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Chapter 17 The Citric Acid cycle Outline 17.1 pyruvate Dehydrogenase Links Glycolysis to the Citric Acid cycle 17.2 The Citric Acid Cycle Oxides Two-Carbon Units 17.3 Entry to the Citric Acid Cycle and Metabolism Through It Are Controlled 17.4 The Citric Acid Cycle Is a Source of Biosynthesis Precusors 17.5 The Glyoxylate cycle Enables Plants and Bactreria to Grow on Acetate 2 醣解作用 葡萄糖 Energy investment phase能量投資期 果糖1,6雙磷酸 丙酮酸 Energy payoff phase 能量收益期 檸檬酸循環 氧化磷酸化作用 3 Fig 17-1 One molecule of glucose is converted to two molecule of pyruvate The Central Role of the Citric Acid Cycle in Metabolism 檸檬酸循環在代謝作用中所扮演的角色 • Organisms can obtain far more energy from nutrients by aerobic oxidation than by anaerobic oxidation 藉由有氧氧化,生 物體可自營養物中得到比厭氧作用更多的能量 •Glycolysis糖解作用 produces only 2 molecules of ATP for each molecule of glucose metabolized 每分子葡萄糖經代謝作 用只能產生兩分子的ATP •In complete aerobic oxidation to CO2 and water在完全的有氧 氧化成二氧化碳與水時 30-32 molecules of ATP can be produced from each molecule of glucose metabolized 每分子葡萄糖可產生30至32分子的ATP • three processes of aerobic metabolism 有氧代謝 –The citric acid cycle 檸檬酸循環 –Electron transport 電子傳遞 –Oxidative phosphorylation 氧化磷酸化 •Metabloism 代謝作用 –Catabolism異化作用;分解代謝 •The oxidative breakdown of nutrients 氧化分解營養物質 –Anabolism合成代謝 •Reductive synthesis of biomolecules 還原合成生物分子 •The citric acid cycle is amphibolic雙重代謝 it plays a role in both catabolism and anabolism It is the central metabolic pathway •The citric acid cycle also as: kerbs cycle克氏循環 : Sir Hans Krebs, who first investigated the pathway (1953 Nobel Prize) tricarboxylic acid cycle (TCA cycle)三羧酸循環: some of the molecules involved are acids with three carboxyl groups • The citric acid cycle, also called tricarboxylic acid (TCA) cycle – The final common pathway for the oxidation of fuel molecules – Pyruvate acetyl CoA (key molecule) – Take place: mitochondria matrix Fig 17.1 Mitochondria 6 The citric acid cycle harvests high-energy electrons • Central metabolic hub of the cell – Gateway to the aerobic metabolism of any molecule – Important source of precusors for amino acids, nucleotide bases and porphyrin – TCA cycle component oxaloacetate is an important precusor to glucose 3 NADH 1 FADH2 1 ATP ATP 7 Fig 17.2 Overview of the citric acid cycle ATP NADH FADH2 H+ Fig 17.3 Cellular respiration 8 產生乙醯輔酶A 乙醯輔酶A氧化作用 電子轉移及 氧化磷酸化 乙醯輔酶A FIGURE 19.1 The central relationship of the citric acid cycle to catabolism In stage 1: Amino acids, fatty acids, and glucose can all produce acetyl-CoA In stage 2: acetyl-CoA enters the citric acid cycle Stages 1 and 2 produce reduced electron carriers (e-) 還原電子攜帶者 In stage 3, the electrons enter the electron transport chain, which then produces ATP 9 Fig. 19-1, p.546 Acetly-CoA ATP Fig 17.15 The Citric Acid cycle 10 17.1 pyruvate Dehydrogenase Links Glycolysis to the Citric Acid cycle Aerobic condition 有氧條件下 由糖解作用而來 丙酮酸 丙酮酸去氫酶 •The pyruvate is oxidized to 1.CO2 2.Acetyl group linked to CoA (Acetyl-CoA 乙醯輔酶) •NAD+ is reduced to NADH 由脂肪酸的b-氧化作用而來 乙醯輔酶A Enters the TCA cycle 11 Fig 19.3 An overview of the citric acid cycle. Fig. 19-3a, p.548 How Pyruvate Is Converted to AcetylCoA 丙酮酸如何轉換成乙醯輔酶A? • Pyruvate – From many source, including glycolysis – Move from cytosol into the mitochondria via a specific transporter (特定轉運蛋白) pyruvate + CoA-SH + NAD+ Acetyl-CoA +CO2 + H+ +NADH exergonic 釋能, NADH is used to generate ATP via electron transport chain • Enzyme system: pyruvte dehydrogenase complex 丙酮酸去氫酶複合物 • CoA-SH 輔酶A – there is an –SH group at one end of the CoA molecule (acetyl group is attached) » Acetyl-CoA is a thioester (high energy compounds) 12 Pyruvate dehydrogenase complex •A large, highly integrated complex of three distinct enzymes •a family of homologous complexes include α-ketoglutarate dehydrogenase complex •Molecular masses range from 4-10 million dalton 13 Mechanism: The synthesis of acetyl coenzyme A from pyruvate requires three enzyme and five coenzyme pyruvate dehydrogenase complex 1. Pyruvate dehydrogenase (PDH) Involved in the conversion 2. Dihydrolipoyl transacetylase of pyruvate to acetyl-CoA 3. Dihydrolipoyl dehydrogenase •Thiamine pyrophsophate as coenzyme (TPP; metabolite of Vitamin B1) 塞胺焦磷酸鹽當作輔酶 Lipoic acid (lipoate) 硫辛酸 •一種維他命,不像其他輔酶,是維他命的代謝物 •Act as an oxidizing agent, involves hydrogen transfer •Also in formation of a thioester linkage with acetyl group 1. 丙酮酸去氫酶 2. 二氫硫辛酸轉乙醯基酶 3. 二氫硫辛酸去氫酶 14 The conversion of pyruvate into acetyl CoA consists of three steps: 15 1. Decarboxylation • Pyruvate combines with TPP and is then carboxylated to yield hydroxyethyl-TPP • Catalyzed by the pyruvate dehydrogenase component 負碳離子 16 Fig 17.6 Mechanism of the E1 decarboxylation reaction 2. Oxidation • The hydroxyethyl-TPP is oxidized to form an acetyl group and transfer to lipoamide (lipoic acid linked to lysine by amide linkage) – Formation of an energy-rich thioester bond • Also catalyzed by the pyruvate dehydrogenase Two sulfhydryl group component (E1) Disulfide group oxided form reduced form Thioester linkage 17 3. Formation of Acetyl CoA • The acetyl group is transferred from acetyllipoamide to CoA and form acetyl CoA • Catalyzed by dihydrolipoyl transacetylase (E2) 18 Dihydrolipoamide is oxidized to lipoamide • Catalyzed by dihydrolipoyl dehydrogenase (E3) – 此酵素因具FAD, 故稱之為flavoprotein黃素蛋白 19 Flexible linkage allow lipoamide to move between different active sites lysine Fig 17.7 Schematic representation of the pyruvate dehydrogenase complex 8 20 Fig 17.8 Structure of the transacetylase (E2) core • 反應物與酵素彼此間非常的相近,所以反應的不同階段,可以更有效率的發生 • 硫辛酸與它所連結的離胺酸側鏈,有足夠長度可當成「擺動臂」(swinging arm), 藉此可以移動到反應的每個步驟應有的位置 21 Fig 17.9 Reaction of the pyruvate dehydrogenase complex 17.2 The citric acid cycle oxidizes Two-Carbon Units Step 1: Formation of Citrate 檸檬酸的形成 •The reaction of acetyl-CoA and oxaloacetate to form citrate and CoA-SH – Called a condensation because a new C-C bond formed – Catalyzede by the citrate synthase 檸檬酸合成酶(condensing enzyme縮合酵素) • A synthase is an enzyme that make a new covalent bond, but it does not require the direct input of ATP • An exergonic reaction 釋能反應 (hydrolysis of a thioester releases energy) aldol condensation hydrolysis 22 Mechanism: the mechanism of citrate synthase prevents undesirable reactions • Citrate synthase is a dimer of identical 49kd subunit – Oxaloacetate binds first, followed by acetyl CoA • Oxaloacetate induces a major structural rearrangement leading to the creation of a binding site for acetyl CoA Fig 17.11 Mechanism of synthesis of citryl CoA by citrate synthase 23 Step 2: Isomerization of citrate to Isocitrate 檸檬酸異構化成異檸檬酸 • Citrate is isomerized into isocitrate to undergo oxidative decarboxylation – Catalyzed by aconitase • An iron-sulfur protein, or nonheme-iron protein dehydration hydration 4Fe-4S iron-sulfur cluster 24 Step 3: Isocitrate is Oxidized and decarboxylated to α-ketoglutarate •The first of four oxidation-reduction reactions in the TCA cycle •Catalyzed by isocitrate dehydrogenase Isocitrate + NAD+ α-ketoglutarate +CO2 + NADH Oxidation Decarboxylation Unstable β-ketoacid 25 Step 4: succinyl coenzyme A is formed by the oxidative decarboxylated of α-ketoglutarate • The oxidative decarboxylation of α-ketoglutae closely resembles the of pyruvate α-ketoglutarate dehydrogenase 26 Step 5: Formation of Succinate • In mammals, there are two isozyme – One specific for ADP •Tissues perform large amounts of cellular respiration, such as skeletal and heart muscle – One specific for GDP •Tissues that are perform many anabolic reaction, such as liver succynyl-CoA synthetase ADP ATP GTP + ADP GDP + ATP Nucleoside diphosphokinase 27 Mechanism: succynyl-CoA synthetase transform types of biochemical energy • Energy in the thioester molecule is transfer into phosphory –roup-transfer potiential Displace Coenzyme A by orthophosphate Fig 17.13 Reaction mechanism of succinyl CoA synthetase 28 Step 6-8: Oxaloacetate is regenerated by the oxidation of succinate succinate dehydrogenase fumarase Hydration malate dehydrogenase 29 succinate dehydrogenase • An iron-sulfur protein – Three kinds of iron-sulfur cluster •2Fe-2S, 3Fe-4S and 4Fe-4S – Consists of a 70kd and a 27kd subunit – An integral protein of the inner mitochondrial membrane (the other enzymes are in the matrix) •Directly associated with the electron-transport chain 30 • Citric acid cycle Acetyl-CoA + 3NAD+ + FAD + ADP + Pi + 2H2O 2CO2 + CoA + 3NADH + 2H+ + FADH2 + ATP 31 32 Fig 17.15 The citric acid cycle 33 17.3 Entry to the citric acid cycle and metabolism through it are controlled The pyruvate dehydrogenase complex is regulated allosterically and by reversible phosphorylation • High concentration of reaction products inhibit the reaction – Acetyl CoA inhibits the transacetylase component (E2) – NADH inhibits the dihydrolipoyl dehydrogenase (E3) Fig 17.16 From glucose to 34 acetyl CoA Fig 17.18 Response of the pyruvate dehydrogenase complex to the energy charge •At rest, the muscle cell will not have significant energy demands – NADH/NAD+, acetyl CoA/CoA, ATP/ADP ratio will high deactivation of pyruvate dehydrogenase pyruvate dehydrogenase is switched off when the energy charge is high 35 Pyruvate dehydrogenase kinase I (PDKI) : Associated with the transacetylase component (E2) In some tissue, the phosphatase is regulated by hormones (14.1) In liver, epinephrine binds to the adrenergic receptor initiate the phosphatidylinositol pathway increase Ca2+ concentration activates the phosphatase In fatty acid synthesis tissue—liver, Pyruvate dehydrogenase phosphatase (PDP) adipose tissue insulin stimulates the phosphatase Fig 17.17 Regulation of the pyruvate dehydrogenase complex • In rest – NADH/NAD+, acetyl CoA/CoA, ATP/ADP ratio will high promote phosphorylation deactivation of pyruvate dehydrogenase • As exercise begins – ADP, pyruvate activate the dehydroganse by inhibiting kinase – Ca2+ stimulate phosphatase 36 The citric acid cycle is controlled at several points Citrate synthase (in bacteria) ATP Isocitrate dehydrogenase α-ketoglutarate dehydrogenase 37 Fig 17.19 Control of the citric acid cycle Control of the Citric Acid Cycle Proper •Three control points – The reaction catalyzed by citrate synthase, isocitrate dehydrogenase, and the α-ketoglutarate dehydrogenase complex – The first regulatory site -- Citrate synthase (In many bacteria) •An allosteric enzyme inhibited by ATP, NADH, succinyl-CoA and its own product citrate – The second regulatory site -- isocitrate dehydrogenase •Allosteric activator: ADP, NAD+ •Inhibited by ATP, NADH – The third regulatory site -- α-ketoglutarate dehydrogenase complex •Inhibited by ATP, NADH, succinyl-CoA 有些酵素的活性,會被它下游的產物所調節,是為 迴饋控制 (feedback) 現象;這類酵 素的分子上,除了有活性區可與其基質結合外,還有可與其下游產物結合的位置,稱 38 為調節區 (regulatory site),這種酵素則稱為異位酶 (allosteric enzyme) 。 Control mechanism Pyruvate dehydrogenase complex citrate synthase Isocitrate dehydrogenase -ketoglutarate dehydrogenase complex Fig 19.8 Control points in the conversion of pyruvate to acetyl-CoA and in the citric acid cycle 39 17.4 The citric acid cycle is a source of biosynthetic precusor Fig 17.20 Biosynthetic roles of the citric acid cycle 40 41 Fig. 19-15, p.570 Mitochondria Cytosol The various catabolic pathways that feed into the TCA cycle A summary of catabolism, showing the central role of the citric acid cycle42 Fig. 19-10, p.565 The citric acid cycle must be capable of being rapidly replenished • The TCA cycle is a source of starting materials for the biosynthesis of many important biomolecules – If a component of the citric acid cycle is taken out for biosynthesis, it must be replaced 中間產物被利用來合成其他 分子,之後這些中間產物就必須被補充 • [Oxaloacetate] maintained at a level sufficient to allow acetylCoA to enter the cycle • A reaction that replenishes a citric acid cycle intermediate is called anaplerotic reaction 回補反應 – 當身體能量過低時,TCA cycle中間產物不足時,體內一些 物質也會分解產生這些中間產物,以維持TCA cycle的活性 – In some organisms, acetyl-CoA can be converted to oxaloacetate by glyoxylate cycle – In mammals, oxalocacetate is produced from pyruvate by 43 pyruvate carboxylase (丙酮酸羧化酶) Fig 17.21 Pathway integration: pathway active during exercise after a night’s rest Pyruvate + CO2 +ATP + H2O oxaloacetate +ADP+ Pi + 2H+ 44 17.5 The Glyoxylate Cycle Enables Plants and Bacteria to Grow on Acetate • Some plants and bacteria can produce glucose from fatty acid – glyoxylate Cycle有些植物可以利用脂肪分 解而得的Acetyl-CoA以生成葡萄糖 --乙醛酸循環 • Two enzyme involved – Isocitrate lyase 異檸檬酸裂解酶 • Cleaves isocitrate, producing glyoxylate and succinate 將 異檸檬酸分解產生乙醛酸和琥珀酸 – Malate synthase 蘋果酸合成酶 • Catalyzes the reaction of glyoxylate with acetyl-CoA to produce malate 脂肪分解而得 45 Fig 17.23 The glyoxylate pathway 46 •The net reaction: 2 Acetyl CoA + NAD+ +2H2O succinate + 2 CoA +NADH + 2 H+ •The glyoxylate cycle takes place: – In plants: in glyoxysomes乙醛酸體, specialized organelles devoted to this cycle – In yeast and algae: in the cytoplasm •Helps plants grow in the dark: – Seeds are rich in lipids, which contain fatty acids – During germination, plants use the acetyl-CoA produced in fatty acid oxidation to produce oxaloacetate and other intermediates for carbohydrate synthesis (TCA cycle and glyoxylate cycle can operate simultaneously) – Once plants begin photosynthesis and can fix CO2, glyoxysomes disappear 47 48