Respiratory Control & Lipid Metabolism - Kevin Ahern's BB 451 Lecture #36 2017
1. Contact - [email protected] 2. Kevin's lectures with The Great Courses - https://www.thegreatcoursesplus.com/b... 3. Kevin's Lecturio videos for medical students - https://www.lecturio.com/medical-cour... 4. Course materials at https://kevingahern.com/biochemistry-... 5. Course video channel at • Citric Acid Cycle I - Kevin Ahern's BB 451... 1. Mitochondria which are "tightly coupled" have intact membranes AND the only way protons get back into the matrix is by passing through Complex V. 2. When mitochondria are tightly coupled, metabolic (respiratory) control exists. This means that electron transport will stop if oxidative phosphorylation stops. When electron transport stops, NADH accumulates and the citric acid stops. Conversely, if one stops electron transport with cyanide, oxidative phosphorylation will stop very shortly because the proton gradient is lost when no protons are being pumped. 3. When mitochondria are uncoupled, electron transport is no longer limited by oxidative phosphorylation and runs amok. That is why heat is generated. Protons are pumped, but they fall back in throught the hole in the mitochondrial inner membrane. No ATP is made. NADH is rapidly converted to NAD+, so the citric acid cycle and other pathways run rapidly. 4. Things that affect these processes are ADP, oxygen, NADH, and NAD+ (needed for citric acid cycle). Glycerolipid and Sphingolipid Metabolism 1. Phosphatidic acid is an immediate precursor of CDP-diacylglycerol, which is a precursor of the various glycerophospholipids . CTP combines with phosphatidic acid to yield a pyrophosphate and CDP-Diacylglycerol. Activation by CDP yields a high energy activated intermediate that can be readily converted to phosphatidyl glycerophospholipids. 2. Phosphatidyl ethanolamine (and phosphatidyl choline - derived from phosphatidyl ethanolamine) can both be made independently of phosphatidic acid biosynthesis. For this pathway, CDP-ethanolamine is the activated intermediate and the phosphoethanolamine of it is added to diacylglycerol to form phosphatidylethanolamine. 3. Sphingolipids are synthesized beginning with palmitoyl-CoA and serine. Addition of a fatty acid to the amine group yields a ceramide. Addition of sugars to a ceramide yields either a cerebroside (single sugar added) or a ganglioside (complex sugar added). 4. Thus, glycerophospholipids can be made by 1) activating the phosphatidic acid with CDP and adding it to the "add-on" molecule; 2) activating the "add-on" molecule with CDP and adding it to diacylyglycerol; or 3) swapping one add-on molecule with another on a phosphatide (such as swapping serine for ethanolamine in phosphatidylethanolamine to make phosphatidylserine. 5. Deficiencies in enzymes that degrade sphingolipids (particularly cerebrosides and gangliosides) are linked to neural disorders. One such disorder is Tay-Sachs disease. 6. Cholesterol is an important component of membranes, particularly in the brain. Cholesterol can be synthesized totally from acetyl-CoA. 7. Steroids include all compounds synthesized from cholesterol. This includes steroid hormones, vitamin D, bile acids, and other related compounds. 8. Isoprenes are 5 carbon units - 1) isopentenyl pyrophosphate and dimethylallyl pyrophosphate. Each is made from acetyl-CoA molecules. Synthesis of isopentenyl pyrophosphate and dimethylallyl pyrophosphate comes from mevalonate, which, in turn, comes from HMG-CoA, so isoprenoid biosynthesis overlaps partly with ketone body synthesis. HMG-CoA is the branch molecule. 9. The most important enzyme in cholesterol biosynthesis is HMG-CoA reductase. It converts HMG-CoA to mevalonate and is the primary regulatory enzyme in cholesterol biosynthesis. Cholesterol is a feedback inhibitor of the enzyme. 10. HMG-CoA reductase is also a target for statin drugs to inhibit cholesterol synthesis. Cholesterol in the body arises from 1) diet; 2) synthesis; and 3) storage. 11. In cholesterol synthesis, reaction of isopentenyl pyrophospahte with dimethylallyl pyrophosphate yields a 10-carbon intermediate, geranyl pyrophosphate 12. Reaction of geranyl pyrophosphate with isopentenyl pyrophosphate yields a 15 carbon intermediate - farnesyl pyrophosphate. 13. Reaction of two farnesyl pyrophosphates yields a 30 carbon intermediate - squalene. 14. Further reaction of squalene yields a cyclic intermediate, lanosterol. Synthesis of cholesterol from lanosterol requires an additional 19 steps. From cholesterol, one can synthesize the bile salts, which are useful in solubilizing fat in the diet. Cholesterol also leads to synthesis of the steroid hormones. 15. Cholesterol in the body is either there as a result of 1) synthesis; 2) diet; or 3) storage/recycling. 16. In the digestive system, bile acids and mechanical agitation of the stomach help emulsify fats.
