Presentation is loading. Please wait.

Presentation is loading. Please wait.

Regulation of Metabolism

Similar presentations


Presentation on theme: "Regulation of Metabolism"— Presentation transcript:

1 Regulation of Metabolism

2 Regulation of Metabolism
How does the body know when to increase metabolism? Slow metabolism? What might be some indicators of energy status within the cell? Requires communication Works through allosteric regulation of enzyme activity

3 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

4 Types of Regulatory Mechanisms
Non-covalent interactions Covalent modifications Changes in abundance of the enzyme

5 Non-covalent Interactions Substrate 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

6 Non-covalent Interactions Allosteric Regulation
Binding of allosteric effectors at allosteric sites affect catalytic efficiency of the enzyme

7 Non-covalent Interactions Allosteric Regulation
Allosteric Activators Decrease Km (increases the enzyme binding affinity) Increases Vmax (increases the enzyme catalytic efficiency)

8 Non-covalent Interactions Allosteric Regulation
Allosteric Inhibitors Increases Km (decreases enzyme binding affinity) Decreases Vmax (decreases enzyme catalytic efficiency)

9 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

10 Non-covalent Interactions Protein-Protein Interactions
Calmodulin (CALcium MODULted proteIN) Binding of Ca++ to calmodulin changes its shape and allows binding and activation of certain enzymes

11 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

12 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

13 Calmodulin plays a role in:
Muscle contraction Inflammation Apoptosis Memory Immune response…. Metabolism Activates phosphorylase kinase Stimulates glycogen degradation during exercise

14 Types of Regulatory Mechanisms
Non-covalent interactions Covalent modifications Changes in abundance of the enzyme

15 Covalent Regulation of Enzyme Activity Phosphorylation and Dephosphorylation
Addition or deletion of phosphate groups to particular serine, threonine, or tyrosine residues alter the enzymes activity

16 Covalent Regulation of Enzyme Activity Limited Proteolysis
Specific proteolysis can activate certain enzymes and proteins (zymogens) Digestive enzymes Blood clotting proteins Peptide hormones (insulin)

17 Covalent Regulation of Enzyme Activity Enzyme Cascades
Enzymes activating enzymes allows for amplification of a small regulatory signal

18 Types of Regulatory Mechanisms
Non-covalent interactions Covalent modifications Changes in abundance of the enzyme

19 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

20 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

21 Hormones, Receptors, and Communication Between Cells Intracellular Receptors

22 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

23 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

24 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

25

26 G-protein-linked receptors
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))

27 Intracellular Messengers: Signal Transduction Pathways
Cyclic AMP (cAMP) Diacylglycerol (DAG) & Inositol Triphosphate (IP3) Cyclic GMP (cGMP)

28 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

29 G Proteins G proteins are trimers Three protein units Alpha Beta gamma

30 G Proteins 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

31 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)

32 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

33 What does cAMP do? Activation of Protein Kinase A by cAMP
Activates or inhibits several enzymes of CHO and Lipid metabolism Inactive form: regulatory+catalytic subunits associated Active form: binding of cAMP disassociates subunits

34 DAG & IP3 Phosphotidylinositol Signal Transduction Pathway
Protein kinase C activated by DAG and calcium Synthesis of DAG and IP3

35 Synthesis of DAG and IP3

36 cGMP The 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

37 cGMP The 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

38 cGMP The cGMP Signal Transduction Pathway


Download ppt "Regulation of Metabolism"

Similar presentations


Ads by Google