solute carrier proteins

May 1, 2023 Dept of Plant Biotechnology 1

ROLE OF SOLUTE CARRIER PROTEINS

UPASANA MOHAPATRAJr.MSc PLANT

BIOTECHNOLOGYPALB 6290

UAS,GKVK,Bengaluru



CONTENTS1. CELL MEMBRANE2. TRNASPORT THROUGH CELL MEMBRANE3. TRANSPORT PROTEINS4. DIFFERENCE BETWEEN TRANSPORT AND CARRIER

PROTEINS5. SLC PROTEINS AND ITS REQUIREMENTS6. MODE OF WORKING OF SLC PROTEINS7. NOMENCLATURE AND CLASSIFICATION OF SLC

PROTEINS8. SLC PROTEINS AND DISORDERS9. ROLE OF SLC PROTEINS10. TRANSPORTERS AS TARGET OF DRUGS(CASE STUDY)

Dept of Plant Biotechnology 4

CELL MEMBRANE Structure of cell

membraneLipid Bilayer -2 layers

of phospholipids (Gorter & Grendel (1925)

a. Phosphate head is polar (water loving)

b. Fatty acid tails non-polar (water fearing)

c. Proteins embedded in membrane

Phospholipid

Lipid BilayerMay 1, 2023


Polar heads love water & dissolve. Fluid Mosaic

Model of the cell

membraneProteins in membrane

Polar heads love water & dissolve.

Non-polar tails hide from water.


Transport Through Cell Membranes

Transport

Carrier Mediated

Active

Primary Secondary

Facilitated

Non Carrier Mediated

Passive


TRANSPORT MECHANISMS

TRANSPORT

Passive processActive process

Primary Transport

Secondary Transport

Simple diffusion

Facilitated diffusion

Osmosis

Bulk flow

Filtration

Require energy

Don’t require energy


1. DIFFUSION

• Diffusion is the net movement of molecules (or ions) from a region of their high concentration to a region of their lower concentration.

• The molecules move down a concentration gradient.

• Molecules have kinetic energy, which makes them move about randomly.

• As a result of diffusion molecules reach an equilibrium where they are evenly spread out.This is when there is no net movement of molecules from either side.


Molecules That Diffuse Through Cell Membranes

1. Oxygen – Non-polar so diffuses very quickly.

2. Carbon dioxide – Polar but very small so diffuses quickly.

3. Water – Polar but also very small so diffuses quickly.


2. Facilitated Diffusion

Movement of molecules is still PASSIVE just like ordinary diffusion, the only difference is, the molecules go through a protein channel instead of passing between the phospholipids.


Molecules will randomly move through the opening like pore, by diffusion. This requires no energy, it is a PASSIVE process. Molecules move from an area of high concentration to an area of low conc.


3. Osmosis

‘The diffusion of water from an area of high concentration of water molecules (high water potential) to an area of low concentration of water (low water potential) across a semi permeable membrane.’

Isotonic solution-solution with the same solute concentration as that of the cytosolHypotonic solution -lower concentration of non permeating solutes than that of the cytosol (high water concentration),cells absorb water, swell and may burst (lyse)Hypertonic solution -has higher concentration of nonpermeating solutes than that of the cytosol (low water concentration)cells lose water.


4. VESICULAR TRANSPORTIt is the transport of membrane bounded substances moving across plasma membrane

It is classified into: 1. Exocytosis 2. Endocytosis.


Endocytosis

A. It is a process by which the large number of particles are taken with forming the vesicle into the cell

B. It is classified into: 1. Phagocytosis- It is a process by which the large number of particles are

engulfed into the cell. 2. Pinocytosis It is a process by which the large number of particles

which are soluble in water are taken into the cell


5. Active transport

A. Active transport is the transport of substances from a region of lower concentration to higher concentration using energy, usually in the form of ATP.

B. Examples: Na, K and Ca active transport.

• 1.Sodium-potassium pump• 2.Calcium pump• 3.Potassium hydrogen pump


Active Transport needed for,

1.Maintaining the Chemical and Electrical Charge at rest.

2.Intake of Substances through gated Channels.

3.Collecting of ions with more concentration.


NEED OF ACTIVE TRANSPORT

1. Cells cannot rely solely on passive movement of substances across their membranes.

2. In many instances, it is necessary to move substances against their electrical or chemical gradient to maintain the appropriate concentrations inside of the cell or organelle.


PRIMARY ACTIVE TRANSPORT

1. Primary active transport is the transport of sustances uphill using energy (ATP hydrolysis)

2. It cause a conformational change that results in the transport of the molecule through the protein.

3. Eg. Na+-K+ pump.

http://web.mit.edu/esgbio/www/eb/chem/energetics.html


In this energy stored in the electrochemical gradient of an ion is used to drive the transport of another solute against a concentration or electrochemical gradient. The ion moving down its electrochemical gradient is referred to as the driving ion because it is movement of this ion that drives the uphill movement of another ion/molecule (driven ion/molecule). May be 1) Antiport2) Symport

Secondary active transport or Co-transport


Transport Proteins

1. A transport protein (variously referred to as a transmembrane pump, transporter protein, escort protein, acid transport protein, cation transport protein, or anion transport protein) is a protein that serves the function of moving other materials like ions, small molecules, or macromolecules, such as another protein, across a biological membrane within an organism.

2. Transport proteins are integral transmembrane proteins; that is they exist permanently within and span the membrane across which they transport substances.


Difference between transport proteins and carrier proteins.

1. The proteins may assist in the movement of substances by facilitated diffusion or active transport.

2. The two main types of proteins involved in such transport are broadly categorized as either channels or carriers

3. Transport proteins and the carrier proteins are not same as carrier protein is a type of transport protein.


Difference Between Carrier And Channel Proteins

Carriers

1. A carrier is not open simultaneously to both the extracellular and intracellular environments. Either its inner gate is open, or outer gate is open.

2. Carriers have binding sites.3. But only 100 to 1000

molecules typically pass through a carrier molecule in the same time.

Channels1. A channel can be open to

both environments at the same time, allowing the solutes it transports to diffuse without interruption.

2. But pores and channels do not.

3. When a channel is opened, millions of ions can pass through the membrane per second.


https://en.wikipedia.org/wiki/File:Scheme_facilitated_diffusion_in_cell_membrane-en.svg


SLC PROTEINS AND ITS REQUIREMENTS

1. SLC proteins are the solute carrier proteins that transport the solutes across the membrane.

2. Lipid bilayers are highly impermeable to most polar molecules.

3. To transport small water-soluble molecules into or out of cells or intracellular membrane-enclosed compartments, cell membranes contain various membrane transport proteins, each of which is responsible for transferring a particular solute or class of solutes across the membrane. these are known as solute carrier proteins.



SLC PROTEINS AND ITS REQUIREMENTS

These are required because1) Some molecules(including charged, uncharged polar

molecule) can not pass through the phospholipid bilayer of membrane which is impermeable to them.

2) Some molecules also move against the direction of concentration gradient.

3) The liquid inside and outside the cell have different substances. Sometimes cell has to work and use some energy to maintain proper balance of ions and molecules..


HYDROPHOBIC MOLECULES

SMALL UNCHARGED POLARMOLECULES

LARGE UNCHARGED POLAR MOLECULES

IONS

CO2, O2

ETHANOL

GLUCOSE

H+

,

HCO3 -

Ca2+ , Mg2+

MOVEMENT ACROSS LIPID BILAYER

May 1, 2023 27Dept of Plant Biotechnology

https://www.ncbi.nlm.nih.gov/books/NBK26815/figure/A1990/?report=objectonly


Mode Of Working Of Slc Proteins Or Types Of Solute Movement

SOLUTE MOVEMENT

ACTIVE TRANSPORT PASSIVE TRNSPORT

PRIMARY ACTIVE TRANSPORT

SECONDARY ACTIVE TRANSPORT

SIMPLE DIFFUSION

FACILLATED DIFFUSION

OSMOSIS



Mechanism Of Facilitated Diffusion

• To pass through a lipid bilayer, a polar or charged solute must first give up its interactions with the water molecules in its hydration shell, then diffuse through a solvent (lipid) in which it is poorly soluble

• The energy used to strip away the hydration shell and to move the polar compound from water into and through lipid is regained as the compound leaves the membrane on the other side and is rehydrated.

• The intermediate stage of transmembrane passage is a high-energy state comparable to the transition state in an enzyme-catalyzed chemical reaction.



Mechanism Of Facilitated Diffusion

• An activation barrier must be overcome to reach the intermediate stage . The energy of activation (G‡) for translocation of a polar solute across the bilayer is so large that pure lipid bilayers are virtually impermeable to polar and charged species over periods of time.

• Membrane proteins lower the activation energy for transport of polar compounds and ions by providing an alternative path through the bilayer for specific solutes.



(a) Insimple diffusion, removal of the hydration shell is highly endergonic,and the energy of activation (G‡) for diffusion through the bilayer is very high. (b) A transporter protein reduces the G‡ for transmembrane diffusion of the solute. It does this by forming noncovalent interactions with the dehydrated solute to replace the hydrogen bonding with water and by providing a hydrophilic transmembrane passageway.

Principles of biochemistry Lehinnger


Mechanism of primary active transport (P-type Na-K ATPase)

1. In virtually every animal cell type, the concentration of Na is lower in the cell than in the surrounding medium, and the concentration of K is higher.

2. This imbalance is maintained by a primary active transport system in the plasma membrane. The enzyme Na-K ATPase, discovered by Jens Skou in 1957, couples breakdown of ATP to the simultaneous movement of both Na and K against their electrochemical gradients.

3. ATPase cycles between two forms, a phosphorylated form (designated P-EnzII) with high affinity for K and low affinity for Na, and a dephosphorylated form (EnzI) with high affinity for Na and low affinity for K ion.


•Because three Na ions move outward for every two K ions that move inward, the process is electrogenic—it creates a net separation of charge across the membrane.•The result is a transmembrane potential of 50 to 70 mV (inside negative relative to outside), which is characteristic of most animal cells and essential to the conduction of action potentials in neurons.


MOVEMENT ACROSS TONOPLAST IN PLANT CELL

Plant Physiology 5th EditionTeiz And Zeiger


CLASSIFICATION OF SLC PROTEINS AND NOMENCLATURE

Molecular Aspects of Medicine 34 (2013) 95–107


NOMENCLATURE OF SLC PROTEINS

1. The SLC gene nomenclature system was originally established in the 1990s by Matthias Hediger in collaboration with Phyllis McAlpine, the first chair of the HGNC.

2. In general, the genes are named using the root symbol SLC, followed by a numeral (e.g., SLC1, solute carrier family 1), followed by a letter which defines the subfamily (only A is used when the family has not been subdivided) and finally a number designating the individual transporter gene (e.g., SLC3A1).

3. Transporters are assigned to a specific family if the encoded protein has at least 20% amino acid sequence identity to other members of that family


Classification Of Solute Carrier Proteins


SLC PROTEINS AND DISORDERSSLC SERIES FUNCTION DISORDERSGlutamate transport (SLC1 family)

play a critical role in the central nervous system by maintaining extracellular glutamate concentrations below excitotoxic levels

Amyotrophic Lateral Sclerosis (ALS) as well as Alzheimer disease (AD).

Urate transport (SLC2 family)

SLC2A9 initially considered aglucose or fructose transporter, is now established as a urate transporter

Genetic defects of SLC2A9 are linked to early-onset nephropathy

Neuro transmitter transport (SLC6 family)

transport substrates such as serotonin, dopamine, norepinephrine,GABA, taurine, creatine, as well as amino acids

Mood disorders such as depression, addiction, aggression, post-traumatic stress disorder (PTSD), anxiety, obsessive compulsive disorder (OCD), and disorders such as attention deficit hyperactivity disorder (ADHD)

Di- and tri-carboxylate/sulfate transport (SLC13 family)

Na+-coupled di- and tri-carboxylate/sulfate transporter

Pathogenesis of the twoInborn metabolic diseases glutaric aciduria type 1 (GA1) and Canavan disease (CD).


SLC PROTEINS AND DISORDERSSLC SERIES FUNCTION DISORDERS

Organic anion transport (SLC17 family)

organic anion transporters

Gout, and possibly schizophrenia, as well as amyotrophic lateral sclerosis (ALS), Alzheimer disease,and Huntington disease (VGLUTs).

Mitochondrial transporter (SLC25 family)

muscle pain, progressive hypertrophic cardiomyopathy (severe anemia with hypochromia, microcytosis and ringed sideroblasts in the bone marrow).

Anion transporters (SLC26 family)

anion transporters and channels,

oxalate urolithiasis, gastric hypochlorhydria, distal renal tubular acidosis, and maleinfertility.

Zinc transport (SLC30 and SLC39 families)

zinc transporters

Abnormal zinc metabolism has also been shown to be associated with the risk ofdiabetes, breast cancer and prostate cancer

Riboflavin transport (SLC52 family)

Multiple acyl-CoA dehydrogenase deficiency (MADD), Brown-Vialetto-Van Laere Syndrome, a rare autosomal recessive neurologic disorder characterized bysensorineural hearing loss and a variety of cranial nerve palsies


Role Of Transporters Or SLC Proteins In Other Prospects

1. Transporters can serve as drug targets or as a mechanism to facilitate drug delivery to cells and tissues. Recently exploited drug transporter targets include neurotransmitter transporters (SLC6 family),intestinal bile acid transporters (SLC10 family) and cation-Cl cotransporters (SLC12 family).

2. Dapaglifloxin (Forxiga), the first of a class of inhibitors of the SGLT2 (SLC5A2) sugar transporters, has been approved in Europe for treatment of Type 2 diabetes.

3. The intestinal oligopeptide transporter PepT1 (SLC15A1) or transporters at the blood–brain barrier (various SLC families) are proving to be important drug delivery systems.


SLC Transporters As Therapeutic Targets: Emerging Opportunities

Objective1. The role of SLC transporters in human health

and discuss how defects in SLC transporters cause disorders.

2. Methodologies that may be used to develop drugs to treat diseases associated with genetic variants of SLC transporters.

Lawrence Lin et al.,Nature 2015


Types Of Mutations In SLC Transporter Genes


The Transporters As Target Of DrugsSl no. Transporter family Used for

1 SLC12 transporters as targets of diuretic drugs

used to treat hypertension and heart failure

2 SLC6 transporters as neuropsychiatric drug targets

Drugs for treating depression

3 Glucose transporter inhibitors to decrease blood glucose level.

4 Uric acid transporter inhibitors for Gout

5 Glycine transporter inhibitors.- for schizophrenia

6 Bile acid transporter inhibitors – for lowering blood cholesterol level and prevnting cardiovascular diseases.

7 Nutrient transporter inhibitors. –. for prevention of tumor cell growth in cancer


CONCLUSION1. As protein structures become ever more available, improved

strategies emerge using this information, along with improvements in rational drug discovery approaches, to facilitate development of both new drugs as well as research tools to more deeply understand the biological roles of transporters.

2. The future challenge for the scientific community will be the biochemical, biophysical, physiological and pharmacological assessment of all these novel gene products in a manner that can be used to improve our understanding of transporter biology, with a focus on human physiology, pathophysiology and drug discovery.


REFERENCES1. The Abcs Of Membrane Transporters In Health And

Disease(slc Series): Introduction Matthias A et al.,. Mol Aspects Med. 2013 Apr; 34(2-3): 95–107.

2. SLC Transporters As Therapeutic Targets: Emerging Opportunities Lawrence Lin1,et al., Nat Rev Drug Discov. 2015 Aug; 14(8): 543–560.

3. Principles Of Biochemistry Lehinnger 5th Edition

4. Plant Physiology Fifth Edition Lincoln Teiz And Eduardo Zeiger

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