Chapter 16 - Lipid Metabolism
Acetyl-coA > fatty acids. Formation of fatty acids from acetyl coA. Occurs when the cell does not need energy. Occurs in cytosol.
what is Fatty acid synthesis and where does it occur?
excess build up of acetyl coA can be concerted to ketone bodies such as acetoacetate and B-DHydroxybutyrate. These can leave the liver cells and enter tissues such as the brain, muscles and heart. The ketone bodies can be converted back to acetyl coA to enter the citric acid cycle & oxidative phosphorylation to generate ATP.
How can ketone bodies be used for energy?
Elongation enzymes increase the number of carbons in the fatty acid chain of palmitate using malonyl Co-A to form stearate. Desaturation enzymes are endoplasmic reticulum membrane bound that use O2 to oxidize the fatty acid...this adds a double bond to the fatty acid chain to make an unsaturated fatty acid. For example, stearate to oleate.
What are elongation and desaturation enzymes?
Fatty Acid Oxidation CoA dependent NAD/FAD+ dependent Multiple enzymes carnititine transferase is RLE (malonyl-coA inhibits this when cell energy levels are high) Location: mitochondria Fatty Acid Synthesis ACP dependent NADPH dependent 2 enzymes (one is multifunctional [b-ketoacyl ACP synthase, reductase, & dehydrogenase Malonyl-coA is RLE Location: cytosol
Compare and contrast Fatty Acid Synthesis with Fatty Acid Oxidation -What substrates are fatty acid oxidation and synthesis dependent on? -Location -How many enzymes are involved in each? -What are the rate limiting enzymes?
Carnitine Transport Cycle 1. Fatty acids, like palmitate combine with CoA to form palmitoyl-coA. 2. The coA group is temporarily exchanged with carnitine from carnitine acyltransferase I forming palmitoylcarnitine. 3. The fatty acid can now cross the double mitochondrial membrane and enter the matrix. 4. Once inside the matrix, carnitine is replaced with coA via carnitine acyltransferase II. 5. This molecule is now ready to enter the four step beta oxidation pathway.
How do fatty acids enter the mitochondrial matrix to be oxidized? Explain the steps and the name of this cycle.
Once citrate enters the citosol and converts to acetyl coA...acetyl coA is now ready to undergo fatty acid synthesis via fatty acid synthase. First we need to prime it... Acetyl coA binds to the KS domain to prime fatty acid synthase. Meanwhile, an acetyl coA is carboxylated by acetyl-coA carboxylase (the Rate limiting enzyme) to produce malonyl-coA. Malonyl coA then binds to a protein carrier, ACP located inside the fatty acid synthase. ACP anchors the growing fatty acid chain to the fatty acid synthase so the growing can begin. Let the 4 step process begin! 1. Condensation (B-ketoacyl ACP Synthase) 2. Reduction (B-ketoacyl ACP Reductase) - needs NADPH, releases NADP+ 3. Dehydration (B-ketoacyl ACP Dehydrogenase) 4. Reduction (Enoyl ACP Reductase) - needs NADPH, releases NADP+
How does fatty acid synthase accomplish the four reaction steps of fatty acid synthesis?
Within the liver... When energy levels in the cell are high, citrate within the citric acid cycle is transported out of the mitochondria via the citrate shuttle. The conversion of citrate to oxaloacetate forms acteyl coA. Acetyl coA can now undergo fatty acid synthesis and be turned into fatty acid. First acetyl-coA is turned in malonyl-coA via acetyl-coA carboxylase. Malonyl-coA is turned into fatty acids via fatty acid synthase. Fatty acids are attached to a glycerol backbone to form triaglycerols, packaged back into VLDLS, transported out of the liver cell and into adipose tissue.
How does fatty acid synthesis work and why does excess glucose lead to getting fat haha?
High malonyl co-A means we need to synthesize fatty acids. Therefore, acetyl-coA will be activated, which means AMPK kinase will be inhibited and protein phosphatase will be activated.
How does malonyl co-A affect AMPK kinase?
Triaglycerol Synthesis: formed from phosphatidic acid, dephosphorylation occurs, bonded by esterification Phospholipid Synthesis
How does trioglycerol differ from fatty acid synthesis?
27 - 4 rings (3 six carbon and 1 five carbon rings)
How many carbons does cholesterol have? How many rings?
Palmitate is a 16 carbon fatty acid chain. Therefore, this would require 8 rounds of fatty acid synthesis, as each round builds 2 carbons. 8 acetyl co-A + 7 ATP + 14 NADPH + 14 H+ >>> palmitate + 8 co-A + 14 NADP+ + 7 ADP + 7 Pi + 6 H2O
If palmitate were synthesized, what would be the overall reaction? (Include ATP, NADPH, etc.)
8 acetyl-coA into the citric acid cycle : ---24 NADH = 60 ATP ---8 FADH = 12 ATP ---8 GTP = 8 ATP 7 NADH = 17.5 ATP 7 FADH2 = 10.5 ATP
If the fatty acid that goes under fatty acid oxidation has 16 carbons, how many ATP are produced after fatty acid oxidation & the citric acid cycle?
Stage 3
In what stage of cholesterol synthesis is squalene made?
Review figure on other side of card. Step 1. Oxidation via Acyl-coA Dehydrogenase. Beta carbon single bond is oxidized to a double bond. Output: 1 FADH21 Step 2. Hydration via Enoyl-coA hydratase. Adds H2O to the C=C double bond Step 3. Oxidation via 3-hydroxyacyl-coA dehyrogenase. Output: 1 NADH Step 4: Thialysis via B-Ketoacyl coA thiolase. Output: 1 acetyl coA + the remaining acyl-coA chain with 2 less carbons because those 2 carbons were used to form acetyl coA.
What are the 4 steps to the beta oxidation cycle?
Stage 1: formation of mevalonate Stage 2: formation of isopentenyl diphosphate Stage 3: Formation of squalene Stge 4: cyclization of squalene
What are the four stages of cholesterol synthesis?
-Fatty Acyl-CoA Synthetase -Acetyl Co-A Carboxylase *Rate limiting step in fatty acid synthesis* -Carnitine Acyl-Transferase I *Rate limiting in fatty acid oxidation* -Fatty Acid Synthase
What are the key enzymes involved in fatty acid metabolism?
Acetyl-coA Carboxylase is the rate limiting enzyme. Allosteric activator: citrate Alloesteric inhibitor: palmitoyl coA Hormones: Glucagon: signals AMP-activated protein kinase to inhibit fatty acid synthesis (phosphorylate acetyl co-A carboxylase) Insulin: signals protein phosphatase to dephosphorylate acetyl-coA carboxylase and activate it fatty acid synthesis
What are the major control points in fatty acid synthesis?
Different enzymes are used. Step 1. The fatty acid undergoes 3 cycles of b-oxidation, shortening the chain by 6 carbons and forming 3 acetyl-coA. Step 2. Enoyl-coA isomerase Step 3. beta oxidation, produces 1 acetyl coA Step 4. 2,4 DienoylcoA Reductase, produces 1 NADP+ Step 5. enoyl-coA isomerase Step 6. hyration, oxidation, & thiolysis + 4 cycles of beta oxidation = 5 acetyl coA Total acetyl coA = 9 acetyl coA
What are the steps for fatty acid oxidation for a unsaturated fatty acids or odd numbered fatty acids? pretend it is an 18 carbon unsaturated fatty acid.
Step 1: adenylation Adenosine + Fatty Acids >>Fatty Acyl-CoA synthetase>>> adenylate intermediate Step 2: CoA-SH attacks intermediate and Fatty Acyl-CoA synthetase converts intermediate to Fatty Acyl-CoA. Releases AMP
What are the steps involved with Fatty Acyl-CoA synthetase?
Malonyl CoA. Malonyl coA inhibits carnitine-acyl transferase, preventing fatty acyl-coA to enter the mitochondrial matrix. Malonyl coA is released when energy levels in the cell are high and the cell does not need fatty acid oxidation.
What controls carnitine-acyl transferase?
HDL particles reverse the transport of cholesterol by taking them from peripheral tissues and back to the liver.
What do HDL particles do in terms of cholesterol transport?
The citrate shuttle is how citrate is transported out of the mitochondria into the cytosol and converted to oxaloacetate via citrate lyase. Acetyl co-A is formed during this conversion, which is the primary component that starts fatty acid synthesis. Without the citrate shuttle, fatty acids wouldnt be able to be stored in adipose tissue for later use.
What does the citrate shuttle do?
Recall that... The first step of fatty acid oxidation is a oxidation reaction. It converts fatty acyl-coA to trans-enoylacyl-coA via acyl-coA dehydrogenase. This step produces FADH₂ and converts the beta C-C bond to C=C. When the bond is transformed to a C=C bond, electrons that are released from the single bond transfer goes up to ETF, which reduces FAD to FADH2. The electron pair is eventually passed up to coenzyme Q where it is admitted into the electron transport chain into complex III.
What does the first step of beta oxidation undergo and how does this associate with the electron transport chain?
When cell energy is high and we do not need more energy: Fatty Acid synthesis. Fatty Acyl-CoA doesnt enter mitochondrial matrix because it is inhibited my malonyl coA. When cell energy is low and we need energy: Fatty acid oxidation. Fatty Acyl-CoA is imported into the mitochondrial matrix by the carnitine transport cycle. Degrades fatty acids into acetyl coA, FADH2 and NADH.
What happens to fatty acyl co-A once it is formed?
statins. Drugs that inhibit this enzyme reduce the formation of cholesterol to decrease risk of cardiovascular disease.
What inhibits HMG-CoA reductase?
Fatty acids > acetyl CoA. the metabolic breakdown of fatty acids to acetyl CoA; also called beta oxidation. Occurs when the cell needs energy. Occurs in mitochondria matrix.
What is fatty acid oxidation and where does it occur?
To form steroids or bile acids
What is the 2 directions cholesterol can go?
HMG-CoA reductase - in step 1 (formation of mevalonate)
What is the RLE of cholesterol synthesis? What step in cholesterol synthesis is this used?
1. Stored in lipid droplets 2. brought to small intestine as bile acids 3. packed in VLDL's and released into circulatory system
What is the fate of cholesterol formed in the liver?
ACP is required for fatty acid synthesis. ACP is what anchors the growing fatty acid chain to fatty acid synthase. It moves the fatty acid chain to different domains of fatty acid synthase so that proper reactions and enzymes can occur and the fatty acid can grow by 2 carbons per round of fatty acid synthesis.
What is the importance of acyl carrier protein ? (ACP)
Purpose: to generate energy for the cell when the cell is low on it. Turns fatty acids into acetyl coA inside the mitochonrial matrix. Major outputs: NADH, FADH2 & acetyl coA
What is the purpose and major outputs of fatty acid oxidation?
SREBP's are activated when there are low levels of intraellular cholesterol. SREBP's bind to SRE sequences on transcriptional genes. This increases LDL receptor proteins and endocytosis of cholesterol.
What is the purpose os SREBP's
Ketogenesis occurs during starvation and when there are limited carbohydrate sources and gluconeogenesis can no longer occur. The body will undergo beta oxidation to turn fatty acidds into acetyl co-A. The excess acetyl co-A will turn into ketones so that it can cross the blood brain barrier and enter the brain.
When does ketogenesis occur?
liver
Where does cholesterol synthesis occur?
ketones - exported from the liver
acetoacetate & D-β-hydroxybutyrate are what? Where are they exported from?
fatty acid synthesis, cholesterol synthesis, ketone bodies
acetyl co-A can go in three directions...what are they?