BCH210H1 Lecture Notes - Lecture 32: G Protein–Coupled Receptor, Adenylyl Cyclase, Adrenergic Receptor
25 May 2018
School
Course
Professor
Lecture 32: Fat Catabolism
Accessing Fat Stores
• Initial response to epinephrine/glucagon is muscle/liver glycogen breakdown
• Epinephrine/glucagon can also initiate fat breakdown via GPCR signalling
• Adipose tissue store excess carbons as triacylglycerides (TAGs)
• Fatty acid chains can be used for ATP synthesis, however this requires catabolism, mobilization and oxidation
Triaglycerol (triglycerides)
• Three fatty acid chains bound to glycerol backbone via ester linkages
• Stored in saturated chain length to have close packing
• Breakdown structure to generate ATP from fatty acid chains
Hormone Sensitive Lipase (HSL)
• Epinephrine or glucagon binding to GPCR
• a-subsunit bound to GTP → adenylyl cyclase → cAMP → PKA →
phosphorylase triaglycerol lipase (active) → hydrolyze ester linkages
to form free fatty acids and liberate glycerol molecule
- glycerol for energy or GNG
• Export to generate energy (can be transported through blood), need
carrier protein albumin
Prolong fat mobilization via cAMP
• cAMP → caffeine inhibition of phosphodiesterase → AMP
- Caffeine inhibits the enzyme phosphodiesterase → concentration of cAMP remains high in adipose tissue →
activate PKA → phosphorylate hormone sensitive lipase → breakdown triglyceride → glycerol → ATP
• Caffeine in energy drinks – exercise inhibits this process so that signalling pathway is still active (breakdown of
fat and generate energy)
Fat mobilization via B adrenergic signalling
• Epinephrine/glucagon binds to G protein coupled receptors (GPCRs) on adipose cells – B adrenergic receptor
• “igallig respose: Gα-GTP → adenylate cyclase → cAMP production → PKA activation
• Caffeine prolongs fat mobilization by inhibiting cAMP breakdown
• PKA activates hormone sensitive lipase (HSL)
• TAGs are hydrolyzed to 3 fatty acids + glycerol, which can travel in
bloodstream to other cells to generate ATP
Fat metabolism overview
• Fatty acids → fatty acid oxidation → a) CREB b) ETC
• 2 Glycerol → gluconeogenesis → glucose
find more resources at oneclass.com
find more resources at oneclass.com
Fatty acid activation in the cytoplasm
• After fatty acid arrives at muscle cells, it needs to be trapped
in the cells through binding to acyl CoA
• Acyl CoA synthetase ligates CoA onto fatty acid tail
(nucleophilic attack) and use ATP → AMP + PPi for energy
• ATP → AMP + PPi -32kJ/mol
• FA chain + CoA → Acyl CoA +32kJ/mol
Net = 0kJ/mol (reversible)
• PPi + H2O → 2Pi ΔGº′= -19.3kJ/mol (drives reaction forward)
• Large free energy change drives fatty acid activation
- Doubling the free energy that drives reaction forward
Review – fatty acid activation
• Fatty acids that are delivered to cells are activated and trapped in the cell by the covalent attachment to CoA
• Acyl CoA synthetase uses ATP and Coenzyme A to form the fatty acyl CoA molecule
- Pyrophosphate (PPi) and AMP are released
• Acyl CoA synthetase reaction is reversible; pyrophosphatase helps drive the reaction forward by hydrolyzing the
PPi side product to 2 Pi
• New thio-ester linkage has been made
Why are 2 ATPs actually required when Acyl CoA synthetase only needs 1?
• You need 2 ATPs for AMP +PPi (although enzyme only uses one) due to regenerating ATP from AMP
• Major way of making ATP is through ATP synthase (ADP + Pi → ATP)
- Convert AMP back to ADP using second ATP molecule
- Adenylyl kinase transferases phosphate from second ATP transferred to AMP → 2 ADP to create more ATP
Mitochondria structure
• Catabolism of fatty acid chain takes place in the mitochondrial matrix
• Porins allow molecules to diffuse into inner membrane space
- Acyl CoA cannot cross however, due to a large, charged molecule
Coenzyme A
• Lots of negative charges, large molecule and thiol group
• We need import them into matrix for B-oxidation
Acyl CoA and B-oxidation
• Al CoA is ade i the toplas, ut β-oxidation occurs inside the matrix
• Acyl CoA can pass through outer membrane into the intermembrane space via
porins, but it cannot cross the inner membrane since there is no transport
mechanism
• CoA is also too large and water soluble making it unable to cross membranes
• The point of making fatty acyl CoA outside the matrix if it is only used in the matrix is due to regulation (fatty
acid chains have different roles – make phospholipid in cytosol or make ATP in matrix
find more resources at oneclass.com
find more resources at oneclass.com
49
BCH210H1 Full Course Notes
Verified Note
49 documents
Document Summary
Triaglycerol (triglycerides: three fatty acid chains bound to glycerol backbone via ester linkages, stored in saturated chain length to have close packing, breakdown structure to generate atp from fatty acid chains. Prolong fat mobilization via camp camp caffeine inhibition of phosphodiesterase amp. Fat metabolism overview: fatty acids fatty acid oxidation a) creb b) etc, 2 glycerol gluconeogenesis glucose. Amp + ppi -32kj/mol: fa chain + coa acyl coa +32kj/mol. Net = 0kj/mol (reversible: ppi + h2o 2pi g = -19. 3kj/mol (drives reaction forward) Large free energy change drives fatty acid activation. Doubling the free energy that drives reaction forward. Pyrophosphate (ppi) and amp are released: acyl coa synthetase reaction is reversible; pyrophosphatase helps drive the reaction forward by hydrolyzing the. Ppi side product to 2 pi: new thio-ester linkage has been made. Convert amp back to adp using second atp molecule. Adenylyl kinase transferases phosphate from second atp transferred to amp 2 adp to create more atp.
