295M mutation on glucose docking is illustrated in top right panel where the green stick model of glucose is absent from the mutant at the external vestibular tunnel but present in control (red stick) glucose. D Comparison of tunnels in control and M295 mutants. The tunnel between the external solution and vestibule is occluded by the mutant
Fig. 4
Fig. 4
A Graphic simulating various phases of the staged diffusion model of glucose transport via GLUT1 where gates operated by small scale conformation change permit net and exchange transference across the transport network. B Figure showing the central tunnel traversing XylE isoform 4GC0 (Quistgaard et al. ; Cunningham and Naftalin 2014). The yellow mesh shows the tunnel limits as determined by the program
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