Solute Transport across Membranes:- The Glucose Transporter of Erythrocytes Mediates Passive Transport

Energy-yielding metabolism in erythrocytes depends on a constant supply of glucose from the blood plasma, where the glucose concentration is maintained at about 5 mM. Glucose enters the erythrocyte by facilitated diffusion via a specific glucose transporter, at a rate about 50,000 times greater than the uncatalyzed diffusion rate. The glucose transporter of erythrocytes (called GLUT1 to distinguish it from related glucose transporters in other tissues) is a type III integral protein (Mr ~45,000) with 12 hydrophobic segments, each of which is believed to form a membrane-spanning helix. The detailed structure of GLUT1 is not yet known, but one plausible model suggests that the side-by-side assembly of several helices produces a transmembrane channel lined with hydrophilic residues that can hydrogen-bond with glucose as it moves through the channel (Fig. 11–30). The process of glucose transport can be described by analogy with an enzymatic reaction in which the “substrate” is glucose outside the cell (Sout), the “product” is glucose inside (Sin), and the “enzyme” is the trans porter, T. When the rate of glucose uptake is measured as a function of external glucose concentration (Fig. 11–31), the resulting plot is hyperbolic; at high external glucose concentrations the rate of uptake ap proaches Vmax. Formally, such a transport process can be described by the equations

in which k1, k 1, and so forth, are the forward and re verse rate constants for each step; T2 is the transporter conformation that faces out, and T2 the one that faces in. The steps are summarized in Figure 11–32. The rate equations for this process can be derived exactly as for enzyme-catalyzed reactions (Chapter 6), yielding an expression analogous to the Michaelis Menten equation:

in which V0 is the initial velocity of accumulation of glucose inside the cell when its concentration in the surrounding medium is [S]out, and Kt (K_transport) is a constant analogous to the Michaelis constant, a combi nation of rate constants that is characteristic of each transport system. This equation describes the initial velocity, the rate observed when [S]in=0. As is the case for enzyme-catalyzed reactions, the slope-intercept form of the equation describes a linear plot of 1/V₀ against 1/[S]out, from which we can obtain values of Kt and Vmax (Fig. 11–31b). When [S]=Kt, the rate of up take is 1⁄2 V_max; the transport process is half-saturated. The concentration of blood glucose, 4.5 to 5 mM, is about three times Kt, which ensures that GLUT1 is nearly saturated with substrate and operates near V_max. Because no chemical bonds are made or broken in the conversion of S_out to S_in, neither “substrate” nor “product” is intrinsically more stable, and the process of entry is therefore fully reversible. As [S]in approaches [S]_out, the rates of entry and exit become equal. Such a system is therefore incapable of accumulating the substrate (glucose) within a cell at concentrations above that in the surrounding medium; it simply achieves equilibration of glucose on the two sides of the membrane much faster than would occur in the absence of a specific transporter. GLUT1 is specific for D-glucose, having a measured Kt of 1.5 mM. For the close analogs D mannose and D-galactose, which differ only in the position of one hydroxyl group, the values of K_t are 20 and 30 mM, respectively; and for L-glucose, K_t exceeds 3,000 mM. Thus, GLUT1 shows the three hallmarks of passive transport: high rates of diffusion down a concentration gradient, saturability, and specificity.

Twelve glucose transporters are encoded in the hu man genome, each with unique kinetic properties, pat terns of tissue distribution, and function (Table 11–4). In liver, GLUT2 transports glucose out of hepatocytes when liver glycogen is broken down to replenish blood glucose. GLUT2 has a Kt of about 66 mM and can therefore respond to increased levels of intracellular glucose (produced by glycogen breakdown) by increasing out ward transport. Skeletal muscle and adipose tissue have yet another glucose transporter, GLUT4 (Kt=5 mM), which is distinguished by its stimulation by insulin: its activity increases when release of insulin signals a high blood glucose concentration, thus increasing the rate of glucose uptake into muscle and adipose tissue (Box 11–2 describes some malfunctions of this transporter).

FIGURE 11–30 Proposed structure of GLUT1. (a)Transmembrane he lices are represented as oblique (angled) rows of three or four amino acid residues, each row depicting one turn of the helix. Nine of the 12 helices contain three or more polar or charged amino acid residues, often separated by several hydrophobic residues. (b) A helical wheel diagram shows the distribution of polar and nonpolar residues on the surface of a helical segment. The helix is diagrammed as though observed along its axis from the amino terminus. Adjacent residues in the linear sequence are connected with arrows, and each residue is placed around the wheel in the position it occupies in the helix; re call that 3.6 residues are required to make one complete turn of the α helix. In this example, the polar residues (blue) are on one side of the helix and the hydrophobic residues (yellow) on the other. This is, by definition, an amphipathic helix. (c) Side-by-side association of five or six amphipathic helices, each with its polar face oriented toward the central cavity, can produce a transmembrane channel lined with polar and charged residues. This channel provides many opportunities for hydrogen bonding with glucose as it moves through the trans porter. The three-dimensional structure of GLUT1 has not yet been determined by x-ray crystallography, but researchers expect that the hydrophilic transmembrane channels of this and many other trans porters and ion channels will resemble this model.

FIGURE 11–31 Kinetics of glucose transport into erythrocytes. (a) The initial rate of glucose entry into an erythrocyte, V0, depends upon the initial concentration of glucose on the outside, [S]out. (b) Double reciprocal plot of the data in (a). The kinetics of facilitated diffusion is analogous to the kinetics of an enzyme-catalyzed reaction. Compare these plots with Figure 6–11, and Figure 1 in Box 6–1. Note that Kt is analogous to Km, the Michaelis constant.

FIGURE 11–32 Model of glucose transport into erythrocytes by GLUT1. The transporter exists in two conformations: T1, with the glucose-binding site exposed on the outer surface of the plasma mem brane, and T₂, with the binding site exposed on the inner surface. Glucose transport occurs in four steps. 1 Glucose in blood plasma binds to a stereospecific site on T₁; this lowers the activation energy for 2 a conformational change from Sout T₁ to Sin T₂, effecting the trans membrane passage of the glucose. 3 Glucose is now released from T₂ into the cytoplasm, and 4 the transporter returns to the T₁ conformation, ready to transport another glucose molecule.

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مواضيع ذات صلة

Solute Transport across Membranes:- Ion-Selective Channels Allow Rapid Movement of Ions across Membranes

Solute Transport across Membranes:- ABC Transporters Use ATP to Drive the Active Transport of a Wide Variety of Substrates

Solute Transport across Membranes:- P-Type Ca2+ Pumps Maintain a Low Concentration of Calcium in the Cytosol

Solute Transport across Membranes:-Active Transport Results in Solute Movement against a Concentration or Electrochemical Gradient

Solute Transport across Membranes:-The Chloride-Bicarbonate Exchanger Catalyzes Electroneutral Cotransport of Anions across the Plasma Membrane

Solute Transport across Membranes:- Transporters Can Be Grouped into Superfamilies Based on Their Structures

Solute Transport across Membranes:- Passive Transport Is Facilitated by Membrane Proteins

Membrane Dynamics:- Membrane Fusion Is Central to Many Biological Processes

The Composition and Architecture of Membranes:- Sphingolipids and Cholesterol Cluster Together in Membrane Rafts

The Composition and Architecture of Membranes:- Peripheral Membrane Proteins Are Easily Solubilized

The Composition and Architecture of Membranes:- A Lipid Bilayer Is the Basic Structural Element of Membranes

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins:- Cooperative Ligand Binding Can Be Described