regulation of metabolism fcsn 543 advanced nutritional biochemistry dr. david l. gee
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Regulation of Metabolism
FCSN 543
Advanced Nutritional Biochemistry
Dr. David L. Gee
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Characteristics of Regulatory Enzymes
• Catalyze a rate-limiting step
• Catalyze a committed step– Early step unique to a pathway– Irreversible step
• Requires energy
• Often results in a phosphorylated compound
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Types of Regulatory Mechanisms
• Non-covalent interactions
• Covalent modifications
• Changes in abundance of the enzyme
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Non-covalent InteractionsSubstrate availability
• Non-regulatory enzymes generally exhibit hyperbolic kinetics (Michaelis-Menton)
• At low substrate concentration, reaction rate proportional to substrate concentration
• Regulatory enzymes generally exhibit sigmoidal kinetics (positive cooperativity)
• Changes of substrate concentrations at normal physiological levels greatly alter reaction rate
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Non-covalent InteractionsAllosteric Regulation
• Binding of allosteric effectors at allosteric sites affect catalytic efficiency of the enzyme
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Non-covalent InteractionsAllosteric Regulation
• Allosteric Activators– Decrease Km (increases the enzyme binding
affinity)– Increases Vmax (increases the enzyme catalytic
efficiency)
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Non-covalent InteractionsAllosteric Regulation
• Allosteric Inhibitors– Increases Km (decreases enzyme binding
affinity)– Decreases Vmax (decreases enzyme catalytic
efficiency)
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Molecues that act as allosteric effectors
• End products of pathways– Feedback inhibition
• Substrates of pathways– Feed-forward activators
• Indicators of Energy Status– ATP/ADP/AMP– NAD/NADH– Citrate & acetyl CoA
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Non-covalent InteractionsProtein-Protein Interactions
• Calmodulin (CALcium MODULted proteIN)
– Binding of Ca++ to calmodulin changes its shape and allows binding and activation of certain enzymes
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Binding of calcium to Calmodulin changes the shape of the protein
Unbound Calmodulin on left
Calcium bound Calmodulin on right. Stars indicate exposed non-polar ‘grooves’ that non-covalently binds proteins
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Calmodulin
• Extracellular [Ca] = 5 mM
• Intracellular [Ca] = 10-4 mM– Most of Ca bound inside cells– Bound Ca can be released by hormonal action,
nerve innervation, light, ….– Released Ca binds to Calmodulin which
activates a large number of proteins
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Calmodulin plays a role in:
• Muscle contraction• Inflammation• Apoptosis• Memory• Immune response….• Metabolism
– Activates phosphorylase kinase• Stimulates glycogen degradation during exercise
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Types of Regulatory Mechanisms
• Non-covalent interactions
• Covalent modifications
• Changes in abundance of the enzyme
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Covalent Regulation of Enzyme ActivityPhosphorylation and Dephosphorylation
• Addition or deletion of phosphate groups to particular serine, threonine, or tyrosine residues alter the enzymes activity
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Covalent Regulation of Enzyme ActivityLimited Proteolysis
• Specific proteolysis can activate certain enzymes and proteins (zymogens)– Digestive enzymes– Blood clotting proteins– Peptide hormones (insulin)
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Covalent Regulation of Enzyme ActivityEnzyme Cascades
• Enzymes activating enzymes allows for amplification of a small regulatory signal
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Types of Regulatory Mechanisms
• Non-covalent interactions
• Covalent modifications
• Changes in abundance of the enzyme
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Changes in Enzyme Abundance
• Inducible vs Constitutive Enzymes
• Induction is caused by increases in rate of gene transcription.– Hormones activate transcriptional factors
• Increase synthesis of specific mRNA
• Increase synthesis of specific enzymes
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Hormones, Receptors, and Communication Between Cells
• Intracellular receptors
• lipid soluble hormones• Steroid hormones, vitamin D, retinoids, thyroxine
• Bind to intracellular protein receptors – This binds to regulatory elements by a gene– Alters the rate of gene transcription
• Induces or represses gene transcription
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Hormones, Receptors, and Communication Between Cells
Intracellular Receptors
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Hormones, Receptors, and Communication Between Cells
• Cell-surface receptors– Water soluble hormones
• Peptide hormones (insulin), catecholamines, neurotransmitters
• Three class of cell-surface receptors– Ligand-Gated Receptors– Catalytic Receptors– G Protein-linked Receptors
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Hormones, Receptors, and Communication Between Cells
• Ligand-gated receptors– Binding of a ligand (often a neurotransmitter) affects flow of
ions in/out of cell
• Gamma-amino butyric acid (GABA) binds and opens chloride channels in the brain– Valium (anti-anxiety drug) reduces the amount of GABA
required to open the chloride channels
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Hormones, Receptors, and Communication Between Cells
Cell-Surface Receptors
• Catalytic receptors– Binding of hormone activates tyrosine kinase on receptor
which phosphorylates certain cellular proteins
– Insulin receptor is a catalytic receptor with TYR Kinase activity
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Hormones, Receptors, and Communication Between Cells
Cell-Surface Receptors
• G-protein-linked receptors– Binding of hormone
activates an enzyme via a G-protein communication link.
– The enzymes produces intracellular messengers
• cAMP• diacylglycerol (DAG))
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Intracellular Messengers:Signal Transduction Pathways
• Cyclic AMP (cAMP)
• Diacylglycerol (DAG) & Inositol Triphosphate (IP3)
• Cyclic GMP (cGMP)
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G-Protein-Linked Receptors:The cAMP Signal Transduction Pathway
• Two types of G-Proteins• Stimulating G protein (Gs)
– Activate adenylate cyclase
• Inhibitory G proteins (Gi)
– Inhibit adenylate cyclase
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G Proteins
• G proteins are trimers – Three protein units
• Alpha
• Beta
• gamma
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• Alpha proteins are different in Gs and Gi
– Both have GTPase activity
– Alpha proteins modify adenylate cyclase activity• AC stimulated by Alpha(s) when activated by a hormone
• AC Inhibited by Alpha(I) when activated by other hormones
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Family of G Proteins
• Binding of hormones to receptors causes: – GTP to displace GDP – Dissociation of alpha
protein from beta and gamma subunits
– activation of the alpha protein
– Inhibition or activation of adenylate cyclase
– GTPase gradually degrades GTP and inactivates the alpha protein effect (clock)
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The cAMP Signal Transduction Pathway
• cAMP – intracellular messenger– Elevated cAMP can either activate or inhibit regulatory
enzymes• cAMP activates glycogen degradation• cAMP inhibits glycogen synthesis
• [cAMP] affected by rates of synthesis and degradation– Synthesis by adenylate cyclase– Degradation by phosphodiesterase
• Stimulated by insulin• Inhibited by caffeine
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What does cAMP do?Activation of Protein Kinase A by cAMP
• Protein kinase A– Activates or inhibits several enzymes of CHO and
Lipid metabolism
– Inactive form: regulatory+catalytic subunits associated
– Active form: binding of cAMP disassociates subunits
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DAG & IP3
Phosphotidylinositol Signal Transduction Pathway
• Protein kinase C activated by DAG and calcium
• Synthesis of DAG and IP3
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cGMPThe cGMP Signal Transduction Pathway
• cGMP effects: • lowering of blood pressure & decreasing
CHD risk– Relaxation of cardiac muscle– Vasodilation of vascular smooth muscle– Increased excretion of sodium and water by
kidney– Decreased aggregation by platelet cells
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cGMPThe cGMP Signal Transduction Pathway
• Two forms of guanylate cyclase• Membrane-bound
• Activated by ANF (atrial natriuretic factor)– ANF released when BP elevated
• Cytosolic• Activated by nitric oxide• NO produced from arginine by NO synthase
– Nitroglycerine slowly produces NO, relaxes cardiac and vascular smooth muscle, reduces angina
• cAMP activates Protein Kinase G– Phosphorylates smooth muscle proteins
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cGMPThe cGMP Signal Transduction Pathway