beta oxidation - Overall view of catabolic pathways for...

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Unformatted text preview: Overall view of catabolic pathways for dietary nutrients Diet Proteins Carbohydrates Triglycerides L-Amino acid Monosaccharides D-Glucose Glycerol n tio ida -ox Fatty acids NH4+ Urea cycle Urea α-Keto acids Pyruvate Acetyl coenzyme A β Krebs cycle H2O, CO2 ATP NADH FADH2 Oxidative phosphorylation 1 ATP Storage and catabolism of dietary fatty acid Fatty acid β-Oxidation Acetyl CoA Triglyceride (storage) Krebs cycle Energy as ATP H2O CO2 2 Fatty acid metabolism • β-oxidation of fatty acids • even-chained versus odd-chained fatty acids • saturated versus unsaturated fatty acids • energy generation from acetyl CoA (product of β-oxidation) • alternative fate of acetyl CoA: ketone bodies formation 3 β-oxidation • energy of fatty acids is released by removal of 2-C at a time (oxidation) at the β-carbon position (C3) • 2-C are released in the form of acetyl CoA, which can then enter TCA cycle to generate ATPs • 3 steps: – activation of fatty acid (cytosol) • fatty acid + CoA => fatty acyl CoA – transport of fatty acyl CoA into mitochondria – β oxidation (mitochondrial matrix) oxidation 4 RC C H2 O O Fatty acid + O O O O O O O P O P O P O Adenosine (ATP) H2O PPi O RC C H2 O 2 Pi O P O Adenosine O Fatty acyl adenylate .. CoA-SH O RC C H2 S CoA + AMP + H + Fatty acyl-CoA Mechanism of fatty acyl-CoA ligase reactions Activation of fatty acid Activation of fatty acid • fatty acids are activated by esterification to coenzyme A (CoA or CoASH) • occurs in cytosol • catalyzed by acyl-CoA synthase • 2 ATP equivalents are need per fatty acid • four different acyl-CoA synthases with specificity for different chain lengths of fatty acids 5 Transport of acyl CoA into mitochondria • Acyl CoA, synthesized in cytosol, is transported into the mitochondrial matrix by a shuttle system • mediated by – Carnitine acyltransferase I (intermembrane space) – Carnitine acyltransferase II (inner membrane) • overall results: removal of fatty acyl CoA from cytosol and generation of fatty acyl CoA in mitochondrial matrix 6 The carnitine cycle, for transport of fatty acyl-CoAs into mitochondrial matrix acyl- INNER MEMBRANE INTERMEMBRANE SPACE MATRIX Acyltransferase I Fatty acyl-CoA CoA-SH Carnitine Translocase Carnitine Fatty acylcarnitine Acyltransferase II Fatty acyl CoA CoA-SH Fatty acylcarnitine 7 β-oxidation • products: – acetyl CoA • => enters TCA cycle => 10 ATP – NADH • => enters oxidative phosphorylation (2.5 ATP) – QH2 (Ubiquinone) • => enters oxidative phosphorylation (1.5 ATP) – fatty acids shortened by 2-C • => repeats the β-oxidation cycle 8 O H3C (CH2)11 CH2CH2CH2 C16 acyl-CoA 1 Dehydrogenation H H3C (CH2)11 CH2 C β C S CoA FAD FADH2 α O C S CoA C H trans-∆2-Enoyl-CoA 2 Hydration H2O H H3C (CH2)11 CH2 C β CH2 α O C S CoA OH L-3-Hydroxyacyl-CoA NAD+ 3 Dehydrogenation NADH + H+ O O H3C (CH2)11 CH2 C β CH2 CoA-SH α C S CoA 3-Ketoacyl-CoA 4 Thiolytic cleavage O H3C (CH2)11 CH2 C S CoA + O H3C C S CoA C14 acyl-CoA 6 additional cycles of reactions 1-4 Acetyl-CoA O 7 H3C C S CoA Acetyl-CoA Outline of the β-oxidation of fatty acids Generation of ATP • β-oxidation generates a large amount of ATP • Palmitoyl CoA (16C) + 7 CoASH + 7 Q + 7 NAD+ + 7 H2O => 8 Acetyl CoA + 7 QH2 + 7 NADH + 7 H+ = 8 X 10 + 7 X 1.5 + 7 X 2.5 = 108 ATPs • 2 ATP equivalents are needed for activation of fatty acid (palmitate generates 106 ATP) 9 β-oxidation of odd-chain fatty acids produces propionyl CoA • most fatty acids in nature have even number of carbon atoms • odd-chain fatty acids are oxidized the same way as even-chain fatty acids. But the final thiolytic cleavage product is propionyl CoA (3C), rather than acetyl CoA (2C) • propionyl CoA can be converted to succinyl CoA which can then enter TCA cycle 10 O H3C CH2 C S CoA Propionyl-CoA Propionyl-CoA carboxylase ATP , HCO3ADP + Pi COO-O H3C C H C S CoA D-Methylmalonyl-CoA Methylmalonyl-CoA epimerase H H3C C O C S CoA COO- L-Methylmalonyl-CoA Methylmalonyl-CoA mutase (B12 coenzyme) O -OOC CH2CH2 C S CoA Succinyl-CoA Pathway for catabolism of propionyl-CoA Oxidation of unsaturated fatty acids • unsaturated fatty acids are common in nature – e.g. C18, cis cis Δ9,12 octadecadienoate octadecadienoate • β-oxidation, starting from the carboxyl end, proceeded normally in the saturated region until a double bond is encountered (cis-β,γ Δ3) • only α−β is the substrate of acyl-CoA α−β dehydrogenase (1st step of βoxidation) 11 β-oxidation of unsaturated fatty acids • β −γ – isomerase: β − γ => α − β • γ−δ – γ−δ => 1st step of β-oxidation => γ−δ, α−β γ−δ α−β (cannot proceed further normally) reductase: γ−δ, α−β => β−γ γ−δ α−β β−γ isomerase: β−γ => α−β β−γ α−β 12 O 13 12 18 10 9 3 2 C S CoA 18:2c∆9,12 Linoleyl-CoA 3 cycles ofβ-oxidation O 7 12 Enoyl-CoA isomerase 7 12 1 cycle of β-oxidation 5 10 Acyl-CoA dehydrogenase 4 6 3 6 4 3 2 C S CoA 12:2c∆3,6 (β,γ) 2 C O S CoA 12:2t∆2,c∆6 (α,β) C O FAD S CoA 10:1c∆4 FADH2 5 10 4 3 2 C O S CoA 10:2t∆2,c∆4 (α,β) (γ,δ) 2,4-DienoylCoA reductase NADPH + H+ NADP+ 5 2 4 3 10 Enoyl-CoA isomerase C O S CoA 10:1c∆3 (β,γ) O 3 10 4 cycles of β-oxidation 4 2 C S CoA 10:1t∆2 (α,β) Acetyl-CoA β-oxidation pathway for polyunsaturated fatty acids ketone bodies are fuel molecules • most acetyl CoA from β-oxidation enters TCA cycle. • excess acetyl CoA is converted to ketone bodies in liver mitochondrial matrix and exported to other tissues (ketogenesis) • ketone bodies can be transported in bloodstream as “water-soluble lipids” • 3 types of ketone bodies – – – β-hydroxybutyrate acetoacetate acetone (not important) 13 ketone bodies oxidized in mitochondria • ketone bodies – generated in large amount in liver during starvation when liver glycogen is used up, substituting glucose as the source of fuel for brain cells • β-hydroxybutyrate and acetoacetate – enter the mitochondria of those cells (heart, muscle) that use these ketone bodies for energy – generating acetylCoA (enters TCA cycle) 14 O 2 H3C C S CoA Acetyl-CoA β-Ketothiolase CoA-SH O H3C C CH2 O C S CoA Acetoacetyl-CoA HMG-CoA synthase O C S CoA H3C CoA-SH OH -OOC CH2 C CH3 CH2 O C S CoA β-Hydroxy-βmethylglutaryl-CoA (HMG-CoA) O HMG-CoA lyase H3C O C S CoA -OOC CH2 C Acetoacetate CH3 CO2 O H3C C CH3 OH -OOC CH2 C H CH3 NADH , H+ β-Hydroxybutyrate dehydrogenase Acetone NAD+ β-Hydroxybutyrate Biosynthesis of ketone bodies in the liver O H3C C CH2 COO-OOC CH2CH2 O C S CoA Acetoacetate Succinyl-CoA transferase O H3C C CH2 O C S CoA Succinyl CoA -OOC CH2CH2 COO- Acetoacetyl CoA CoA-SH Succinate Conversion of acetoacetate to acetyl CoA. Succinyl-CoA transferase catalyzes the conversion of acetoacetate and succinyl CoA to acetoacetyl CoA and succinate. AcetoacetylCoA is then converted to two molecules of acetyl CoA by the action of thiolase. 15 Thiolase O H3C C S CoA H3C O C S CoA Acetyl CoA Acetyl CoA Fatty acid metabolism • • • • β-oxidation of fatty acids even-chained versus odd-chained fatty acids saturated versus unsaturated fatty acids energy generation from acetyl CoA (product of β-oxidation) • alternative fate of acetyl CoA: ketone bodies formation 16 ...
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This note was uploaded on 02/05/2009 for the course APPLIED BI ABCT taught by Professor Yuwingyiu,larrychow during the Fall '09 term at Hong Kong Polytechnic University.

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