Uniporter substrate binding and transport: reformulating mechanistic questions

Abstract

Transporters are involved in material transport, signaling, and energy input in all living cells. One of the fundamental questions about transporters is concerned with the precise role of their substrate in driving the transport process. This is particularly important for uniporters, which must utilize the chemical potential of substrate as the only energy source driving the transport. Thus, uniporters present an excellent model for the understanding of how the difference in substrate concentration across the membrane is used as a driving force. Local conformational changes induced by substrate binding are widely considered as the main mechanism to drive the functional cycle of a transporter; in addition, reducing the energy barrier of the transition state has also been proposed to drive the transporter. However, both points of view require modification to allow consolidation with fundamental thermodynamic principles. Here, we discuss the relationship between thermodynamics and kinetics of uniporters. Substrate binding-induced reduction of the transition-state energy barrier accelerates the transport process in kinetic terms, while the chemical potential of the substrate drives the process thermodynamically.

Energy coupling mechanisms of AcrB-like RND transporters

“…Such a reduction can be achieved through stronger binding of the substrate to the transporter at the transition state relative to the “ground” state. This mechanism of reducing the transition-state barrier is likely to also contribute to the substrate specificity observed for transporters (Zhang and Han 2016 ).…”

Thermodynamic secrets of multidrug resistance: A new take on transport mechanisms of secondary active antiporters

“…This assumption is based on the fact that protonation per se has a smaller effect on the transition state than the binding of the substrate. In addition, because substrate binding often reduces the energy barrier, 80 we further propose that the energy barrier of the substrate-carrying I-O transition is significantly lower than the other two barriers, as shown in Fig. A1.…”

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

“…This brings the net energy change around the cycle to zero, and hence apparently no energy is expended in completion of the net transport cycle, as in Fig. 1A and D (Lapointe et al 2009; Zhang and Han 2016a).…”

“…Instead Mueckler and Thorens contend that the passive glucose transport system is symmetrical and its apparent asymmetries are due to the experimental error obtained owing to very rapid glucose fluxes at or above room temperatures. Zhang and Han (2016a, b) also claim that dissociation constants for glucose at the inside and outside of the transporter namely K D in and K D out are nearly identical.…”

“…Various arguments have been advanced in support of the legitimacy of the claim that asymmetric distribution of unliganded carrier is thermodynamically correct (Lapointe et al . 2009; Zhang and Han 2016a).…”