9 information metabolism

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Lecture 9

INTRODUCTION TO INFORMATION METABOLISM

Information metabolism comprises: How cells receive, process, and respond to

information from the environment. Approximately half of the 25 largest protein familiesencoded by human genome deal primarily with information processing.

Principle of signal transduction:An environmental signal, such as a hormone, is first received by interaction with a

cellular component, most often a cell-surface receptor. The signal is then converted into

other chemical forms, or transduced. The signal is often amplified before evoking a

response. Feedback pathway often regulates the entire signal process.

Amplification

SIGNAL-

Reception ----------------

Transduction----

>>>>Response

Membrane receptors transfer information from the environment to the cell’s

interior:

Most signal molecules are too large and too polar to pass through the membrane,

and no appropriate transport systems are present. In such cases a membrane associatedreceptor protein often performs the function of information transfer across the membrane.

A few non-polar signal molecules (estrogens and other steroid hormones) are able to

diffuse through the membrane. These molecules can bind to proteins that interact directly

with DNA and modulate gene transcription. Thus, a chemical signal enters the cell and

directly alters gene-expression patterns.

•Receptor is an intrinsic membrane protein that has both extracellular and intracellular

domains. A binding site on the extra cellular domain specifically recognizes the signal

molecule, often referred to as ligand. The interaction of the ligand and the receptor altersthe tertiary or quaternary structure of the receptor, including the intracellular

domain. These structural changes are not sufficient to yield an appropriate response,

because they are restricted to a small no of receptor molecules in the cell membrane. Theinformation embodied by the presence of the ligand, often called the primary messenger,

must be transduced into other forms that can alter the biochemistry of the cell.

The seven transmembrane-helix (7-TM) receptor (also called serpentine receptor) is thelargest and one of the most important classes of receptor. They are responsible for

transmitting information initiated by signals as divers as: smell, taste, vision,

neurotransmission, control of blood pressure, viral infection, carcinogenesis etc.7-TMs contain 7 helices that span the membrane bilayer. The binding of a ligand from

outside the cell induces a conformational change in the 7-TM receptor that can be

detected inside the cell. Ligand binding to 7TM receptors leads to the activation of G protein, a heterotrimeric protein (G for guanyl nucleotide) that triggers the exchange of



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GTP for GDP bound to the alfa subunit of the G-protein. The activated G protein

stimulates the activity of other enzymes (such as, adenylate cyclase, phosphodiesterase)

that increases the conc of second messenger (such as cAMP, GMP). When signaltransmission is over the G protein reset themselves through GTP hydrolysis. After GTP

hydrolysis and release of Pi, the GDP-bound form of G-alpha then reassociates with G-

beta-gamma to form heterotrimeric protein.

Second messenger relay information from the receptor-ligand complex.

Particularly important second messengers include cyclic AMP, cyclic GMP, Ca ion, -.

•Second messengers are intracellular molecules that change in concentration in response

to environmental signals. That change in concentration conveys information inside the

cell.

The use of second messengers (SM) has several consequences:

a. They are often free to diffuse to other compartments of the cell, such as the nucleus,where they can influence gene expression and other processes.

b. The signal may be amplified significantly in the generation of second messengers.Thus a low concentration of signal in the environment, even as little as single molecule,

can yield a large extracellular and response.

c. Input from several signaling pathways (cross talk) permits more finally tune regulation

of cell activity.

Protein phosphorylation is a common means of information transfer:

Many SM elicit responses by activating protein kinases. These enzymes transfer phosphoryl groups from ATP to specific serine, threonine, and tyrosine residues in

proteins.

Signal termination:

•Protein phosphatases are one mechanism for the termination of signaling process.

Without such termination, cells lose their responsiveness to new signals.•Failing termination may lead to uncontrolled cell growth and possibility of cancer.



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Example: Vision

1. Receptor activation:

2. GDP/GTP exchange and G protein dissociation

3. G α activation of enzyme activity

4. Closing of ligand-gated ion channel.



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Signaling pathway: Response:Step 1: Receptor activation

Step II: GDP/GTP exchange and G protein dissociation

Step III: G ∞ activation of enzyme activity

Step IV: Opening and closing of ligand gated ion channels.

Recovery from a signal receptor in vision

Step 1: Gα deactivation : Gα dissociate itself from phosphodiesterase when it hydrolyses

from bound GTP to GDP.



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Step 2:



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Step 4: With Gα dissociated, cGMP phosphodiesterase is able to once again inhibit itself.

Increase in cGMP concentration is aided by a feedback mechanism involving Ca 2+.When ion channel closed in response to light signal, the intracellular Ca 2+ rapidly drops

because Ca 2+ continues to be pumped out of the cell but no longer leak back in. As Ca 2+

conc falls guanylate cyclase become more active, rapidly replenishing cGMP that had been hydrolysed during the response of light. cGMP binds to the ligand gated ion

channels, reopening them. Positive ions including Ca 2+ , can once again begin entering

the cells.



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Signaling pathway: Recovery:

Step 1: G ∞ activation

Step II: G protein assemblyStep III: Rhodopsin inactivation

Step IV: Phosphodiesterase reinhibition

Step V: cGMP conc replenishedStep VI: Gated ion channel reopened.

Step VII: Membrane polarization decreased.

• phosphoinositidine cascade

•Another ubiquitous second messenger is phosphoinositidine cascade. The receptor-

triggered activation of phospholipase C generates 2 intracellular messengers, namely,inositol 1,4,5-triphosphate and diacylglycerol, by hydrolysis of phosphatidyl inositol 4,5-

biphosphate.

•Inositol triphosphate opens calcium channels in the ER and SR (sarcoplasmic Reticulum

which is the ER in smooth muscle) membrane, leading to an elevated level of calcium inthe cytosol, which triggers smooth muscle contraction, glycogen breakdown, and vesicle

release.

•Calcium ion is a ubiquitous cytosolic messenger. Why this ion is commonly found as

mediator of so many signaling processes ?

•Ans: 1. Ca complexes of phosphorylated and carboxylated compounds are often

insoluble, but such compounds are fundamental to many biochemical processes in the

cells. Thus, the intracellular level of Ca must be kept low to prevent precipitation of thesecompounds.

•The low intracellular level of Ca is maintained by transport system for the extrusion of

Ca. In eukaryotic cells, Ca-ATPase and Na-Ca exchange are important. Because of their action the level of Ca in cytosol (100nM) is several order of magnitude lower than in the

blood (5 mM).This steep conc gradient is an opportunity to utilize for cell signaling.

•The cytosolic Ca level may be abruptly raised for signaling purposes by transientlyopening Ca channels in the plasma membrane or in an intracellular membrane.

•A 2nd property of Ca that make it highly suitable intracellular messenger is that it can

bind tightly to protein. Ca activates the regulatory protein Calmodulin, which stimulates

many enzymes and transporters. Calmodulin (CaM), a protein with 4 Ca binding sites,

serve as a Ca sensor in nearly all eukaryotic cells. Calmodulin is activated by the bindingof Ca when cytosolic Ca level is raised above about 500nM. The Ca-calmodulin complex

stimulates a wide array of enzymes, pumps, and other target proteins. Two targets areespecially noteworthy: one that propagate the signal and the other that abrogate it.

•Calmodulin dependent protein kinase (CaM kinase) phosphorylates many different proteins. These enzymes regulate fuel metabolism, ionic permeability, neurotransmitter



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synthesis and release. The binding of Ca-calmodulin to CaM kinase activates the enzyme

and enables it to phosphorylate target proteins.

•The plasma membrane Ca-ATPase pump is another important target of Ca-calmodulin.

Stimulation of the pump by Ca-calmodulin drives the Ca level down to restore the low Ca

basal state, thus helping to terminate the signal.

•Small G Proteins (or small GTPases):This large superfamily of signaling proteins grouped into subfamilies called Ras, Rho,

Arf, Rab, and Ran- plays a major role in a host of cell functions including growth,

differentiation, cell motility, cytokinesis, and transport of materials through out the cells.

Like heterotrimeric G proteins, the small G proteins cycle between an active GTP-boundform and an inactive GDP-bound form. They differ from heterotrimeric G protein in

being smaller (20-30 kd vs 30-35 kd) and monomeric.

•Defects in signaling pathways can lead to cancer and other diseases.

•Cancer, a set of diseases characterized by uncontrolled or inappropriate cell growth, isstrongly associated with defects in signal-transduction proteins.

•Wide spread occurrence of over active Protein kinase in cancer cells suggest that protein

kinase inhibitors may be effective anticancer drugs. E.G. Gleevec

Cholera and whooping cough are due to altered G-protein activity.

•Cholera, caused by Vibrio cholera, is an acute diarrheal disease causes voluminous

secretion of electrolytes and fluids from the intestines.•The toxin, choleragen, is a protein composed of 2 functional units A & B

•B binds to GM1gangliosides of the intestinal epithelium

•’A’ enter the cell and catalyzes the covalent modification of a G-alpha-s protein by the

attachment. The modification stabilizes the GTP-bound form of G-alpha-s protein,trapping the molecule in the active conformation.

•The active G-protein, in turn, continuosly activates protein kinase A (PKA).

•PKA open the chloride channel by phosphorylation resulting in excess loss of NaCl andlarge amount of water into the intestine.

•Treatment consists of rehydration with a glucose–electrolyte solution.

•Pertussis, or whooping cough, is a result of the opposite situation.

•Pertussis toxin also adds an ADP-ribose moiety, in this case to a G-apha-i protein, a G-alpha protein that inhibits adenyl cyclase, closes Ca+ channels, and open K+-channels.

•The effect in this case is to lower the G protein’s affinity to GTP and making it to off position.

• Pertussis toxin secreted by Bordetella pertussis

.

9 information metabolism

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