Carrier Proteins

7 Key excerpts on "Carrier Proteins"

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  eBook - ePub

  Molecular Pharmacology

  From DNA to Drug Discovery

  • John Dickenson, Fiona Freeman, Chris Lloyd Mills, Christian Thode, Shiva Sivasubramaniam, Christian Thode(Authors)
  • 2012(Publication Date)
  • Wiley

    (Publisher)

  Chapter 5 Transporter Proteins 5.1 Introduction 5.2 Classification 5.3 Structural analysis of transporters 5.4 Transporter families of pharmacological interest 5.5 Transporters and cellular homeostasis 5.6 Summary References

  5.1 Introduction

  Transporters are membrane embedded proteins that facilitate the movement of ions, small molecules and peptides across the lipid bilayer. They can be divided into two groups: channels and carriers. Channels (and pores) facilitate diffusion down the substrate's concentration gradient, whereas carrier-mediated transport involves movement of the transporter and its bound substrate across the membrane.

  Carriers can be further divided depending upon whether they use a source of energy for substrate transportation. If energy is derived from a primary source such as a chemical reaction, light adsorption or electron flow then this is known as primarily active transport. However, if a second source of energy is also utilised from, for example, the electrochemical gradient at the expense of the primary energy source, then this is known as secondary active transport; in other words the energy was indirectly provided by a primary active transporter to establish an electrochemical gradient. Tertiary active transport uses energy derived from a secondary active transport-generated gradient. An example of tertiary active transport would be organic anion transporters (OAT) which are involved in maintaining cytosolic organic anion concentrations. They are found in epithelia cells throughout the body and have been studied primarily for their role in urine production in the kidney. OAT use a dicarboxylate gradient to move substrate into the cell; this tertiary gradient is generated by the secondary active transporter, Na+ /dicarboxylate co-transporter and the Na+ ion gradient is due to the primary active transporter, Na+ /K+ ATPase which pumps Na+ ions out of the cell at the expense of ATP hydrolysis (see Figure 5.1

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  eBook - ePub

  Transport in Biological Media

  • Sid M. Becker, Andrey V. Kuznetsov, Sid Becker, Andrey Kuznetsov(Authors)
  • 2013(Publication Date)
  • Elsevier

    (Publisher)

  Chapter 5

  Carrier-Mediated Transport Through Biomembranes

  Ranjan K. Pradhan, Kalyan C. Vinnakota, Daniel A. Beard and Ranjan K. Dash,    Biotechnology and Bioengineering Center and Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA

  Acknowledgment

  This work was partially supported by the National Institute of Health grants R01-HL095122 (RKD) and P50-GM094503 (DAB).

  5.1 Introduction

  Biological membranes are composed of phospholipid bilayers, which act as a selective barrier within or around a cell [1] . Transporters or carriers are specialized proteins spanning the phospholipid bilayer that facilitate the translocation of ions, metabolites and macromolecules across the membrane. Transport processes are usually classified as active (primary or secondary) or passive transport [2] . Primary active transport involves the movement of a solute against its electrochemical gradient facilitated by coupling to a process that provides the required free energy, e.g., pump driven by ATP hydrolysis, whereas passive transport is always driven by the solute electrochemical gradient. Secondary active transport is also commonly known as ion-coupled solute transport, and is where the electrochemical gradient of an ion maintained by an active transport process is utilized to transport a different solute. This is another commonly observed mode of transport in biological membrane systems (e.g., -glucose cotransporter [3] , -monocarboxylate cotransporter [4] and exchanger [5]

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  eBook - PDF

  Pratt's Essential Biochemistry

  • Charlotte W. Pratt, Kathleen Cornely(Authors)
  • 2020(Publication Date)
  • Wiley

    (Publisher)

  These transporters function like enzymes by accelerating the rate at which a substance crosses the membrane. And like enzymes, they can be saturated by high concentrations of their “substrate,” and they are susceptible to competitive and other types of inhibition. For obvious reasons, transport proteins tend to be more solute-selective than porins or ion channels. Their great variety reflects the need to transport many different kinds of metabolic fuels and build- ing blocks into and out of cells and organelles. An estimated 10% of the genes in microorganisms encode transport proteins. EXTRACELLULAR SPACE CYTOSOL Transporter Glucose Glucose (hexagon) binds to a site on the transporter that faces the cell exterior. 1. Glucose binding triggers a conformational change that exposes the glucose-binding site to the cell interior. 2. Glucose dissociates from the transporter. 3. The transporter reverts to its original conformation. 4. FIGURE 9.11 View of the aquaporin pore. Hydrophobic residues are colored yellow and the two asparagine residues are red. [Courtesy Yoshinori Fujiyoshi, Kyoto University. ] FIGURE 9.12 Operation of the red blood cell glucose transporter. Would this transport protein allow water or ions to move across the membrane? Active Transport 245 CYTOSOL outward-facing inward-facing Some transport proteins can bind more than one type of ligand, so it is useful to classify them according to how they operate (Fig. 9.14): 1. A uniporter such as the glucose transporter moves a single substance at a time. 2. A symporter transports two different substances across the membrane. 3. An antiporter moves two different substances in opposite directions across the membrane. FIGURE 9.13 Conformations of GLUT proteins. Two GLUT proteins are shown as ribbon models. Analogs of glucose (red) occupy the binding sites of the proteins in the outward-facing (left) and inward-facing (right) conformations.

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  eBook - ePub

  Cell Biology E-Book

  Cell Biology E-Book

  • Thomas D. Pollard, William C. Earnshaw, Jennifer Lippincott-Schwartz, Graham Johnson(Authors)
  • 2016(Publication Date)
  • Elsevier

    (Publisher)

  + -glucose symporter is shown as a model for the open-out conformation of the GLUT1 uniporter.

  (For reference, see Protein Data Bank [PDB; www.rcsb.org ] files 4GC0 and 4PYP and Deng D, Xu C, Sun P, et al. Crystal structure of the human glucose transporter GLUT1. Nature . 2014;510:121–125.)

  Carriers are also known as facilitators, transporters, or porters. This book uses “carrier” because the term unambiguously identifies them, whereas “transporter” is also used to describe pumps, leading to unnecessary confusion.

  Basic Carrier Mechanism

  Atomic structures of carriers reveal a variety of protein folds, so multiple carrier genes must have arisen during the early days of life on earth. Remarkably, these proteins converged during evolution on a common mechanism.

  All carriers are composed of bundles of transmembrane helices that form a binding site for one or more substrates in the middle of the membrane bilayer (Fig. 15.1 ). Carrier Proteins have at least two conformations: one where the substrate has access to the binding site from outside the cell and one where access is available from inside the cell. Both conformations have tight seals formed by hydrophobic residues that keep solutes from crossing the membrane. Some carriers have an additional occluded conformation, where the substrate-binding site is closed on both sides of the membrane. By alternating between the open-out and open-in conformations, the carrier provides a pathway across the membrane.

  Carriers work step by step like enzymes, binding substrates on one side of membranes, undergoing a conformational change that reorients this binding site, and releasing substrate on the opposite side of the membrane. In many cases a simple rocking motion, shown diagrammatically in Fig. 15.1 , explains this alternating access mechanism. The conformational change that moves substrates across the membrane is rate limiting (on the order of 0.1 to 1000 events per second), whereas channels transfer ions at rates of 106 to 109  s−1 during the brief times that they open (see Chapter 16

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  eBook - PDF

  Drug Transporters

  Volume 1: Role and Importance in ADME and Drug Development

  • Glynis Nicholls, Kuresh Youdim(Authors)
  • 2016(Publication Date)
  • Royal Society of Chemistry

    (Publisher)

  3 compounds within the body and in the ADME of drugs. Two superfamilies of transporters, the ATP binding cassette (ABC) and the solute carrier (SLC), comprising between them over 500 members, have now been identified in the human genome, although only a few transporters of specific interest to the pharmaceutical industry are described here. This chapter summarises the discovery of transporters, their function in cellular processes, location and mechanism(s) of action, as well as out-lining the key transporters currently considered to be clinically relevant. A description of how and why they are evaluated within drug discovery and development is included, outlining some of the key pharmacokinetic (PK) concepts useful to transporter scientists, and briefly discussing the methods and strategies used. While there are many different transporters within the body, this overview concentrates primarily on those transporters currently known to influence drug ADME and will not cover the transport of oligo-nucleotides or proteins. Links to current transporter databases and reviews are also included throughout the text for those wishing to pursue the area further. 1.2 The History of Transporter Science 1.2.1 The Discovery of Transport Processes The basic functional unit of eukaryotic organisms is the cell, with each cell enclosed by a plasma membrane that forms an inherent physical barrier to the free transport of solutes. While small hydrophobic molecules are able to move freely across these phospholipid membranes by simple diffusion, the more water-soluble molecules require the presence of membrane proteins or channels embedded within the plasma membrane to gain access into and out of cells. This concept of transport via membrane proteins (‘transporters’ or ‘drug transporters’) and their involvement in the ADME of small drug molecules was first noted in the 1950’s, although there were much earlier indications that transport processes may be present within the body.

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  Textbook of Biochemistry with Clinical Correlations

  • Thomas M. Devlin(Author)
  • 2015(Publication Date)
  • Wiley-Liss

    (Publisher)

  Mammalian cells have a wide variety of transporters and in many instances use different subfamilies of transporters to translocate the same substrate depending on the specific require- ments of the cell or tissue. Transport systems are present in plasma as well as intracellular membranes, including mitochondria, lysosomes, peroxisomes, and endosomes. The number of active transporters present in a membrane at a given time establishes the maximum rate of uptake by a cell or organelle. Thus, in many cases, the synthesis of the protein transporter and incorporation into a membrane controls the concentration of a particular substrate in a cell or cellular compartment. All of these translocation systems are regulated, permitting moment-by-moment control of transport. Many genetic diseases are attributable to defects in the various transport systems (Clin Corr. 12.4). 12.9 • ELECTROCHEMICAL-POTENTIAL-DRIVEN TRANSPORTERS Electrochemical-potential-driven transporters utilize 1. a uniport mechanism where a single solute is transported either by mediated diffu- sion or in a membrane-potential-dependent manner if the solute is charged; 488 • PART III FUNCTIONS OF PROTEINS 2. an antiport mechanism where two or more solutes are transported in opposite di- rections in a tightly coupled process not utilizing any form of energy other than the electrochemical-potential gradient; the gradient across the membrane of one solute can drive the movement of the other solute 3. a symport mechanism where two or more species are transported together in the same direction in a coupled process not utilizing any form of energy other than the electrochemical-potential gradient of one substrate; the gradient of one solute drives the movement of the other solute Hundreds of such transporters have been reported, many exclusively in bacteria, with specificity for inorganic ions, sugars, amino acids, and other metabolic intermediates.

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  eBook - ePub

  The Biology of Thought

  A Neuronal Mechanism in the Generation of Thought - A New Molecular Model

  • Krishnagopal Dharani(Author)
  • 2014(Publication Date)
  • Academic Press

    (Publisher)

  7.3 ) that span the entire thickness of the membrane (in contrast, some membrane proteins do not pass the entire thickness of the membrane but are limited to either the exofacial layer or the cytofacial layer). Transmembrane proteins have channels within them that selectively allow the substances to pass through. They have long and coiled segments of non-polar amino acids in their structures so that they can accommodate themselves in the non-polar lipid bilayer. The transmembrane proteins also have segments that protrude to the outside or inside of the cell, and these segments are chiefly made up of polar amino acids.

  Figure 7.3 Pores in the membrane.

  Types of Transport

  Now we will briefly see how this transfer of substances takes place across the membranes (Hardin et al. 2012 , pp. 197–216). Only a few simple substances, such as water and oxygen, can cross the membrane by simple diffusion . However, many of the substances require some sort of transport proteins for their passage across the membrane. The process of rapid diffusion towards the concentration gradient without the expense of energy is called facilitated diffusion . This is carried out by two types of proteins – Carrier Proteins and channel proteins . Carrier Proteins bind to the molecules and undergo structural changes, allowing molecular transport across the membrane. Examples of Carrier Proteins are glucose transporter and the erythrocyte anion exchange protein – but Carrier Proteins are outside the scope of this chapter.

  Channel proteins (Fig. 7.3 ) are of particular interest in this chapter, as they are the most numerous in neurons. There are chiefly three types – ion channels , porins and aquaporins . Ion channels are responsible for the electrical properties of the neuronal membranes, in which they are characteristically abundant. These channels are controlled either by voltage or by ligands (Ch. 2 , p. 38). We will study them in the section ‘Signal Transduction’, below.

  The other important transport mechanism is the active transport (i.e. against equilibrium). This uses energy (in the form of ATP) for their transport; examples are sodium-potassium pump (Ch. 2 , p. 37), proton pumps , electron transport chains

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