Basic concepts of Metabolism Metabolism and metabolic pathway• Metabolic Map• Catabolism • Anabolism- Regulation of Metabolism • Signals from within the cell (Intracellular)• Communication between cells. - Biosignaling: Signal transduction * Transduction by Intracellular receptors * Transduction by Cell-surface receptors
a. Ligand-Gated Ion channels b. Receptor enzyme c. Receptors involving second messenger molecules
i. Adenylate cyclase systemii. Phosphatidylinositol systemiii. Ca+ as second messenger
* Other messenger systemsa. cGMPsb. Nitric oxide
References:chapter 8 of Lippincotschapter 13 of Lehningers
* Enzymes catalyze different reactions that don't occur in isolation but organized into multi step sequence called pathway.
* The product of one reaction will be the substrate of the subsequent reaction
* Different pathways intersect forming an integrated reactions collectively called Metabolism
* Metabolic MapA picture containing the central pathways of energy metabolism. Each pathway is composed of multienzyme sequence and each enzyme has catalytic or regulatory features
The Metabolic MapShows the links between pathways, indicates the intermediates between different cycles (pathways) and shows the effect on different intermediates if one pathway is blocked
* Metabolic MapIt is a picture containing the central pathways of energy metabolism. Each pathway is composed of multienzyme sequence and each enzyme has catalytic or regulatory features
The Metabolic MapShows the links between pathways, indicates the intermediates between different cycles (pathways) and shows the effect on different intermediates if one pathway is blocked
Catabolic and Anabolic Pathways
Pathways can be classified as either catabolic (degradative) or anabolic (synthetic)
Catabolic: degradation of complex molecules (polysaccharides, proteins) into simple molecules like CO2, NH3 and water. Catabolism is convergent process: a wide variety of molecules are transformed into a few common end products
Anabolic reactions are the synthesis of complex molecules from simple precursor.Anabolic is divergent process in which few biosynthetic precursors form a wide variety of polymeric or complex products.
Catabolism- catabolic reactions provide chemical energy in the form of the ATP from the degradation of the energy-rich fuel compound. The catabolism is essential for providing energy necessary for building up the complex compound
Energy generation occur in three stepsStage IStage IIStage IIIEnergy is librated from the transfer of electrons from NADH and FADH2 to O2 through the electron transport chain
Anabolism
- Anabolic reactions combine small
molecules as amino acids to form
large complexes as proteins. These
processes require energy which is
provided by the break down of ATP
to ADP
- The biosynthetic pathway usually
is different from degredative
pathway of the same compound so
the two processes respond to
different regulatory
- Anabolic reactions involve
chemical reduction in which the
reducing power is NADPH
Regulation of Metabolism
•Pathways of the metabolism must be coordinated so that the
catabolism and the anabolism must meet the needs of the cell.
• The cell is not present in isolation it present in a tissue, in which
all the cells communicate together with regulatory signals.
• Regulatory signals including hormones, nervous system and
availability of nutrients which affect the signals generated within
the cell itself.
*Signals from within the cell (Intracellular)
the rate of a metabolic pathway may respond to regulatory
signals from the cell, e.g. the rate of the pathway may be
influenced by the availability of the substrate, product inhibition
or alterations in the level of allosteric activators or inhibitors.
These intracellular signals provide rapid responses and are
important for the moment to moment regulation metabolism
*Communication between cells.
Signals between cells provide for long-range integration of
metabolism and show slower response. Cell communication involves
surface interactions. For metabolism the chemical signaling is
involved like hormones and neurotransmitters released by nervous
system
Biosignaling: Signal transduction
Signal transduction is specific and very sensitive
* Specificity is achieved by precise molecular complementary
between signal and receptor molecule.
Epinephrine affect glycogen metabolism in hepatocyet and not in
erythrocyte because of the absence of the receptors.
The affinity of the signal to the receptor is very high highly
sensitive
Two Basic mechanisms of Signal transduction
Intracellular receptors
Cell-surface receptors
Vit D, steroidal hormones, retinoic acid
and thyroxine act through intracellular
receptors located in the cytosol or the
nucleus. The receptor-ligand complex
inter the nucleus and bind to specific
regions of the DNA (enhancer region)
causing increasing the expression of the
specified gene. These hormones should
penetrate the cell membrane and bind to
specific region. Their effect are not
immediate because time is required for
gene transcription and then mRNA
translation. But the duration of action will
be longer.
Transduction by intracellular receptors steroid
c
Transduction by cell-surface receptors.
• Signals transduction by hormones and neurotransmitters is
initiated by ligand binding to receptors located in the
plasma membrane.
• This transduction dose not regulate the gene expression
directly. Simply signal interact with receptors activated
receptors interact with cellular machinery producing a
second signal or change in the activity of a cellular protein
metabolic change in target
Three general classes of cell-surface receptors based
on their mechanism of signal transduction.
a. Ligand-Gated Ion channels (Neurotransmitter receptors
linked to ion channels).
b. Receptor enzyme (Catalytic receptors)
c. Receptors involving second messenger molecules.
Three general classes of cell-surface receptors based on their mechanism of signal transduction
Ligand-Gated Ion channels
Commonly called transmitter-gated ion channels or ionotropic receptors
- Involved in rapid synaptic signaling
- Best example for this type is Nicotinic acetylcholine receptors
- Acetylcholine receptors are allosteric protein with two binding sites for
Ach.
- Classically defined by acetylcholine (ACh) receptor at neuromuscular
junction
- Nerve impulse depolarize axon, signal travels to nerve terminal leading
to opening of voltage-gated Ca+ channels, Ca+ flows in and Ach is
released to post synaptic neuron or myocyte.
- Ach binds receptors on muscle cells leading to opening of cation (Ca+,
Na+) channel and Na+ flows in and thus depolarization of the receiving
cell initiates another action potential (neuron) or contraction of the
muscle cell (if myocyte)
Voltage-Gated Ion channels open and close as response to electrical
change
Voltage-gated Na+ channel
Voltage-gated K+ channel
Voltage-gated Ca+ channel
figure 13-5Role of voltage-gated and ligand-gated ion channels in neural transmission. Initially, the plasma membrane of the presynaptic neuron IS polarized (inside negative) through the action of the electrogenic Na+-K+ ATPase. which pumps 3 Na+ out for every 2 K+ pumped Into the neuron , (1) A stimulus to this neuron causes an action potential to move along the axon (white arrow), away from the cell body. The opening of one voltage-gated Na+ channel allows Na+ entry and the resulting local depolarization causes the adjacent Na+ channel to open, and so on. The directionality of movement of the action potential is ensured by the brief refractory period that follows the opening of each voltage-gated Na+ channel. (2) When the wave of depolarization reaches the axon tip, voltage-gated Ca+2 channels open, allowing Ca+2 entry into the presynaptic neuron. (3) The resulting increase in internal [Ca+2] triggers exocytic release of the neurotransmitter acetyleholme into thesynaptic cleft. (4) Acetylcholine binds to a receptor on the postsynaptic neuron, causing its ligand-gated Ion channel to open. (5) Extracellular Na+ and Ca++ enter through this channel, depolarizing the postsynaptic cell. The electrical signal has thus passed to the cell body of the postsynaptic neuron and will move along its axon to a third neuron by the same sequence of events.
Ach binds receptors on muscle cells leading to opening of cation (Ca+,
Na+)
channel and Na+ flows in and thus depolarization of the receiving cell
initiates
another action potential (neuron) or contraction of the muscle cell (if
myocyte)
Neural transmission
Receptor Enzyme•These Transmembrane catalytic receptors have an
inherent enzymatic activity as part of their structure.• have ligand binding domain on the extracellular
surface of the plasma membrane and enzyme active
site on the cytosolic side.• Commonly they are a protein kinase that
phosphorlate Tyr residues in the specific target
proteins• Insulin receptor is prototype for this type • The binding of the a ligand (insulin) to its receptor
activates the tyrosine kinase activity which transfer
the phosphate group from ATP to the –OH group of
the Tyr residues of target proteins and of the receptor
itself
figure 13-6Insulin receptor. The insulin receptor consists of twoα chains on the outer face of the plasma membrane and two chains that traverse tile membrane and protrude from the cytosolic face. Binding of insulin to the α chains triggers a conformational change that allows the autophosphorylation of Tyr residues in the carboxyl-terminal domain of the subunits. Autopllosphorylation further activates the tyrosine kinase domain, which then catalvzes phosphorvlation of other target proteins.
Receptors involving second messenger molecules.
Many signals when bind to their receptors initiate a series of reactions in form of cascade reactions that at the end result in a specific intracellular response. The intracellular messenger systems function as signal amplification.
signal amplification.
Receptors involving second messenger molecules
I. Adenylate cyclase system-Typical example is the adrenergic receptors β-receptors that bind to
epinephrine and then trigger either an increase or decrease in the
activity of the adenylate cyclase.- Adenylate cyclase convert the ATP into cAMP which act as second
messenger and activate other enzymes to produce the activity. - Many signals (hormones) act through activating the cAMP like
glucagon - the effect of signals on the second messenger is not direct but
mediated through G-proteins. GTP-dependent regulatory proteins. The
inactive form of G-protein binds to GDP while the active form bind to
GTP.- The binding of hormone to its receptor activate the G-protein which
affect the activity of adenylate cyclase- The activity of signal depends one the type of G-proteins. Gs
stimulates the adenylate cyclase while Gi inhibits it. - The actions of G-protein _GTP complex are short lived because G-
protein has an inherent GTPase activity, resulting in rapid hydrolysis of
GTP to GDP and this causes the inactivation of G-protein.
Adenylate cyclase convert the ATP into cAMP which act as second messenger
Receptors involving second messenger
molecules Adenylate cyclase system
Role of G-Proteins in Signal Transduction
Activation Adenylate cyclase system via G-Proteins
cAMP activates Protein Kinases A.
-The next link in the cAMP second messenger system is the activation of Protein Kinases by cAMP.- Family of enzymes called cAMP-dependent protein kinases. - Protein Kinase A is the typical example, consists of 4 monomers. 2 catlytics and 2 regulatory.-The active subunits catalyze the transfer of phosphate from ATP to specific serine or threonine residues of protein substrate.- the phosphorylated protein can act directly or can activate or inhibit other enzymes to produce the effect.- Not all protein kinases respond to cAMP, other types are cAMP-independent protein kinase like proetin kinase C.- The phosphate group can be removed by proetin phosphatases. - cAMP is rapidly hydrolyzed to 5-AMP by phosphodiesterase.
Activation of cAMP-
dependent protein
kinase, PKA
Activation of cAMP-dependent protein
kinase (PKA)
Phosphatidylinositol 4,5 bisphosphate
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IP3
Second messengers derived from Phosphatidylinositol
Role of Phosphatidylinositol 4,5 bisphosphate in Signal transduction
IP3 activates the release of Ca+
Ca+ is a second messenger in many
signal transductions-Ca+ serves as a second messenger that
triggers intracellular responses as exocytosis
in neurons and endocrine cells, contraction
in muscle and others- Ca+ is released from endoplasmic
reticulum in response to signals (hormones,
neurotransmitters)- Ca+ bind to Ca-binding proteins that called
calmodulin- Calmodulin-ca complex binds and activates
protein molecules usually enzymes, - Calmodulin is regulatory subunit of
phosphorylase b kinase of muscle that
activated by Ca activating the break down
of glycogen. - Many enzymes are know to be modulated
by Ca+ through calmodulin.
Ca+ is a second messenger in many signal transductions
Other messenger systems
a. cGMP
b. Nitric oxide
* Cyclic guanosine monophosphate
It is analogous to cAMP pathway
Synthesized from GTP by guanylate cyclase, it an integral
part of the receptor (not separated like Adenylate cyclase), it
contains heme as prosthetic group and stimulated by nitric
oxide.
Activate a spcific form of protein kinase called cGMP-
dependent protein kinase also called protein kinase G
cGMP is hydrolyzed by phosphodiesterase
cGMP is a specialized messenger being involved in smooth
muscle relaxation, platelet aggregation and the visual
system. cAMP affects a wide variety of processes.
Nitric Oxide
NO act as endothelium relaxing factor, causes vasodilatation by relaxing
vascular smooth muscle and also acts as neurotransmitters, prevents
platelet aggregation and has a role in macrophage function.
It is highly toxic. Nitrous oxide ( NO2) the “ laughing gas” that used as
anesthetic.
NO is very short lived and unstable converted into oxygen and nitrate and
nitrite.
Synthesis of NO
-NO synthase catalyzes the formation of NO from amino acid Arginine,
FMN, FAD, and tetrahydrobiopterin are coenzymes for the enzymes
- NO is synthesized in endothelial cells and diffuses to vascular smooth
muscle activate the guanylate cyclase rise in cGMP which causes
muscle relaxation.
- Synthesis of NO is stimulated in the macrophages by bacterial
liopolysaccharides activated macrophages form oxygen free radical that
combine with NO to form compounds that are more bactericidal than NO
itself
Nitric Oxide act as endothelium relaxing factor, causes vasodilatation by relaxing vascular smooth muscle and also acts as neurotransmitters, prevents platelet aggregation and many functions