Chapter 8 (Lectures 8-11)

Basic Concepts of Metabolism

Unit II: Intermediary Metabolism

AJG

1 Introduction to metabolism

A. Define metabolism in terms of anabolic and catabolic processes1. Compare, contrast, anabolic & catabolic pathways2. Include the concept and the importance of electron carriers3. Explain why catabolic pathways are considered convergent4. Explain why anabolic pathways are considered divergentB. Explain the importance of cell-cell communication in the regulation ofmetabolism.C. List the 4 different types of receptors and their basic mechanism of actionD. Give examples of the four types of receptors.E. Describe the two second messenger systems( adenylate cyclase) and thephophoinositide systemF. Indicate the receptors, G-protein and effector enzyme in each of thesesystems.G. Indicate what second messenger(s) are produced by activation of adenylatecyclase and phospholipase C.H. Indicate which protein kinase (PKA, PKC) is activated in both systems

Learning objectives: Introduction to metabolism

Catabolism

• degradation• convergent• “oxidative”

• products:

ATPFADH2

NADHNADPH

Anabolism

• synthesis• “reductive”• divergent• uses ATP

• products:

NAD+

FADADPNADP+

Stages of Catabolism

Stage 1

Stage 2

Stage 3

Regulation of Metabolism

The pathways of metabolism must be coordinated so that the production of energy or the synthesis of end products meets the needs of the cell.

An efficient communication system is necessary to coordinate the functions of the body.

Regulation depends on:

• intercellular signals

• intracellular signals- signal trasduction

Intercellular signals

Extracellular signals are converted to Intracellular

signals

Signal Transduction

OR

Intercellular signals

Intracellular signals

cAMP

are converted

to an intracellular signal in the

adjacent cell

Enzyme-P

4 basic types of signal transduction pathways:

1. Steroid receptor

2. Gated ion channel

3. Receptor enzyme (Catalytic receptor)

4. G-protein coupled receptor (GPCR)

produce intracellular 2nd messengers

Receptor-mediated Signal Transduction (Extracellular signals)

Four general types of receptorsGPCR

1. Steroid receptor mechanism of signal transduction

1. Steroid receptor mechanism of signal transduction

mechanism may take hours or days (slow)

2. Gated ion channel

• receptor linked to ligand or voltage-gated ion channel

• binding of neurotransmitter causes channel to open

• results in rush of ions through ion channel altering membrane potential promoting or inhibiting nerve impulse transmission

• Examples: nicotinic ACh receptors of muscle or nerve and -aminobutyric acid (GABA) and glycine receptors in the CNS

2. Gated ion channel

3. Receptor enzyme (Catalytic receptor)

3. Receptor enzyme (Catalytic receptor)• Transmembrane catalytic receptors that have enzymatic activity as part of their structure

• Enzyme is a tyrosine-specific protein kinase(adds a phosphate to specific tyrosine residues)

• Several cell-surface receptors contain an extracellular domain for binding ligands and an intracellular domain with tyrosine kinase activity

• Example: insulin receptor in which binding of ligand ATP cleavage, autophosphorylation and phosphorylation of specific tyrosine residue in target proteins

G-protein coupled receptor (GPRC)

produce intracellular 2nd messengers

• Hormones and neurotransmitters are signals and receptors are signal detectors

• Receptors indicate receipt of a signal through the production a “second messenger” inside the cell

• Second messengers trigger a cascade of intracellular events in response to the binding of a

hormone to its receptor

• Examples: 1. Adenylate cyclase system (cAMP)2. Calcium/phosphatidylinositol system (IP3, DAG, Ca2+)

4. GPCR and Intracellular Second Messengers

4. Intracellular Second Messengers

• Definition: Second messengers are small molecules produced in the cytoplasm in response to the activation of a cell surface receptor

• Examples :

• cAMP• IP3, DAG, Ca2+

• cGMP• Nitric Oxide (NO)

Second messengers start a cascade of intracellular events (enzyme activation, inhibition) resulting in a specific cellular response

• Adenylate cyclase sytem:• c-AMP(second messenger)

• Protein kinase A

second messenger systems

Stimulus: epinephrin/norepinephrine or glucagon

Receptors: β-adrenergic receptor or glucagon receptor

Adenylate cyclase system

• second messenger is cAMP

• cAMP activates protein kinase A

• protein kinase A phosphorylates target proteins

• phosphodiesterase hydrolyzes cAMP to 5’-AMP

G-protein coupled receptor (GPRC)

produce intracellular 2nd messengers

• Phosphoinositide system:• Inositol tris-phosphate

• Calcium• Diacylglycerol

• Protein kinase C

G-protein coupled receptor (GPCR)

produce intracellular 2nd messengers

P

P

Phosphatidylinositol 4, 5-bis-phosphate

Phosphatidylinositol 4, 5-bis-phosphate (PIP2)

Phosphatiylinositol-4,5-bis-phosphate (PIP2)

Phospholipase C cleaves PIP2 to

generate IP3 and

DAG

DAG

IP3

Phospholipase C (PLC) cleaves PIP2 to produce two second messengers:

Diacylglycerol (DAG) and Inositol tris-phosphate (IP3)

Plasma membrane Plasma

membrane

Cytoplasm

Nucleus

DAG

IP3

Receptor-mediated activation of phospholipase C

Phosphoinositide system

• second messengers produced are IP3, DAG and Ca2+

1. Gqα activates phospholipase C (PLC)

2. PLC cleaves PIP2 to IP3 and DAG

3. IP3 causes Ca2+ release from ER

Phosphoinositide system4. DAG activates

membrane-bound protein kinase C

5. Protein kinase C phosphorylates substrate proteins

resulting in cellular responses

Protein kinase C requires DAG, Phospholipids and Ca2+ for maximal activity.