HUN3224Intermediate Metabolism of Nutrients IExam III Study GuideLIPID METABOLISMPhospholipid and triacylglycerol (TAG) synthesisI. How does the synthesis of glycerol-3-PO4 in adipose tissue differ from that in liver?A. From glycerol via glycerol kinase in the liver onlyB. From DHAP (liver and adipose tissue) II. What reactions are required to synthesize phophatidic acid?A. From 2 fatty acyl-CoA’s (fatty acid that was activated with a CoA) + glycerol-3-Po4 (glycerol backbone)B. Enzymes: Transferase I & IIi. Transferase I adds the 1st fatty acid to the glycerol-3-PO4ii. Transferase II adds the 2nd fatty acid to the glycerol-3-PO4C. Once we have the glycerol-3-PO4 with the two fatty acids we form phosphatidic acid (1,2-diacylglycerol-PO4)III. What role does phosphatidic acid play in the synthesis of both phospholipids and TAG?A. A common intermediate in phospholipid and triacylglycerol synthesis. B. Phosphatidate phosphohydrolase cleaves the phosphate from phosphatidic acid, allowing the formation of 1,2-diacylglycerol. C. From 1,2-diacylglycerol we have two different steps either the synthesis of TAGs or the synthesis of phospholipids. i. Most of the time when there is free fatty acids available that are not being used for energy, they escaped -oxidation, they will be used to synthesis phospholipids.ii. Once the phospholipids have been synthesized then we will use the fatty acids to synthesize TAGs, for storage.D. TAG synthesisi. Rate limiting step in TAG synthesis: addition of a fatty acyl-CoA to diacylglycerol via diacylglycerol transferase which transfers the fatty acyl-CoA to the diacylglycerol. As this happens the CoA is released, yielding the triacylglycerol. IV. Describe 2 ways in which phosphatidylcholine can be formed. A. From diacylglyceroli. Choline needs to be available along with ATP for the formation of phospholipids ii. ATP is hydrolyzed activating choline, followed by a connection to CTP which is hydrolyzed giving us CDP which attaches to the choline. iii. CDP-choline is hydrolyzed and the choline is added to the 1,2-diacylglycerol forming phosphatidylcholine, and releasing CMPiv. Can be done with ethanolamine and inositol alsoB. From phosphatidylethanolaminei. Methylation of phosphatidylethanolamine to phosphatidylcholine via SAM. 1. SAM donates the methyl group, 3 methyl groups to phosphatidylethanolamine in order to become phosphatidylcholine. ii. If no choline available or need more phosphatidylcholine for a particular reason and if you have already produced phosphatidylethanolamine through the first pathway from diacylglycerol. V. Distinguish between the different types of phospholipids in terms of nitrogenous base attached. A. PhosphatidylcholineB. PhosphatidylethanolamineC. PhosphatidylinositolD. Phosphatidylserinei. Formed by adding serine to phosphatidylethanolamineii. Convert it back to phosphatidylethanolamine via decarboxylation Cholesterol I. SynthesisA. Recognize and name the basic ring structure. Distinguish between steroids and sterols in terms of general structure.1. Cyclopentanoperhydrophenanthrene Ring2. –OH denotes a sterol; not present in steroids. a. Once the steroids are produced from the cholesterol they lose their hydroxyl group. 3. Functionsa. Component of cell membranesb. Synthesis of bile acidsc. Synthesis of steroid hormonesd. Precursor for vitamin D 4. All cells with a nucleus are capable of cholesterol synthesisa. Mainly in liver 10% and intestinal cells 10%b. Take place in the cytoplasm and the smooth ER5. Half of the cholesterol in our bodies is consumed the other half is supposed to be made. B. HMG-CoA – what other pathway is this intermediate for besides cholesterol synthesis?1. Cholesterol is made from acetyl-CoA2. Also in ketosis (same steps up till HMG-CoA)C. Stage 1 of cholesterol Synthesis1. Cholesterol Synthesis occurs in 6 stages; stage 1 is where the drugs target in order to inhibit the synthesis of cholesterol. 2. Synthesis of mevalonate (6C) from 3 acetyl-CoA’s (2C)3. Thiolase adds 2 acetyl-CoA molecules together, as that happens we form acetoacetyl-CoA and we lose a CoA.4. HMG-CoA synthetase catalyzes the reaction adding the 3rd acetyl-CoA to the acetoacetyl-CoA forming HMG-CoA and we lose another CoA5. HMG-CoA Reductase with the coenzyme NADPH+H+, which donates its H’s to HMG-CoA in order to reduce it to mevalonate. NADPH+H+ becomes oxidized to NADP+a. The enzyme requires NADPH instead of NADHa. Also HMP Shunt requires NADPH and regenerates NADP to NADPH, which is used for the synthesis of fatty acids, cholesterol, (lipids in general)D. Stages 2-5 of cholesterol synthesis1. Stage 2: Formation of isoprene (5C) via a decarboxylation by loss of CO22. Stage 3: Condensation of 6 isoprene molecules to form squalene (30C)3. Stage 4: Cyclization (take it from the linear form to the rings) of qualene to form lanosterol (a parent steroid: simplest compound, that others are derived from)4. Stage 5: Formation of cholesterol from lanosterol by removing 3 methyl groups (demethylation)E. How is the activity of HMG-CoA reductase in the liver controlled?1. Feedback inhibition (not allosteric): by cholesterol and bile acids2. Covalent modification: hormone induces a signaling which leads to phosphorylation or dephosphorylation of a certain enzyme activating ti or deactivating it. a. Inactive with a PO4b. Active without a PO4c. Favored by insulin:a. Phosphodiestrase breaks down cAMP into 5aMP, preventing phosphorylation. b. Activates protein phosphatases which cleave the PO4 once the enzyme has already been phosphorylated d. Inhibited by glucagonF. What implications (or what basis) might this and other means of controlling cholesterol synthesis have for therapeutic attempts to lower serum cholesterol levels?1. Lower cholesterol by inhibiting HMG-CoA reductase by use of statin drugs.a. Not able to reduce HMG-CoA to mevalonate therefore not able to synthesis cholesterol from it. b. Up regulate LDL receptors in the cell, which increases the uptake of cholesterol into the cell to be used.a. Adrenal glands and liver are the ones mainly accepting the cholesterol2. Bile Acids are synthesized from cholesterol, a majority of bile acids are reabsorbed in the ileum of the small intestine. This means that you decrease the amount synthesized cholesterol via feedback inhibition because the bile acids are coming back which will decrease HMG-CoA activity. 3. If you increase fiber in your diet you will have a greater
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