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Questions and Answers
What is the main role of triacylglycerol in the body?
What is the main role of triacylglycerol in the body?
Which of the following statements accurately describes saturated fatty acids?
Which of the following statements accurately describes saturated fatty acids?
What process requires the hydrolysis of fatty acyl chains?
What process requires the hydrolysis of fatty acyl chains?
Which enzyme plays a crucial role in fat synthesis?
Which enzyme plays a crucial role in fat synthesis?
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Which hormone is primarily responsible for the breakdown of glycogen to glucose?
Which hormone is primarily responsible for the breakdown of glycogen to glucose?
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What is the primary role of acyl CoA synthetase in fatty acid metabolism?
What is the primary role of acyl CoA synthetase in fatty acid metabolism?
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How many fatty acids and glycerol are produced during the hydrolysis of TAGs?
How many fatty acids and glycerol are produced during the hydrolysis of TAGs?
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What drives the reaction catalyzed by acyl CoA synthetase in the forward direction?
What drives the reaction catalyzed by acyl CoA synthetase in the forward direction?
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Why is the conversion of ATP to AMP considered energetically inefficient?
Why is the conversion of ATP to AMP considered energetically inefficient?
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Which molecule is primarily responsible for transporting free fatty acids in the blood?
Which molecule is primarily responsible for transporting free fatty acids in the blood?
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Which step of β-oxidation is responsible for the production of FADH2?
Which step of β-oxidation is responsible for the production of FADH2?
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What is produced after the thiolase step in β-oxidation?
What is produced after the thiolase step in β-oxidation?
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How many times does β-oxidation occur for the complete oxidation of 16:0 CoA?
How many times does β-oxidation occur for the complete oxidation of 16:0 CoA?
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What is the total number of ATPs generated from the full oxidation of 16:0 CoA combining all processes?
What is the total number of ATPs generated from the full oxidation of 16:0 CoA combining all processes?
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Which of the following molecules is required for the hydratase step in β-oxidation?
Which of the following molecules is required for the hydratase step in β-oxidation?
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What is the end product of a single round of beta oxidation?
What is the end product of a single round of beta oxidation?
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Which molecule is consumed during each round of beta oxidation?
Which molecule is consumed during each round of beta oxidation?
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What signal molecules play a role in the regulation of fatty acid metabolism?
What signal molecules play a role in the regulation of fatty acid metabolism?
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How many carbon atoms does Acetyl CoA contain?
How many carbon atoms does Acetyl CoA contain?
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Which type of bonds must be broken during beta oxidation of fatty acids?
Which type of bonds must be broken during beta oxidation of fatty acids?
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What is produced as a result of beta oxidation, apart from Acetyl CoA?
What is produced as a result of beta oxidation, apart from Acetyl CoA?
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In beta oxidation, how many rounds are generally required to fully oxidize a fatty acid with 16 carbon atoms?
In beta oxidation, how many rounds are generally required to fully oxidize a fatty acid with 16 carbon atoms?
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What molecule is necessary for the activation of fatty acids before beta oxidation?
What molecule is necessary for the activation of fatty acids before beta oxidation?
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During beta oxidation, which process primarily occurs in the mitochondria?
During beta oxidation, which process primarily occurs in the mitochondria?
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Which substance, produced during fatty acid metabolism, can contribute to energy production?
Which substance, produced during fatty acid metabolism, can contribute to energy production?
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What is primarily produced from the breakdown of glucose during glycolysis?
What is primarily produced from the breakdown of glucose during glycolysis?
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Which cycle is associated with the generation of ATP through oxidative phosphorylation?
Which cycle is associated with the generation of ATP through oxidative phosphorylation?
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Which of the following is a potential side effect of low-carb diets?
Which of the following is a potential side effect of low-carb diets?
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In which metabolic pathway is NH3 produced?
In which metabolic pathway is NH3 produced?
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Which process involves the conversion of pyruvate to glucose?
Which process involves the conversion of pyruvate to glucose?
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What is the main function of ketone bodies in low-carb metabolism?
What is the main function of ketone bodies in low-carb metabolism?
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Which enzyme is essential for the initiation of fatty acid synthesis?
Which enzyme is essential for the initiation of fatty acid synthesis?
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What is the primary role of the Acyl Carrier Protein (ACP) in fatty acid synthesis?
What is the primary role of the Acyl Carrier Protein (ACP) in fatty acid synthesis?
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What occurs during the first step of fatty acid synthesis?
What occurs during the first step of fatty acid synthesis?
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How many cycles of Fatty Acid Synthase are needed to generate a 16-carbon fatty acid?
How many cycles of Fatty Acid Synthase are needed to generate a 16-carbon fatty acid?
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Which molecule is required for the redox reactions in fatty acid synthesis?
Which molecule is required for the redox reactions in fatty acid synthesis?
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What is produced in the second and fourth steps of fatty acid synthesis?
What is produced in the second and fourth steps of fatty acid synthesis?
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What is the initial substrate required for the fatty acid synthesis process?
What is the initial substrate required for the fatty acid synthesis process?
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During what type of reaction is H2O released in the fatty acid synthesis pathway?
During what type of reaction is H2O released in the fatty acid synthesis pathway?
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Study Notes
Fat Metabolism Overview
- Fat is a significant energy store, containing a large amount of stored energy.
- Different hormones (Epinephrine and Insulin) regulate fat metabolism in Muscle and Liver cells.
- Muscle cells store glucose as glycogen.
- Liver cells share glucose from glycogen.
- Fats are broken down through a process known as beta-oxidation.
- Beta-oxidation produces Acetyl CoA, and the body derives ATP through the Citric Acid Cycle (CAC).
- During beta-oxidation, NADH and FADH2 are produced and carry electrons to the electron transport chain to generate ATP.
- Acyl CoA is produced in the cytoplasm, is important for the transportation of fats into the mitochondria for beta-oxidation.
- The process of transporting Acyl CoA into the Mitochondria requires a carnitine shuttle, which includes 2 enzymes (CAT 1& 2).
- The carnitine shuttle moves Acyl chain to carnitine in the intermembrane space to cross into the inner membrane, to then to be broken down using CAT II.
- The product of Beta-oxidation (Acetyl CoA) enters the CAC to produce energy.
- The overall process of beta-oxidation starts with 16:0 CoA and ends with 8 molecules of Acetyl CoA, as well as NADH, FADH2 and H+.
Learning Objectives
- Understand the processes and locations for fat creation/breakdown.
- Understand the ATP production through beta-oxidation via oxidative phosphorylation.
- Know fat synthesis enzymes ACC and FAS.
- Examine lipid synthesis and lipolysis (beta-oxidation) differences.
- Detail the reciprocal regulation of fat metabolism.
Triacylglycerol (Triglyceride, TG)
- Extra carbons are stored in molecules of triacylglycerol, mostly in fat cells and other tissues.
- Acyl chains are attached to a glycerol backbone via ester bonds..
- Fatty acyl chains are saturated to allow for close packing of the chains.
- When fatty chains are used, they must be hydrolyzed.
Fat Mobilization via GPCR signaling
- Epinephrine and glucagon bind to G-protein receptors.
- The signaling involves the activation of Adenylyl cyclase which produces cAMP.
- Protein kinase A (PKA) is activated.
- Triacylglycerol lipase (also known as hormone-sensitive lipase, HSL) is activated.
- TAGs are hydrolyzed to release fatty acids and glycerol.
Mitochondrial Structure
- Mitochondria has an outer membrane and an inner membrane that's folded to form cristae.
- The inner membrane contains porins (outer membrane proteins) permitting the passage of Acyl CoA molecules but, it doesn't cross the inner membrane.
- The intermembrane space lies between the outer and inner membrane.
- The matrix is inside the inner membrane.
Acyl CoA and β-oxidation
- Acyl CoA is produced in the cytoplasm, but β-oxidation happens inside the mitochondria matrix.
- Acyl CoA can move through the outer membrane via porins, but can't penetrate the inner membrane because it is too large and water-soluble.
- The function of making Acyl CoA outside the matrix lies in its necessity for the transportation through the inner membrane, to proceed to the matrix.
Carnitine Shuttle
- The carnitine shuttle assists in the transportation of acyl groups into the mitochondrial matrix to begin beta-oxidation.
- Carnitine Acyltransferase I (CAT I) moves the acyl group onto carnitine. The acyl chain moves from CoA to carnitine.
- Acyl carnitine is transported across the inner membrane in exchange for carnitine.
- Carnitine Acyltransferase II (CAT II) moves the acyl group from carnitine back onto CoA.
- Acyl CoA can be processed to generate energy through Beta-oxidation.
What's the difference between Acyl CoA and Acetyl CoA?
- Acyl CoA has a longer chain compared to Acetyl CoA.
- Acetyl CoA has two carbons, while Acyl CoA has more than two carbons.
Fatty Acid Activation in the Cytoplasm
- Acyl chains are trapped in the cell by the covalent addition of coenzyme A.
- Acyl CoA Synthetase is the enzyme catalyzing the reversible reaction using ATP (→ AMP) to form the fatty acyl CoA molecule.
- Pyrophosphate (PPi) hydrolysis to 2 Pi is favorable and drives this reaction in the forward direction.
ATP→AMP is Energetically Inefficient
- 95% of ATP production occurs through oxidative phosphorylation (using ADP as a substrate).
- AMP gets converted to ADP to form ATP, requiring additional ATP.
- Fatty acid activation requires 2 ATPs.
4 reactions to repeat throughout beta-oxidation
- Each round of beta-oxidation involves 4 reactions to shorten the fatty acid chain, producing NADH, FADH2, and Acetyl CoA.
How many rounds of beta oxidation are needed?
- Determine the number of rounds required for breakdown of 16:0 CoA by calculating the difference in Carbon and divide it by two, because every round requires two carbons.
4 steps of β-oxidation
- Acyl CoA dehydrogenase produces FADH2 and creates a double bond in the fatty acid chain.
- Hydratase adds water across the double bond (β-OH).
- Dehydrogenase produces NADH and creates a keto group on the β-carbon in the chain.
- A thiolase uses CoA to release acetyl CoA, producing a fatty acyl CoA chain with 2 fewer carbons.
Overall β-oxidation of 16:0 CoA in the Mitochondria
- 16:0 CoA + 7 NAD+ + 7 FAD + 7 H2O + 7 CoA → 8 acetyl CoA + 7 NADH + 7 FADH2 + 7 H+
Calculate the number of ATPs and H2O made by the complete oxidation of 16:0 CoA.
- The calculation for ATP and H2O is based on Beta-oxidation, Citric Acid Cycle and Oxidative Phosphorylation.
P/O Ratios and H2O made
- Details the production of ATP and water through the electron transport chain.
- Complex I, III, and IV are crucial to the process.
- The Complexes are accompanied by the release of H2O.
Grand Total for the complete oxidation of 16:0 CoA in the Mitochondrial Matrix
- 16:0 CoA + 108 ADP + 108 Pi + 23O2 → 16 CO2 + 108 ATP + 123H2O +CoA.
- If starting from 16:0 (no CoA) activation of 16:0 requires 2 ATP and 1 H2O.
Summary - Fatty Acid Breakdown
- Epinephrine and/or glucagon trigger TAG breakdown.
- Fatty acids travel in the bloodstream bound to serum albumin, entering muscle cells.
- Fatty acids are activated using Acyl CoA synthetase.
- The enzymes CAT I, translocase, and CAT II control fatty acid import into the matrix, exchanging carnitine for free carnitine (inner membrane).
- Fatty acid chains are converted through β oxidation for energy producing ATP.
- β-oxidation does not produce a substantial amount of ATP directly (but using the Citric Acid Cycle and oxidative phosphorylation).
Using Fats as Fuel
- Acetyl CoA from fat degradation is processed through the Citric Acid Cycle (a crucial component for ATP production in mitochondria).
- CAC depends on the availability of Oxaloacetate.
- Oxaloacetate can be formed from amino acids or pyruvate via pyruvate carboxylase.
Hormonal Response and Fat Synthesis
- When glucose levels rise, insulin signals glucose uptake and breakdown.
- Insulin promotes glucose storage as glycogen in muscles or the liver.
- Once ATP/NADH levels are high in mitochondria, the CAC slows and fatty acid synthesis begins, using Acetyl CoA.
- Excess glucose, amino acids, and fats will be used as precursors to create more fatty acids.
Steps in Fatty Acid Synthesis
- Mitochondrial Acetyl CoA is transported to the cytoplasm for creating fatty acids.
- CoA Carboxylase converts Acetyl CoA to Malonyl CoA.
- Fatty acid Synthase uses Malonyl CoA to create fatty acid chains (16:0).
Step 1- Import & Export differ
- The transportation and movement of molecules like Acetyl CoA and citric acid between the mitochondrial matrix and cytosol are critical for cellular metabolism.
- The inner membrane of mitochondria plays a critical role in regulating transport.
- The Citrate shuttle transports Acetyl CoA (C2s) from mitochondria to the cytosol via the citrate in the form of C6.
- Then, it's converted back into Acetyl CoA again in the cytosol.
Step 1. Acetyl CoA is exported as Citrate
- CoA is unable to cross the mitochondrial membrane.
- It's transported outward through Citrate.
- Citrate is created in the CAC, moving to the cytoplasm and converted back into Acetyl CoA for fatty acid synthesis.
- Pyruvate returns to the mitochondria.
Fatty Acid Synthesis is an Anabolic Process
- Fatty acid synthesis happens in the cytoplasm.
- The committed and regulated enzyme for this synthesis is Acetyl CoA Carboxylase(ACC).
- This reaction uses ATP, while fatty acid synthase (FAS) uses NADPH for reducing power in the anabolic process.
Step 2: Acetyl CoA Carboxylase (ACC)
- Acetyl CoA carboxylase (ACC) is the enzyme responsible in synthesizing Malonyl-CoA from Acetyl-CoA, using ATP and bicarbonate. The addition of the COO- group to the malonyl-CoA promotes fatty acid synthesis by the Fatty Acid Synthase enzyme.
Malonyl → Reciprocal Regulation for Fats
- When the molecule is active, fat synthesis occurs.
- Malonyl CoA stops the cycle of fat breakdown by inhibiting carnitine acyltransferase 1 (a key regulator for fat transportation through the mitochondrial inner membrane..
- Carboxylase regulation is important for fat metabolism (synthesis and breakdown).
ACC Regulation via Phosphorylation
- The regulation of Acetyl CoA Carboxylase (ACC) involves phosphorylation (adding a phosphate group).
- Phosphorylation generally inactivates the enzyme.
- Protein Kinase A (PKA) and AMP-activated protein kinase (AMPK) plays a role in such phosphorylations when the molecule is active.
- The enzyme phosphatase removes the phosphate group and reactivates the enzyme.
- This process is crucial to the reciprocal regulation of fat synthesis and breakdown.
What is the link between exercise and the inhibition of fat synthesis?
- Epinephrine through the G-protein coupled receptor (GPCR) pathway activates protein kinase A (PKA).
- High levels of AMP (indicating a lowered energy state) activate AMP-activated protein kinase (AMPK), which further inhibits Acetyl CoA carboxylase (ACC) to stop fat synthesis.
ACC Regulation via Phosphorylation
- Protein Kinase A participates in activating an inactive carboxylase.
- AMPK is activated when the energy state is low.
- Protein Kinase A and AMPK are activated in a catabolic (energy-requiring) state.
- Insulin activates the phosphatase to inactivate PKA and AMPK, activating the carboxylase.
Regulation of Fat Metabolism
- ACC is the regulated step in fat synthesis.
- Phosphorylation of ACC can decrease activity.
- Rising levels of citrate can increase ACC activity.
- The product of fatty acid synthesis, malonyl CoA, can shut down fat breakdown by inhibiting carnitine acyltransferase 1.
Step 3: Use of malonyl CoA to form fatty acid chains by Fatty Acid Synthase (FAS)
- The enzyme ACP will connect malonyl CoA and Acetyl CoA to form fatty acids.
- The Fatty Acid Synthase (FAS) catalyzes the synthesis of fatty acyl chains from malonyl-CoA.
- ACP is a carrier protein transporting the chain units.
Fatty Acid Synthase (FAS)
- FAS is a large multi-enzyme complex.
- The complex catalyzes the synthesis of fatty acids from acetyl-CoA and malonyl-CoA molecules.
- There are different steps involved in this reaction, using different redox reactions that include NADPH.
- An initial step involves condensation of acetyl-CoA and malonyl-CoA to form a four-carbon molecule.
- Following, there are some redox reactions, dehydration, and further condensation, repeating until a required length of the fatty chain is achieved.
Fat Synthesis
- The synthesis of fatty acids requires both Acetyl-CoA carboxylase (ACC) and Fatty Acid Synthase (FAS).
- Cycles of these, 7 FAS cycles and 1 acetyl-CoA to produce a 16-carbon fatty acid, followed by cycles of malonyl-CoA molecules each cycle.
- The reaction uses up 7 ATPs and 14 NADPHs at each cycle.
- Chain elongation to produce longer-chain fatty acids (greater than 16 carbons), using malonyl-CoA and NADPH.
- Desaturases, with NADPH and oxygen, introduce cis bonds to synthesize fatty acids.
Fatty Acid Synthase vs Beta Oxidation
- FAS (Fatty Acid Synthase), a major anabolic enzyme, works in the cytoplasm.
- β Oxidation, a major catabolic enzyme, works in the mitochondria.
- Different 2-carbon units, coenzymes, and number of reactions (not enzymes) distinguish the two processes.
Low Carb Diets
- Low carbohydrate intake results in lowered glycogen levels, pushing the body to rely on fat breakdown (for energy).
- The body converts pyruvate into Acetyl-CoA, allowing for fat breakdown and energy production though the citric acid cycle.
- Weight loss depends on lowered energy from glycogen stores.
Key Messages
- Excess carbons from fats, carbohydrates, and proteins become stored as triacylglycerol.
- GPCR signaling initiates TAG breakdown. Fatty acids are transported through the blood stream bound to serum albumin.
- Fatty acids are activated and transported into mitochondria where beta-oxidation occurs.
- Fatty acid synthesis, also known as lipogenesis, begins after acetyl-CoA moves out of the mitochondria. Acetyl-CoA carboxylase (ACC) is the main regulated enzyme.
- Fatty acid synthase (FAS) plays a part in this synthesis process.
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Description
This quiz explores key concepts in lipid metabolism, including the roles of triacylglycerol, fatty acids, and enzymes involved in fat synthesis and breakdown. Test your understanding of beta-oxidation and the energy yield of fatty acid oxidation.
