Graphical 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.
Abramson J, Smirnova I, Kasho V, Verner G, Kaback HR, Iwata S, (2003) Structure and mechanism of the lactose permease of Escherichia coli.Science 301:610-615
Akyuz N, Georgieva ER, Zhou Z, Stolzenberg S, Cuendet MA, Khelashvili G, Altman RB, Terry DS, Freed JH, Weinstein H, Boudker O, Blanchard SC, (2015) Transport domain unlocking sets the uptake rate of an aspartate transporter.Nature 518:68-73
Carruthers A, DeZutter J, Ganguly A, Devaskar SU, (2009) Will the original glucose transporter isoform please stand up! Am J Physiol Endocrinol Metab 297:E836-E848
Dang S, Sun L, Huang Y, Lu F, Liu Y, Gong H, Wang J, Yan N, (2010) Structure of a fucose transporter in an outward-open conformation.Nature 467:734-738
Deng D, Yan N, (2016) GLUT, SGLT, and SWEET: structural and mechanistic investigations of the glucose transporters.Protein Sci 25:546-558
Deng D, Xu C, Sun P, Wu J, Yan C, Hu M, Yan N, (2014) Crystal structure of the human glucose transporter GLUT1.Nature 510:121-125
Deng D, Sun P, Yan C, Ke M, Jiang X, Xiong L, Ren W, Hirata K, Yamamoto M, Fan S, Yan N, (2015) Molecular basis of ligand recognition and transport by glucose transporters.Nature 526:391-396
Heng J, Zhao Y, Liu M, Liu Y, Fan J, Wang X, Zhang XC, (2015) Substrate-bound structure of the E. coli multidrug resistance transporter MdfA.Cell Res 25:1060-1073
Huang Y, Lemieux MJ, Song J, Auer M, Wang DN, (2003) Structure and mechanism of the glycerol-3-phosphate transporter from Escherichia coli.Science 301:616-620
James DE, Strube M, Mueckler M, (1989) Molecular cloning and characterization of an insulin-regulatable glucose transporter.Nature 338:83-87
Jardetzky O, (1966) Simple allosteric model for membrane pumps.Nature 211:969-970
Kasahara M, Hinkle PC, (1977) Reconstitution and purification of theD-glucose transporter from human erythrocytes.J Biol Chem 252:7384-7390
Klingenberg M, (2006) Transport catalysis.Biochim Biophys Acta 1757:1229-1236
Klingenberg M, (2007) Transport viewed as a catalytic process.Biochimie 89:1042-1048
Krupka RM, Deves R, (1981) An experimental test for cyclic versus linear transport models. The mechanisms of glucose and choline transport in erythrocytes.J Biol Chem 256:5410-5416
Lowe AG, Walmsley AR, (1986) The kinetics of glucose transport in human red blood cells.Biochim Biophys Acta 857:146-154
Nishimura H, Pallardo FV, Seidner GA, Vannucci S, Simpson IA, Birnbaum MJ, (1993) Kinetics of GLUT1 and GLUT4 glucose transporters expressed in Xenopus oocytes.J Biol Chem 268:8514-8520
Nomura N, Verdon G, Kang HJ, Shimamura T, Nomura Y, Sonoda Y, Hussien SA, Qureshi AA, Coincon M, Sato Y, Abe H, Nakada-Nakura Y, Hino T, Arakawa T, Kusano-Arai O, Iwanari H, Murata T, Kobayashi T, Hamakubo T, Kasahara M, Iwata S, Drew D, (2015) Structure and mechanism of the mammalian fructose transporter GLUT5.Nature 526:397-401
Quistgaard EM, Low C, Guettou F, Nordlund P, (2016) Understanding transport by the major facilitator superfamily (MFS): structures pave the way.Nat Rev Mol Cell Biol 17:123-132
Simpson IA, Carruthers A, Vannucci SJ, (2007) Supply and demand in cerebral energy metabolism: the role of nutrient transporters.J Cereb Blood Flow Metab 27:1766-1791
Smirnova I, Kasho V, Choe JY, Altenbach C, Hubbell WL, Kaback HR, (2007) Sugar binding induces an outward facing conformation of LacY.Proc Natl Acad Sci USA 104:16504-16509
Taylor LP, Holman GD, (1981) Symmetrical kinetic parameters for 3-O-methyl-D-glucose transport in adipocytes in the presence and in the absence of insulin.Biochim Biophys Acta 642:325-335
Vollers SS, Carruthers A, (2012) Sequence determinants of GLUT1-mediated accelerated-exchange transport: analysis by homology-scanning mutagenesis.J Biol Chem 287:42533-42544
Zhang XC, Han L, (2016) How does the chemical potential of the substrate drive a uniporter?.Protein Sci 25(4):933-937
Zhang XC, Zhao Y, Heng J, Jiang D, (2015) Energy coupling mechanisms of MFS transporters.Protein Sci 24:1560-1579
Zhang XC, Zhou Y, Cao C, (2016) Thermodynamics of GPCR activation. Biophys Rep 1(3):115-119