BCH210H1 Lecture Notes - Lecture 26: Protein Kinase A, Glycogen Phosphorylase, Phosphorylase Kinase
25 May 2018
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Lecture 26: Hormone Signalling
Hormonal Metabolic Regulation
• Signalling pathways determine whether catabolic or anabolic pathways are active
• Epinephrine/glucagon (catabolic) and insulin (anabolic) are competing peptide hormones (catabolism vs
anabolism)
• Glycogen can be used to store/supply glucose for later energy requirement
• Mobilization and breakdown of fat stores can also supply large amounts of ATP
Catabolic Hormone Signalling
• Exercise → epinephrine (adrenaline) release
- Muscle response (bind to muscle cell)– glycogen
breakdown for energy production
- ATP production in muscle increases
- Fat (epi bind to fat) catabolism also stimulated, ATP
increases
- Amino acid metabolism – epinephrine from tyrosine
- Epinephrine binds to exterior of beta adrenergic receptor (7 span) - GPCR
• When blood glucose decrease → glucagon release (from pancreas)
- Liver response – breaks down its glycogen reserves to support blood glucose levels
- Bind to glucagon receptor with 7 span - GPCR
GPCR Signaling Pathway
• Lipase phosphorylates and activated leading to breakdown of fats
– in muscles and liver, glycogen breakdown
• Take more time in activating but amplification
Glycogen Phosphorylase
• Protein component (glycogenyn) at centre
• Exterior surface of glycogen – branches and non reducing ends
(cut off glucose molecules)
• Branches have 8-12 residues of glucose joined by a-1-4 bond
• Glycogen phosphorylase takes phosphate in phosphorolysis
reaction
- Phosphate will attack anomeric carbon 1 → chain is one
glucose shorter
- Product = a-D-glucose-1-phosphate
Glycogenolysis (lysis of glycogen)
• Glycogen breakdown is a phosphorolysis reaction, releasing glucose 1-phosphate (non-reducing sugar) from
non-reducing ends
• Glycogen phosphorylase is activated by phosphorylation Ser14 but also allosterically regulated by ATP/AMP
(inactivate/activate) and glucose 6-phosphate (inactivate)
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• Caveat – glucose 1-phosphate cannot be used directly in glycolysis it must be converted to glucose 6-phosphate
What does the liver do with Glc-1-P?
• Glucose-1-phosphate phosphoglucomutase→ glucose-6-phosphate
- Moving phosphate from carbon 1 to 6
• Glucose-6-phosphate + H2O → Glucose + Pi (specific for phosphate for C6)
- Via a liver enzyme used in gluconeogenesis (GNG) – glucose-6-
phosphatase which will remove phosphate of C6
• Glucose leaves the liver and enters the bloodstream
• Liver glycogen provides glucose for the brain – very important mechanism
Review – Catabolic Hormones
• Hormone binding (epi/glucagon) to GPCRs, initiate a signalling cascade to active glycogen breakdown
• G1P is released from non-reducing ends
• G1P is either used in glycolysis as G6P (muscle/liver), or released as glucose into the bloodstream by the liver
following glucagon signalling
• GPCR signalling at adipose tissue also activates enzymes that breakdown TAGs; fat synthesis is also inhibited
Protein Kinase A (PKA)
• PKA promotes glycogen breakdown but also turns off glycogen synthesis through phosphorylation
• PKA slows down liver glycolysis by phosphorylating enzymes in glycolysis
• PKA also activates lipases
• The mechanism of action is protein phosphorylation of enzyme targets:
• Phosphorylation stimulates (phosphorylation = active):
- Phosphorylase kinase
- Glycogen phosphrylase
- Hormone sensitive lipse
• Phosphorylation inhibits (phosphorylation = inactive):
- Glycolytic enzymes
- Glycogen synthase
- Fat synthesis
Insulin Signalling (anabolic)
• Following a meal, glucose can stimulate the pancreas to secrete insulin
• Insulin signalling assists with glucose uptake into cells
• Recruitment of glucose transporters allows for glucose uptake
• Glucose can be first used in glycolysis to generate energy
• Glycogen and fat synthesis occur in specific cells
Insulin reverses the effects of epinephrine and glucagon
• Glucose stimulate beta cell (pancreas) → secrete insulin → use
glucose from blood via glucose transporters → glycolysis →
energy to build
4 ways to turn off breakdown of fat and glycogen
1. Consume glucose → insulin release
2. ATP allosterically inhibit
glycphosphorylase
3. Dephosphorylation of
glycogenphosphorylase
4. GTP → GDP/ cAMP → AMP
5. 5. Hormone degradation/unbinding
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find more resources at oneclass.com
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Document Summary
Catabolic hormone signalling: exercise epinephrine (adrenaline) release. Muscle response (bind to muscle cell) glycogen breakdown for energy production. Fat (epi bind to fat) catabolism also stimulated, atp increases. Amino acid metabolism epinephrine from tyrosine. Epinephrine binds to exterior of beta adrenergic receptor (7 span) - gpcr: when blood glucose decrease glucagon release (from pancreas) Liver response breaks down its glycogen reserves to support blood glucose levels. Bind to glucagon receptor with 7 span - gpcr. Lipase phosphorylates and activated leading to breakdown of fats. In muscles and liver, glycogen breakdown: take more time in activating but amplification. Glycogen phosphorylase: protein component (glycogenyn) at centre, exterior surface of glycogen branches and non reducing ends (cut off glucose molecules, branches have 8-12 residues of glucose joined by a-1-4 bond, glycogen phosphorylase takes phosphate in phosphorolysis reaction. Phosphate will attack anomeric carbon 1 chain is one glucose shorter. What does the liver do with glc-1-p: glucose-1-phosphate phosphoglucomutase glucose-6-phosphate.
