Basic Concepts of Metabolism Unit II: Intermediary Metabolism Chapter 8 (Lectures 8-11) Basic Concepts of Metabolism AJG

Learning objectives: Introduction to metabolism A. Define metabolism in terms of anabolic and catabolic processes 1. Compare, contrast, anabolic & catabolic pathways 2. Include the concept and the importance of electron carriers 3. Explain why catabolic pathways are considered convergent 4. Explain why anabolic pathways are considered divergent B. Explain the importance of cell-cell communication in the regulation of metabolism. C. List the 4 different types of receptors and their basic mechanism of action D. Give examples of the four types of receptors. E. Describe the two second messenger systems( adenylate cyclase) and the phophoinositide system F. Indicate the receptors, G-protein and effector enzyme in each of these systems. G. Indicate what second messenger(s) are produced by activation of adenylate cyclase and phospholipase C. H. Indicate which protein kinase (PKA, PKC) is activated in both systems

Catabolism degradation convergent “oxidative” products: ATP FADH2 NADH NADPH

Anabolism synthesis “reductive” divergent uses ATP products: NAD+ FAD ADP NADP+

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 OR Signal Transduction

are converted to an intracellular signal in the adjacent cell Intercellular signals are converted to an intracellular signal in the adjacent cell Intracellular signals cAMP Enzyme-P

Receptor-mediated Signal Transduction (Extracellular signals) 4 basic types of signal transduction pathways: Steroid receptor Gated ion channel Receptor enzyme (Catalytic receptor) G-protein coupled receptor (GPCR) produce intracellular 2nd messengers

Four general types of receptors GPCR

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 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

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

4. GPCR and Intracellular Second 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: Adenylate cyclase system (cAMP) Calcium/phosphatidylinositol system (IP3, DAG, Ca2+)

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: second messenger systems Stimulus: epinephrin/norepinephrine or glucagon Receptors: β-adrenergic receptor or glucagon receptor Adenylate cyclase sytem: c-AMP(second messenger) Protein kinase A

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: G-protein coupled receptor (GPCR) produce intracellular 2nd messengers Phosphoinositide system: Inositol tris-phosphate Calcium Diacylglycerol Protein kinase C

Phosphatidylinositol 4, 5-bis-phosphate

Phosphatidylinositol 4, 5-bis-phosphate (PIP2)

Phosphatiylinositol-4,5-bis-phosphate (PIP2) DAG Phospholipase C cleaves PIP2 to generate IP3 and DAG IP3

Cytoplasm Plasma membrane Plasma membrane Nucleus DAG Phospholipase C (PLC) cleaves PIP2 to produce two second messengers: Diacylglycerol (DAG) and Inositol tris-phosphate (IP3) IP3 Cytoplasm Nucleus

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 system 4. 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.