Lecture 6: Membrane Transport Proteins Flashcards by Brooke Thornburg

Transport system

-moving molecules across cell membrane
-cells need to bring in materials and excrete waste

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Protein transporter steps

bind cargo molecule on one side of membrane
change in protein structure
Release on opposite side

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Pharmacokinetics (PK)

safety and efficacy profiles of drug

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Clinical PK studies on drug interactions

-indicate transporters work together with enzymes in drug absorption and elimination
-drug substrate and inhibitor

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Drug substrate

translocated across a membrane

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drug inhibitor

-impair uptake/efflux of another drug
-not necessarily a substrate

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ATP-dependent Transporters

-ATP-binding cassette
-ABC

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Important transporters in drug distribution

-ATP-dependent
-Solute carrier (SLC)

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P-glycoprotein

-important ABC transporter
-exports many drugs
-responsible for multi-drug resistance
-aka multidrug resistance protein 1

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Human Solute Carrier (SLC) gene superfamily

-encodes membrane-bound transporters
-many substrates
-many of membrane transporters belong here

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SLC transport substrates

-amino acids, oligopeptides
-glucose and sugars
-cations and anions
-bile salts, carboxylate, organic anions
-acetyl CoA
-essential metals, neurotransmitters, amines, vitamins, fatty acids, lipids, nucleosides, ammonium, choline, thyroid hormone, urea

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Classes of Transporters

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1st Class: Electrochemical-potential-driven transporters

-direction determined by electrochemical potentials
-move down concentration gradient
-NO energy input needed
-ports

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uniport

one molecule one way

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antiport

2+ molecules, opposite directions

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symport

2+ molecules, same direction

SLC2 (GLUT) Family of transporters

-glucose transported by passive uniport mechanism

Na+/glucose cotransporter (SGLT, SLC5)

-transport of glucose into cells by a Na+ electrochemical gradient
-symport
-Na+ transport is energy source for cotransport of glucose INTO the cell AGAINST a glucose gradient
-secondary active transport

SGLT inhibitors

-treat type II diabetes
-excretes glucose instead of reabsorbing it in the kidney
-lowers blood glucose levels

More Na+ OUTSIDE the cell

-passive, facilitated transport of Na+ INTO the cell

Na+/K+ ATPase

-maintains Na+ gradient
-reason why Na+/glucose cotransporter is secondary active transport

Energy available from concentration gradient

-move from C1 to C2
dG = G2- G1 = RTln(C2/C1) + ZFdeltaPsi
-slide 9 babe

C2<C1

-transport from high to low
-deltaG < 0
-no need for energy input

2nd class: Primary Active Transporters

-AGAINST gradient
-use energy from ATP hydrolysis
-P, V, F-types, and ABC transporters

P-type

-phosphorylated during transport -Na/K ATPase

V-type

vacuolar

F-type

-mitochondrial

ATP-binding cassette (ABC) transporters

-large family that moves metabolic products, lipids, sterols, drugs -ATP hydrolysis for energy -eukaryotic vs prokaryotic -ABC domain

ABC transporters in prokaryotes

-large number that are both importers (nutrients) and exporters (cell surface components, pathogenesis factors)

ABC transporters in eukaryotes

-exporters/effluxers (NOT importers) that function as pumps out of the cell -49 genes -efflux lipids -some involved in disease -some involved in multi-drug resistance (anticancer drugs conferring resistance to tumors)

Cystic Fibrosis

-ABC transporter involvement -abnormal transport of Cl- and Na+ by CFTR

Multidrug Resistance Family (MDR)

-subfamily of ABC transporters -some extrude xenobiotics -cause drug resistance -overexpressed in cancer cells

ABC exporter mechanism (P-glycoprotein)

-alternating access of multidrug transporters 1. inward facing = access from cytoplasm and membrane (substrates are hydrophobic) 2. substrate binding converts to occuleded state, ATP bound to NBD 3. outward facing= change in TM helices reduces affinity and promotes release to outside cell. ATP hydrolysis brives NBDs apart and converts TMDs back to inward facing step 1

Nucleotide binding domain (NBD), or ABC

-located on cytoplasmic side -highly conserved -ATP hydrolysis does NOT lead to phosphorylation of transporter -exact mechanism is unknown

Mdr1

STRUCTURE SLIDE 15

drug resistance

drugs rapidly transported from cell

inhibitors

increase bioavailability of substrate

Efficiency

-transporters move molecules only 10^2-10^4 /s -ion channels move up to 10^8 ions

What type of compound would be effective for inhibiting p-glycoprotein drug resistance?

-one that binds between TMD1 and TMD2 and competes with drug -one that competes with ATP binding