BBMB 405 1nd Edition Lecture 12Outline of Last Lecture XIV. Chapter 22: Fatty Acid MetabolismC. Unsaturated and odd-chain fatty acids require additional steps for degradationOutline of Current Lecture XIV. Chapter 22: Fatty Acid MetabolismD. Fatty acids are synthesized by fatty acid synthase (FAS)E. Elongation and unsaturation of fatty acids are accomplished by accessory enzyme systemsCurrent LectureXIV. Chapter 22: Fatty Acid MetabolismD. Fatty acids are synthesized by fatty acid synthase (FAS)1. Handout (2/6) De Novo Fatty Acid Synthesis takes place in adipose or liver or both depending on the type of animal (liver is principal anatomical site for de novo)2. Fatty acids are synthesized and degraded by different pathwaysa. Synthesis in cytosol, degradation in mitochondriab. Intermediates during synthesis linked to acyl carrier protein (ACP), intermediates during oxidation attached to CoAc. Synthesis catalyzed by FAS, serval enzymes for oxidation (multifunctional enzyme)d. Synthesis from malonyl ACP (from acetyl CoA) and driven by release of CO2, oxidation releases acetyl CoAe. Synthesis uses NADPH as reductant, oxidations uses NAD+ and FAD as oxidantsf. Synthesis concludes with palmitate, oxidation with acetyl CoAThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.3. Formation of malonyl CoA is committed step in fatty acid synthesis (rate limiting step, uses acetyl CoA carboxylase to drive reaction)4. Intermediates in FAS are attached to acyl carrier protein (ACP)5. Fatty acid synthesis consists of a series of condensation, reduction, dehydration, andreduction reactions (reverse reaction of beta oxidation)a. Where is acetyl CoA made? Mitochondria. But fatty acid synthesis occurs in the cytosol so need to get acetyl CoA out of mitochondria.b.6. Fatty acids are synthesized by multifunctional enzyme complex in animals (don’t memorize catalytic cycle of mammalian fatty acid synthase)7. The synthesis of palmitate requires 8 molecules of acetyl CoA, 14 molecules of NADPH, and 7 molecules of ATPa. Overall reactionb.8. Citrate carries acetyl groups from mitochondria to the cytoplasm for fatty acid synthesisa. ATP-citrate lyase: Ciitrate + ATP + CoA + H2O acetyl-CoA + ADP + Pi + OAAb.c. Notes on diagrami. Cytoplasm (everything in cell except nucleus, includes mitochondria) should be cytosolii. Glucose is converted to pyruvate which can come in in the bottom lefiii. Malic Enzyme (ME): decarboxylation of malate to pyruvate- Ruminant: metabolically set up to not use glucose as precursor tofatty acid- Make own glucose at premium- Malic enzyme is not present so malate reenters mitochondriaiv. Free acetate can be activated by converting to acetyl CoA and come into cycle9. Several sources supply NADPH for fatty acid synthesisa. Malic enzyme: Malate + NADP+ pyruvate + CO2 + NADPHb. Pentose phosphate pathwayc. NADPH isocitrate dehydrogenase: isocitrate + NADP+ alpha-ketoglutarate + NADPHd.10. Fatty acid synthase inhibitors may be useful drugs11. Handout (2/9)a. Fatty Acid desaturationi. Desatuartion: delta4-, delta5-, delta6-fatty acid desaturases; no double bonds above 9 in desaturases in animals so no delta12- or detla15-desaturasesii. Essential fatty acids (we cannot make, we eat then make): C18:2delta9,12 C18:3delta9,12,15 b. Why are C18:2delta9,12 and C18:3delta9,12,15 essential:i. Eicosanoid synthesis (as precursor, ex. proteglandens)ii. Normal membrane structure and functioniii. Eicosapentaenoic acid (EPA; C20:5delta5,11,14,17 )iv. Docosahexaenoic acid (DHA; C22:6delta4,7,10,13,16,19 )v. DHA and EPA prevalent in brain tissue and eyes, DHA in breast milk and can slow down cancer growthc. FA elongation: use elongase (several reactions), attached to the endoplasmic reticulumd. FA desaturation: can only place double bond at 4, 5, 6, 9e. Example of elongation and desaturationi. Start: C18:2delta9,12ii. Delta6-desaturaseiii. C18:3delta6,9,12iv. Elongasev. C20:3delta8,11,14vi. Delta5-desaturasevii. C20:4delta5,8,11,14 arachiolonic acidf. Plant desaturases (use phospholipid)E. Elongation and unsaturation of fatty acids are accomplished by accessory enzyme systems1. Membrane-bound enzymes generate unsaturated fatty acidsa.b. How to get cytosol NADPH: ME gives one, provides 50% of need to make fatty acid from glucose, ruminates use pentose phosphate pathway and isocitratdehydrogenase (replaces need for ME)c.d.e. Oleoic acid (18:1) in adipose and not palmitic acid (16:0) but palmitic acid is synthesized the most by FASf. Desaturase: places at delta9 to form oleoyl, two electrons added to oxygen2. Eicosanoid hormones are derived from polyunsaturated fatty acidsa. Arachidonate is major precursor of eicosanoid hormonesb. Control de novo: inhibits FA synthase, FAS in cancer patients is high so begin tested as chemotherapeutic
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