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Welcome to Class 13! Introductory Biochemistry! Class 13: Outline and Objectives l Lipid Catabolism! l Ketone bodies! l Lipid Biosynthesis ! l Fatty acids! l Triacylglycerols! l Membrane lipids! l Cholesterol! l Lipoproteins and Lipid Transport! 1! 4 Steps of β oxidation:! ➀ 1st oxidation ! ➁ hydration! ➂ 2nd oxidation! ➃ thiolysis! Figure 17-8a! FADH2 Electron Transport! Figure 19-8! 2! After one round of β oxidation:! Palmitoyl-CoA + CoA + FAD + NAD+ + H2O! ↓! Myristoyl-CoA + Acetyl-CoA + FADH2 + NADH + H+ ! Palmitoyl-CoA + 7 CoA + 7 FAD + 7 NAD+ + 7 H2O → ! ! !8 Acetyl-CoA + 7 FADH2 + 7 NADH + 7 H+! Figure 17-8b! β Oxidation generates metabolic energy! Oxidation of Palmitoyl-CoA produces Acetyl-CoA:! Palmitoyl-CoA → 8 Acetyl-CoA + 7 FADH2 + 7 NADH + 7 H+! Acetyl-CoA Enters the Citric Acid Cycle:! 8 Acetyl-CoA → 16 CO2 + 8 FADH2 + 24 NADH + 8 ATP! Net:! Palmitoyl-CoA → 15 FADH2 + 31 NADH + 8 ATP! Oxidative Phosphorylation:! (@1.5)! 22.5 ATP! But remember, it “costs” 2 ATP ! equivalents for! Palmitate → Palmitoyl-CoA! (@2.5)! 77.5 ATP! 108 ATP! 8 ATP! – 2 ATP = 106 ATP! 3! Comparative energy yield! Complete oxidation of palmitoyl-CoA produces 106 ATP! Palmitic acid contains 16 C atoms! The energy yield is 106/16 = 6.625 ATP/C! Recall that complete oxidation of glucose produces 30 to 32 ATP! Glucose contains 6 C atoms! The energy yield is 30/6 to 32/6 = 5 to 5.333 ATP/C! Per C atom oxidized, fatty acids yield 6.625/(5 to 5.333) = 1.24 to 1.325 times more ATP! Additional advantage for storage:! Glucose is stored as the hydrophilic glycogen, requiring 2 to 3 g of water per g glycogen.! Fatty acids are stored as hydrophobic fats.! Not all fatty acids are saturated:! Double bonds require additional reactions:! Our goal:! Figure 17-10! 4! Oxidation of a polyunsaturated fatty acid! Problem 1:! Δ3 double bond! (β,γ double bond).! Solution:! Isomerization to a trans Δ2 double bond (α,β double bond).! Problem 2:! Δ2 and Δ4 double bonds (α,β and γ,δ double bonds).! Figure 17-11! Oxidation of a polyunsaturated fatty acid! Solution: First,! reduction to one trans Δ3 double bond (β,γ double bond).! Then,! isomerization to a trans Δ2 double bond (as before).! Figure 17-11! 5! Another problem: odd-numbered fatty acids! Last β oxidation step yields a C3 compound! Addition of CO2 forms a C4 compound! Figure 17-12! Another problem: odd-numbered fatty acids! Conversion of D configuration to L! Second carbon skeleton rearrangement to form succinyl-CoA! Figure 17-12! 6! Methylmalonyl-CoA mutase catalyzes a carbon skeleton rearrangement! Note: the hydrogen atom does not exchange with the solvent during this reaction! Box 17-2! Coenzyme B12! X-ray structure! 1956! B12-containing enzymes catalyze: molecular rearrangements ! methyl transfer reactions! The core tetrapyrrole (the corrin ring) of coenzyme B12 cannot be synthesized by eukaryotes; ! it is a required nutrient for animals (vitamin B12). ! ! Plants neither synthesize nor need coenzyme B12. ! ! Coenzyme B12 is the major place in biochemistry where the metal cobalt occurs.! Homolytic Bond Cleavage!!!! Box 17-2! 7! More than one fate for fatty acids! FAs! β oxidation! Acetyl-CoA! OR! TCA Cycle! Ketogenesis! Ketone bodies:! ! • Derived from acetyl-CoA! • Transported to other tissues! • Important fuels! p. 686! 8! Ketogenesis:! • occurs in the liver! • source: acetyl-CoA! • generates ketone bodies! • transported from the liver! ➀ Condensation:! Acetyl-CoA + Acetyl-CoA! ➁ Condensation:! Acetoacetyl-CoA + Acetyl-CoA! Figure 17-19! Ketogenesis! ➂ Cleavage →! Acetoacetate + Acetyl-CoA! Figure 17-19! 9! Ketone bodies as fuel:! Conversion to acetyl-CoA! after transport! Figure 17-20! Starvation promote gluconeogenesis,! which depletes citric acid cycle intermediates (via OAA),! which slows the citric acid cycle,! which causes acetyl-CoA to accumulate,! which causes conversion of acetyl-CoA → acetoacetate.! Figure 17-21! 10! Fatty acid catabolism vs. biosynthesis! (cofactor SH)! Fatty acid biosynthesis is not simple reversal of β oxidation! FA biosynthesis occurs in the cytosol: acetyl group shuttle! First, ! Acetyl-CoA must be transported from! mitochondria to the cytosol! Acetyl-CoA is not exported directly! Citrate (C6) is exported;! It is lysed to acetyl-CoA (C2);! the remains (C4 or C3) are reimported! Not a reversal of the acyl-carnitine/carnitine transport system! This route generates cytosolic NADPH! Figure 21-10! 11! Fatty acids are not synthesized directly from acetyl-CoA! Malonyl-CoA (C3) is the major carbon source for FA biosynthesis! Malonyl-CoA is formed by Acetyl-CoA Carboxylase! This is the committed step in FA biosynthesis! Figure 21-1! Reciprocal regulation of fatty acid synthesis and catabolism! Lipase! Carnitine! Acyltransferase I! Active ACC is polymerized and dephosphorylated! Figure 21-11! 12! Fatty acid synthesis is carried out by fatty acid synthase! This complex enzyme has 7 active sites:! ! KS = β-Ketoacyl-ACP Synthase ! MAT = Malonyl/acetyl-CoA-ACP Transferase! DH = β-Hydroxyacyl-ACP Dehydratase! ER = Enoyl-ACP Reductase! KR = β-Ketoacyl-ACP Reductase! ACP = Acyl Carrier Protein ! TE = Thioesterase! Figure 21-3! Both KS and ACP have thioesterforming SH groups:! ! The SH group of β-Ketoacyl-ACP–Synthase (KS) is a Cys residue! The SH group of Acyl Carrier Protein (ACP) is a 4'-phosphopantetheine! Figure 21-5! 13! To begin fatty acid synthesis,! Synthase is loaded:! • with acetyl-CoA! • and malonyl-CoA! KS ! ACP! Fatty acids are synthesized in a repeating 4-step sequence:! ➀ condensation! KS ! ACP! ➁ reduction! (this is the CO2 that was originally condensed with acetyl-CoA to form malonyl-CoA)! KS ! ACP! Figure 21-2! Fatty acids are synthesized in a repeating 4-step sequence:! KS ! ACP! ➂ dehydration! KS ! ACP! ➃ reduction! After the second reduction step, the growing chain is transferred from ACP to KS and then ACP is loaded with another malonyl group for the second round:! KS ! ACP! Figure 21-2! 14! The 4-step sequence is iterated to synthesize palmitate! FA synthase is first charged with acetyl-CoA! Malonyl-CoA is the source of all other C’s! ● 2 C’s are added and 1 CO2 is lost with each cycle! ● ● A palmitate-specific thioesterase cleaves the completed fatty acid from FA synthase! ● Palmitate synthesis requires a total of 7 cycles! ● Figure 21-4! Biosynthesis of palmitate! Formation of Malonyl-CoA requires ATP hydrolysis:! 7 Acetyl-CoA + 7 CO2 + 7 ATP → 7 Malonyl-CoA + 7 ADP + 7 Pi + 7 H+! 7 Cycles:! Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 14 H+ + H2O →! ! !Palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 7 H2O! Note: None of these steps require ATP hydrolysis! Overall:! 8 Acetyl-CoA + 7 ATP + 14 NADPH + 7 H+ →! ! !Palmitate + 8 CoA + 7 ADP + 7 Pi + 14 NADP+ + 6 H2O! Reverse reaction: β Oxidation! Palmitate + 8CoA + ATP + 7 FAD+ + 7 NAD+ →! ! ! ! 8 Acetyl-CoA + 7 FADH2 + 7 NADH + AMP+ 7 H+! 15! Fates of palmitate! Palmitate! used! directly! desaturation! (C=C)! chain! lengthening! Long-chain and desaturated fatty acids are synthesized from palmitate! fatty acid elongation systems! Some desaturations cannot be performed by mammals. The products must be supplied in the diet as “essential fatty acids.”! Figure 21-12! 16! In vertebrates, desaturation to a monounsaturated fatty acyl-CoA involves an electron transport chain! Fatty acyl-CoA desaturase is an example of a “mixed function oxidase”:! ! Reductant 1 + Reductant 2 + O2 → Oxidized reductants 1 and 2 + 2 H2O! ! Saturated fatty acyl-CoA + NADPH + O2 → Monounsaturated fatty acyl-CoA + NADP+ + 2 H2O! Figure 21-13! Biosynthesis of triacylglycerols and ! glycerophospholipids! Figure 10-7! 17! Triacylglycerols and ! glycerophospholipids! are synthesized from! a common precursor! Glucose! Fructose! D-Glyceraldehyde 3-phosphate! Fructose-1P! Glyceraldehyde! Figure 21-17! Phosphatidic Acid ! is the precursor for ! triacylglycerols and ! glycerophospholipids! Figure 21-17! 18! Phosphatidic Acid ! is the precursor for ! triacylglycerols and ! glycerophospholipids! Figure 21-18! Polar head groups are attached by a phosphodiester bond! Figure 21-23! 19! Two general strategies for head group attachment! Strategy 1! Activation of phosphatidic acid! Strategy 2! Activation of head group! Phosphatidic! Acid! CTP! PPi! Both strategies use activation by a nucleotide! Figure 21-24! Glycerophospholipids:! Figure 10-9! 20! Sphingolipid! How in the world do we make this monster! Sphingolipids! ! are not built onto glycerol.! Instead, they are derived from ! serine and palmitoyl-CoA! L stereochemistry! not a fatty acyl ester! amide linkage! Figure 21-31! Head group attachment! → sphingolipids! 21! In animals, N-acylsphinganine is oxidized to! N-acylsphingosine (ceramide)! Figure 21-31! These are important lipids ! in gray matter of the brain! Glycosphingolipids are determinants of blood groups! Figure 10-15! 22! Cholesterol! All carbons in cholesterol are derived from acetate! Figure 10-17, 21-32! Summary of cholesterol biosynthesis! ➀ synthesis of mevalonate (C6) from acetate (3 C2)! ➁ activated isoprene (C5) production ! ➂ condensation of activated isoprene units! ! ➃ cyclization of squalene! Figure 21-33! 23! ➀ Commitment:! This is the committed step in cholesterol biosynthesis! Figure 21-34! ➁ Activation:! isopentenyl pyrophosphate isomerase! Figure 21-35! 24! ➂ Condensation:! Figure 21-36! ➃ Cyclization:! Figure 21-37! 25! Oxidosqualene cyclase! catalyzes cyclization reaction and! membrane insertion of product! Thoma et al, Nature Vol. 432, p. 118, 2004! Fates of cholesterol! Figure 21-38! Figure 21-48! 26! Regulation of cholesterol metabolism! Biosynthesis! Just Enough Cholesterol! (cholesterol metabolites)! Dietary Uptake! (from dietary uptake)! Figure 21-43! Regulation of cholesterol metabolism! HMG-CoA reductase is the target of many “cholesterol-lowering” drugs (statins), which act as competitive inhibitors. ! Box 21-3! Figure 21-44! 27! Lipids are not very soluble in hydrophilic fluids such as blood serum! Plasma lipoproteins are used to transport:! • cholesterol! • cholesterol esters! • triacylglycerols! • phospholipids! 4 classes of lipoproteins! Figure 21-39! 28! Lipoproteins transport lipids in the bloodstream! Figure 21-40! Cholesterol uptake through receptor-mediated endocytosis! Figure 21-41! 29!
