Lipid Metabolism Flashcards
Triglycerides
- esters of glycerol
- fats stores as energy source in form of triacylglycerols
- 3 fatty acids in ester linkage to glycerol
Types of FA (examples)
- palmitate (C16:0)
- stearate (C18:0)
- oleate (C18:1)
Fats as an energy source
- better energy source than carbs
- much more reduced
- very non polar and stored in anhydrous form
- stored at very high density
- we store enough to last us weeks
Lipid Breakdown for Energy
- mobilization from TG in adipose tissue
- transport to tissues by serum albumin
- activation by reaction with CoA
- transport into matrix - conjugatoin to carnitine
- B-oxidation to produce acetyl-CoA
- final oxidatoin in TCA cycle
Fat Release
- hormonal control
- glucagon/adrenaline bind to G protein coupled receptors
- adenylate cyclase activated
- cAMP activated
- PKA activated
- triacylglycerol lipase phosphorylated and activated
- hydrolysis of first FA to diacylglycerol
Activation of FA
- activated by reaction with CoA
- reactive thiol group reacts with carboxylic acid to form thioester
- acyl group carrier
Mechanism of FA activation
2 step reaction catalyses by acyl CoA synthetase
- COO- displace out 2 P of ATP
- nucleophilic attack of SH
- acyl adenylate transformed into acyl-CoA
Carnitine
acyl-CoA reacts with carnitine in a transesterification reaction to give acyl-carnitine
- occurs in IMM
- transported into the matrix where it is broken down to give acyl-CoA
B-oxidation of FA
- initial oxidation involves 4 reactions to release 2C fragments as acetyl CoA
- forms acyl CoA and acetyl CoA so shortens chain by 2C
- process repeats
Palmitate B-oxidation
- C16 compound
1. oxidation - produces FADH2
- forms double C bond
2. hydration - forms hydroxyl group
3. oxidation - forms NADH
- forms ketone group
4. thiolytic cleavage - reaction with CoA-SH
- S-CoA displaces acetyl CoA from compound
end product: C14 acyl-CoA - 6 further cyclesof reactions 1-4
Net Reaction of Palmitate B-oxidation
palmitoyl CoA + 7CoA + 7FAD + 7NAD + 7H20 = 8 acetyl CoA + 7FADH2 + 7NADH + 7H+
- acetyl CoA are oxidised in the TCA cycle to give 24NADH, 8FADH2, 8 ATP
- 108 ATP made in total
- 2 ATP used to activate palmitate
Control of FA degradation
- hormonal control of TG lipase
- free FA only released if glucose is low or energy needed
- inhibited by insulin - transport into mitochondria
- carnitine acyl transferase inhibited by malonyl CoA
- 1st intermediate in FA synthesis
- indicates high concentration of acetyl CoA so don’t need to produce more
FA synthesis
- starts with acetyl CoA
- occurs in cytoplasm
Commited Step of FA synthesis
- catalysed by acetyl CoA carboxylase
acetyl CoA + bicarbonate + ATP = malonyl CoA + ADP + Pi + H+
Acetyl CoA Carboxylase
- biotin is a carrier of carbon dioxide
- bicarbonate reacts with acetyl CoA to give malonyl CoA
- carbon dioxide activated via attachment to biotin
- activate CO2 transferred to acetyl CoA
Acyl Carrier Protein
- intermediates in FA synthesis attached to acyl carrier protein
- also contains a thiol group
- ACP part of FA synthase complex
Elongation of FA
- starts with acetyl-ACP and malonyl-ACP
- all carbon in aFA chain comes from acetyl-CoA
- repeating cycle of 4 reactions
1. acetyl ACP + malonyl-ACP combine in condensation reaction and release CO2 (bicarbonate)
2. reduction using NADPH to form hydroxyl group
3. dehydration to from double bond
4. reduction using NADPH - gives butyryl-ACP that can react with another malonyl-ACP to elongate chain
5. hydrolysis of final product to release ACP
Malonyl-ACP
- activated donor of 2C units
- decarboxylation reaction drives condensation with acetyl-ACP
Net Reaction of Palmitate Synthesis
acetyl CoA + 7 malonyl CoA + 14 NADPH + 14H+ = palmitate + 7CO2 + 14 NADP+ + 8CoA + 6H2O
Net: 8 acetyl CoA + 7 ATP + 14 NADPH + 14 H = palmitate + 14 NADP + 7 ADP + Pi + 8 CoA + 6H2O
Malonyl CoA Synthesis
7 acetyl CoA + 7CO2 + 7ATP = 7 malonyl CoA + 7 ADP + 7Pi
Acetyl CoA Transport
- IMM impermeable
- citrate acts as carrier of acetyl groups out of mitochondria
- exchanges with malate
1. acetyl CoA combines with citrate that can go into the cytoplasm
2. citrate broken back into acetyl CoA used for FA
3. citrate transformed into OA, malate, pyruvate - malate DH and malic enzyme
4. pyruvate transported back into the matrix
5. pyruvate transformed into OA
6. OA combines with acetyl CoA to make citrate
Malic Enzyme
- malate to pyruvate
- forms NADPH for FA synthesis
- oxidative decarboxylation
Control of FA synthesis
Phosphorylation of acetyl CoA carboxylase
- phosphorylation inactivated carboxylase
- dephosphorylation activates carboxylase
- protein kinase inactivates (glucagon/adrenaline activates the kinase to stop synthesis)
- protein phosphatase activates (promotes FA synthesis)
Allosteric control of acetyl CoA carboxylase
- citrate binds to phosphorylated carboxylase to partially activate it
Characteristics of Synthesis
- cytoplasm
- intermediates covalently linked to sulfhydryl groups of ACP
- chain elongated by sequential addition of 2C units from acetyl CoA
- activated donor is malonyl ACP & driven by CO2 release
- reductant is NADH
Characteristics of Degradation
- mitochondrial matrix
- intermediates linked to sulfhydryl of CoA enzyme
- oxidants are NAD/FAD
Cancer and FA synthesis
Cancer cells display altered metabolism to meet their needs
There is increased FA synthesis for signal molecules
FA synthase inhibitors can treat cancer cells
Regulation of Acetyl CoA carboxylase
- phosphorylation
- switched off by phosphorylation
- AMP protein kinase inactivates enzyme by phosphorylating serine residues - allostery
- citrate activates as energy, materials are abundant
- citrate can partially activate phosphorylated carboxylases - hormonal
- insulin activates: inactivates AMPK by kinase B and promotes phosphate dephosphorylation
- glucagon/adrenaline inactivates: augments AMP activated kinase
