BIOL 541 1st Edition Lecture 19 Outline of Last Lecture I. Lipid metabolism Outline of Current Lecture II.Fatty acid synthesisIII. Schematic diagramIV. Break down of proteinCurrent LectureBiochem lecture 19- Fatty acid synthesis:Deal with the double bonds as the fats are predominantly saturated. Hence, there are 3 different situations depending upon the position of double bonds:Cis delta 3: delta refers to missing H and 3 refers to C from 1st C or 3 C.There are no rotations on the double bonds, thereby cis or trans configuration. Isomerase flips this from cis C3 - C4 to trans C3 --- C2.Dehydrogenase produces trans configuration for subsequent reactions.Add water across double bond and oxidize OH to ketone.Since double bond is already there, no need to pull off H. Cleavage has no need for FADH2 and all cases of double bond needs 2ATP/ double bond.Cis delta 2:These 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.This is the correct position but wrong conformation.Hydratase adds water across cis or trans and generate D- 3 hydroxyl acyl COA and epimerase flips this to oxidize OH to ketone ( minus 2ATP).Cis delta 4: Not much to do, reduce it and reoxidize it.Saturate it and generate double bond in trans position. Oxidation and reduction cancel each other out and lose 2 ATP.Fatty acid synthesis:This is reverse of degradation which occurs in mitochondria where oxidation reaction occurs. Fatty acids are made in liver and fat tissues and during pregnancy and lactation in mammary glands. In cytosol, fatty acid synthesis takes place. In mitochondria, some fatty acid synthesis occurs- bacterial enzymes (eukaryotes cytoplasm is fused and inefficient). Fatty acids 14 C long only done. Synthesis of C8 which is precursor to lipoic acid (coenzyme) is done by this step. The rate limiting step is the 1st step.Using acetyl COA carboxylase extra COOH is attached at end.Malonyl COA allosterically inhibits carnitine for entrance into mitochondria in order to avoid synthesis and degradation occurring at the same time. This is an extremely regulated step and requires citrate/isocitrate.Acetate for synthesis of fatty acid comes form citrate. Acetate formed in mitochondria and fatty acid synthesis occurs in cytosol. Citrate shuttles acetate off. Back up in TCA cycle, acetate diverted to storage.Citrate induces polymerization. Just as Glu phosphorylase is a dimer and phospho fructose kinase is a tetramer in glycolysis.Citrate switches inactive form to filament (active). In addition regulated by phosphorylation by (-) inhibited by PKA and AMPK (low energy). PKA is activated by glucagon during fasting and AMP kinase activated during fasting as acetate is broken down for energy.Gene induction regulation:Mammary gland episodic just like the liver where lactation induces enzyme and prolactin induces chain.All of the remaining steps are catalyzed by protein known as fatty acid synthase (FAS). It takes acetyl COAand rams it into malonyl COA. Fatty acid is polymer of acetate and carboxylation of acetate activates it. CO2 displaces double bonds and used to couple the reaction. 2 acetates are coupled together. Fatty acid has 1 C=O so reduce these.Synthetic pathway:H comes from NADPH.PPP and NADPH isocitrate dehydrogenase: H from NADPH across C=O, reduce ketone to OH.Pull off water, leaves the double bond.Another NADPH, saturate double bond, gives butyric acid. Therefore 2 NADPH/coupling.Steps repeated:Rammed on back by malonyl COA, ketoic hexanoic acid formed. (Reverse of breakdown) H pulled off = bond, add water, OH to ketone and cleaved off. Therefore, synthesis is reverse of break down. Enzymes are separate in bacteria but fused in eukaryotes.Schematic diagram:Faty acid synthase has its own 7 enzymes and borrows 8th from its partner. Its own 8th can be forced to use but less efficient due to position. 2nd is acyl carrier protein. Phospho panthenine arm- covalent form of coenzyme A ending in sulphur group. Arm swings over to no.7 to pick up acetate.Swing to 8 and hold acetate using SH bond donated by CYS.Swing to 6 and pick up malonyl COA.Back to 8 and take acetate.Acetate + malonyl COA where CO2 displaced to form 3 keto acid.Swing to 3 Keto acyl ACP dehydratase where ketone to OH , OH to = enol formed, as = removed.Go to 5 enol reductase to remove = and butyric acid formed.Butyric acid in 8. Collect malonyl and ram malonyl to butyric.Swing to 3 where CO2 displaces =, C=O to OH, water and saturate = and hexanoic acid formed. Another malonyl COA at 8.Swinging arm is assembling line, reaction in sequence till fatty acid is 16 C (palmitic acid) long.Then goes to 1 (thiol esterase) cleaves fatty acid and fatty acid synthase makes another fatty acid.Gene transcription for regulation and induced by glucose and also affected by AMP kinase which inhibits gene transcription and break fatty acid down.Mass production of core and modify: Palmitic acid made and ER where same 4 reactions but located in different enzymes. Palmitic acid is coupled to malonyl COA and same steps of reaction form fatty acid between 20 C’s and 36 C’s.For shorter fatty acid, palmitic acid is paired back just like fatty acid degradation.Acetate produced by pyruvate dehydrogenase where pyruvate is converted to acetate in mitochondria. Fatty acid synthesis occurs in cytosol. There is no transporter for acetyl COA. This is done by using citrate pump.Acetyl COA + oxalo acetate - citrate. Transporter for citrate, citrate leaves mitochondria to cytosol. ATP citrate lyase splits acetyl COA to oxalo acetate and ADP. Acetyl COA goes for fatty acid synthesis.Oxalo acetate goes back into mitochondria to pick up acetate. Therefore, reduce it to malate and then malate dehydrogenase carboxylate malate to pyruvate.Pyruvate channels to mitochondria supplies supply of carboxylate oxalo acetate for additional acetyl COA. NADPH is used for reduction step where NADH is fed into system and NADPH is formed.Bacteria actually form a couple of branched fatty acid, methyl side chain formed.2 ways:Start off with derivative of valine and not acetyl COA. Valine is transaminated NH2 is removed to C=O. Then after decarboxylation and coupled to succinyl COA and malonyl COA and rammed and fatty acid formed a forked tail.Methyl side chain in middle:Unsaturation done after palmitic acid is formed. Methyl group across =:Donor is thio methylinine where ATP coupled