BIO250 Spr11-27

BIO250 Spr11-27 - Reasons to study lipids Fundamental for...

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Unformatted text preview: Reasons to study lipids Fundamental for life, health and disease Energy storage Cell membranes Signaling molecules Cofactors for enzymes Prof. Welte studies them 1 11.3.28 Overview: The Three Stages of Cellular Respiration Stage 1: Acetyl-CoA Stage Production from Production Glucose Fatty Acids Amino Acids Stage 2: Acetyl-CoA Stage Oxidation (TCA cycle) Oxidation Stage 3: Electron Transfer Stage & Oxidative Phosphorylation Phosphorylation 11.3.28 2 Fig. 16-1 Recall Advantages of Using Fats as Fuel: Fats At 38 kJ/gm (or 9.1 kcal/gm), they have over At twice the energy of sugars (~ 3.8 kcal/gm for twice glucose), since fats are almost fully reduced glucose), Fats have no water of hydration, which triples Fats the weight of stored carbohydrates. the Lipid droplets don’t affect osmolarity Nearly insoluble in water Chemically inert Chemically 11.3.28 3 Disdvantages of Fats as Fuel: Fats Nearly insoluble in water Chemically inert Chemically Difficult to disperse and transport To be useful as energy sources, fats must be Solubilized Have their stable bonds activated Transported to the mitochondria 4 11.3.28 Path of Fat from the Diet Fig. 17-1 o ge ra st fuel release distribute solubilize breakdown 5 convert package 11.3.28 The Dreaded “Fat Star” – a Chylomicron 80 % TAGs & CEs Fig. 17-2 6 11.3.28 Path of Fat from “Fat” Adipose tissue (aka “fat”) harbors Adipose very concentrated stored triacylglycerols (TAG’s) triacylglycerols Hormones such as glucagon and Hormones epinephrine (aka adrenalin), which are secreted in response to low blood glucose, stimulate adenylyl cyclase to produce cAMP, cyclase Resulting in phosphorylation by a Resulting cAMP-stimulated kinase of TAG lipase, activating it to cleave TAG’s lipase, TAGs Into glycerol and fatty acids Into glycerol fatty 7 glycerol Fig. 17-3 11.3.28 TAG Lipase After it becomes phosphorylated, the hormone-activated TAG lipase cleaves three bonds to yield one molecule of glycerol and three fatty acids. What hormone activated this enzyme? 8 Fig. 10-3 11.3.28 The Glycerol Gets Into Glycolysis By two simple steps: Activation by glycerol Activation kinase (group transfer from kinase ATP), then ATP), Oxidation by glycerol-3-P Oxidation dehydrogenase dehydrogenase The product, DHAP, is in the The glycolytic pathway, and glycolytic you should know what you happens next… happens 9 (DHAP) Fig. 17-4 11.3.28 And the Fatty Acids Get Activated… In the outer membrane of In mitochondria by acyl-CoA mitochondria synthetases, “driven” by ATP hydrolysis (see also Fig. 14-11) Fig. Isozymes of this family are Isozymes specific for short, medium, and long chain fatty acids and Curiously, neither CoA nor Curiously, these fatty acid-CoA esters can cross the inner mitoinner chondrial membrane… 10 (several Isozymes) Fig. 17-5 11.3.28 Transport of Fat into Mitochondria Ac tiv a te dF As Fig. 17-6 So after transfer of the fatty acid from CoA So to carnitine by carnitine acyltransferase I, carnitine An acyl-carnitine/carnitine antiport transporter brings the FA-carnitine An acyl-carnitine/carnitine ester across the inner membrane by facilitated diffusion, after which ester carnitine acyltransferase II transfers the fatty acyl group back to CoA, releasing free carnitine and FA-CoA into the mitochondrial matrix mitochondrial 11 The net result is…voila! 11.3.28 A Few Points to Note The cytosolic and mitochondrial (Mt) pools of CoA The do not intermingle, and have separate functions: do Cytosolic CoA is used in fatty acid biosynthesis Mt CoA is used in oxidative degradation of fatty Mt acids, pyruvate, and some amino acids acids, Carnitine-mediated transport is the rate-limiting Carnitine-mediated step for fatty acid oxidation in the mitochondria step Once inside, the activated fatty acids rapidly undergo β -oxidation in two-carbon units, with minor go -oxidation variations seen between fatty acids that are variations saturated unsaturated odd-chain length 11.3.28 12 The 3 Stages of β -oxidation Stage 1 has four basic steps Each cycle of removing an acetylCoA 2-carbon unit (and passing it CoA to Stage 2) to Generates one molecule of FADH2 and one of NADH and During oxidation of the β -carbon During -carbon Which, together with those from the Which, TCA cycle, donate their electrons to the respiratory chain in the inner mitochondrial membrane mitochondrial 13 Fig. 17-7 11.3.28 The First Step of β -Oxidation Fig. 17-8a 14 1. Short, medium, and long chain 1. dehydrogenase isozymes catalyze dehydrogenase α− double bond formation β α− 11.3.28 The Second Step of β -Oxidation Fig. 17-8a 15 2. Addition of water by the hydratase 2. hydratase forms a β -hydroxy derivative 11.3.28 The Third Step of β -Oxidation Fig. 17-8a 3. Another dehydrogenase 3. dehydrogenase step forms β -ketoacyl-CoA 11.3.28 16 The Fourth Step of β -Oxidation Fig. 17-8a 17 4. From β -ketoacyl-CoA, the n-2 4. -ketoacyl-CoA, chain can be transferred to free CoA by thiolase, releasing acetyl-CoA 11.3.28 thiolase β -Oxidation of a C16 Fatty Acid The overall equation for this The oxidation is: oxidation Palmitoyl-CoA + 7 CoA + 7O2 + 28 Pi + 28 ADP 8 Acetyl-CoA + 28 ATP + 7H2O Through the TCA cycle, the 8 Through acetyl-CoAs generate another 80 ATPs + 16H2O + 16CO2 80 11.3.28 Fig. 17-8b 18 Summary of Energy Yield Cost of fatty acid activation -2 *Assumption: mitochondrial oxidative phosphorylation produces 1.5 ATP per FADH2 and 2.5 ATP per NADH oxidized 19 Net gain: 106 ATP 11.3.28 Comments on Energetics From a triacylglycerol, only about 5% of the energy From is derived from the glycerol, and 95% from the three fatty acids three The standard free energy for the complete The oxidation of palmitate is 9800 kJ/mol; under prevailing cellular conditions (see Box 13-1) the efficiency of energy recovery in the form of ATP is > 60% (remarkable!) 60% As well as metabolic energy, fatty acid oxidation As provides heat and water (23 molecules/palmitate molecule, for example) – of great benefit to both bears and camels… (see Box 17-1) bears camels 11.3.28 20 Not All β -oxidation Enzymes are the Same Fig. 17-15a,c In mitochondria, short-chain FAs are broken down by 4 In separate soluble enzymes, while separate Very-long-chain FAs are metabolized by membrane-bound Very-long-chain Enz1 plus the dimeric “TFP” (trifunctional protein) Enz1 21 Can you name the 4 activities? 11.3.28 What About MUFAs and PUFAs? Bring on an Isomerase and a Reductase! Fig. 17-9 Mono PolyFig. 17-10 22 Problem: enoyl-CoA hydratase Problem: cannot act on cis-double bonds; cis-double with multiples thereof a reductase is also needed to reposition them is 11.3.28 Some Fatty Acids are Odd… With odd-numbered carbon With chains, the final product of β oxidation will be propionyl-CoA – oxidation what to do? what The cellular answer is: The 1. Carboxylate (needs biotin) 2. Epimerize (D- to L-) 3. Rearrange (which needs 3. coenzyme B12) coenzyme Ending up with succinyl-CoA, and Ending you know where that can go… that 11.3.28 23 Fig. 17-11 Another Alternative: ω -oxidation In the ER (endoplasmic In reticulum) of liver and kidney, fatty acids may be degraded from the other end from After 3 steps, a doubleended (dicarboxylic) FA is ended produced produced Which can be attached to Which CoA at either end, and proceed through β -oxidation 24 Fig. 17-16 11.3.28 Summary of β -Oxidation Stored or ingested TAGs can provide up to 80% of Stored the energy needs of heart and liver by FA oxidation the After activation via a thioester linkage to coenzyme After A, a cyclic 4-step process cleaves off 2-carbon units as acetyl-CoA (in what two different metabolic directions can this go next?) directions Specialized steps act on MUFAs, PUFAs, and oddchain length fatty acids The rate-limiting step for β -oxidation is entry into The -oxidation the mitochondrion, which can be controlled by malonyl-CoA (why?) malonyl-CoA 25 11.3.28 What Are Ketone Bodies? They aren’t “bodies”, and Only two are ketones They build up if there is They ongoing β -oxidation in the -oxidation liver, but liver, The ability of acetyl-CoA The to enter the TCA cycle is limited limited How could this come How about? about? 26 ox rb ca de n io t la y a id ox n io t 11.3.28 β -oxidation of FAs Where Do These “Bodies” Come From? β -HBdH 27 Fig. 17-18 These 3 perfectly soluble small These molecules are molecules Produced in side reactions from Produced acetoacetyl-CoA at the penultimate step in β -oxidation, When there is excess acetyl-CoA for When the TCA cycle the This also produces free CoA Thus allowing continued oxidation of Thus fatty acids in the liver fatty Acetone, the most volatile, is exhaled Note reduction by β -HBdH and the Note -HBdH regeneration of S-CoA… regeneration 11.3.28 Ketone Bodies from Liver Can Be Used as Fuel Elsewhere The ketone bodies are then The exported to other tissues Renal cortex, skeletal and Renal heart muscle, and brain (but it prefers glucose) can oxidize ketone bodies for use in their TCA cycles TCA This occurs particularly during This starvation, when gluconeostarvation, genesis is depleting intermediates of the TCA cycle, mediates thereby slowing it thereby 28 Fig. 17-19 β -HBdH From TCA To TCA 11.3.28 Ketone Bodies Get Exported for Energy When gluconeogenesis is When needed needed The TCA cycle slows Acetyl-CoA builds up Ketone bodies are made Providing fuel for other Providing tissues (which?) tissues Allowing continued β Allowing oxidation (how?) Appreciate the interplay among pathways… among 29 Fig. 17-20 11.3.28 Are you starting to feel like this? 30 BIOCHEM “ In “D fo T h Be o Y rm en Li fo ou ati re s t re on ad ?” Y Ru ou n Ov R Ou erl un t o o O f D ad” ut a , o of y r 11.3.28 ...
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