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OBJECTIVES Identify the key steps in citric cycle acid Describe how TCA is regulated Illustrate biomedical importance of TCA Explain energy yield from TCA. CITRIC ACID CYCLE (TCA CYCLE OR KREBS CYCLE) Pyruvate Acetyl-CoA Acetate CO2 CITRIC ACID CYCLE Oxidizing acetyl-CoA from glucose, lipid and protein catabolism in aerobic respiration to maximize energy gain The cycle supplies precursors for biosynthesis THREE STAGES OF CELLULAR RESPIRATION STAGE 1 Acetyl CoA production from glucose, fatty acids and amino acids STAGE 2 Acetyl CoA oxidation =TCA Cycle = yielding reduced electron carriers STAGE 3 Electron transport and oxidative phosphorylation oxidation of these carriers and production of ATP MANY CATABOLIC PATHWAYS YIELD ACETYL COA FOR THE TCA CYCLE glycogen glucose lactate Pyruvate fatty acids amino acids Acetyl-CoA TCA (Note: AA more than one entry point) Space filled Acetyl CoA A high energy bond Acetyl HS-CoA STAGE 1 Pyruvate (PDH) Acetyl-CoA (PYRUVATE DEHYDROGENASE COMPLEX) Location = Mitochondrial matrix CH3 CH3 C=O + NAD++ HS-CoA C=O +NADH+CO2 COOS-CoA Pyruvate Acetyl-CoA (A high energy compound) IRREVERSIBLE Irreversible means acetyl-CoA cannot be converted backward to Pyruvate Hence “fat cannot be converted to carbohydrate” PYRUVATE DEHYDROGENASE COMPLEX TPP E1 S-S-E2 FAD E3 N A D+ REGULATION OF PYRUVATE DEHYDROGENASE Irreversible reaction must be tightly controlled-- three ways 1. Allosteric Inhibition Inhibited by products: Acetyl-CoA, NADH ATP 2. Allosteric activation AMP Ratio ATP/AMP important Overall Reaction in the TCA cycle ACETYL-COA + 3NAD+ + FAD + GDP + Pi+2H2O 2CO2 + 3NADH + FADH2 + GTP + 2H+ + CoA Both carbons oxidized One GTP Three NADH One FADH2 1- CONDENSING ACETYL-COA WITH OXALOACETATE ACETYL COA O=C-SCoA CH3 + O=C-COO CH2 COOOXALOACETATE H2O CITRATE SYNTHASE COO- + CoASH CH2 + H+ HO-C-COOCH2 COO CITRATE ENZYME:CITRATE SYNTHASE 2 - CITRATEISOCITRATE VIA CIS-ACONITATE CH2-COO- -H2O CH2COO +H2O CH2-COOHOC-COOC-COO H-C-COOCH2-COOH-C-COOHOC-COOCITRATE CIS–ACONITATE ENZYME: ACONITASE ISOCITRATE 3- OXIDATION OF ISOCITRATE TO -KETOGLUTARATE First oxidation in TCA cycle COOCOOCH2 NAD+ NADH CH2 + CO2 HC-COOCH2 HOCH O=C COOCOOISOCITRATE -KETOGLUTARATE ENZYME = ISOCITRATE DEHYDROGENASE ISOCITRATE DEHYDROGENASE Two isoforms One uses NAD+; other NADP+ Reduction to NADH or to NADPH Energy is later derived from these electron carrying molecules -- loss of first CO2 -- Note OH to =O 4- OXIDATION OF -KETOGLUTARATE TO SUCCINYL-COA AND CO2 Second oxidation in TCA cycle -KETOGLUTARATE COOCH2 CH2 O=C COO- NAD+ SUCCINYL COA COO- + CO2 NADH CH2 CH2 O=C SCoA + CoA-SH ENZYME = - KETOGLUTARATE DEHYDROGENASE COMPLEX - KETOGLUTARATEDEHYDROGENASE COMPLEX Loss of second of two CO2 Similar to Pyruvate Acetyl-CoA Enzyme is similar to Pyruvate dehydrogenase complex 5- SUCCINYL COA TO SUCCINATE succinyl-CoA + GDP + Pi COOCH2 + CoA-SH + CH2 GTP COOSUCCINATE --- SUBSTRATE LEVEL PHOSPHORYLATION GTP is equivalent to ATP; GTP to ATP by NUCLEOSIDE DIPHOSPHOKINASE ENZYME = SUCCINYL COA SYNTHETASE 6- OXIDATION OF SUCCINATE TO FUMARATE FLAVIN DEPENDENT OXIDATION Third oxidation of TCA cycle, FAD in flavoprotein reduced to FADH2 COOCOOCH2 + E3-FAD CH + E3-FADH2 CH2 COOHC-COOSUCCINATE FUMARATE Dehydrogenation; note double bond ENZYME = SUCCINATE DEHYDROGENASE 7- HYDRATION COOCH +H2O HC COO-H2O FUMARATE COOHOCH HCH COOL-MALATE ENZYME = FUMARASE 8- OXIDATION OF MALATE TO OXALOACETATE - COO HO CH CH2 COOMALATE - NAD + COO NADH C=O CH2 COOOXALOACETATE FOURTH OXIDATION: another pair of electrons is made available in NADH ENZYME = MALATE DEHYDROGENASE SUMMARY FIRST HALF Introduction of two carbon atoms and their loss, yielding 2 NADH and a GTP (ATP) SECOND HALF Partial oxidation of succinate to oxaloacetate. Another NADH is produced as well as a reduced FADH2 OXALOACETATE IS REGENERATED FOR NEXT CYCLE Overall Reaction Acetyl-CoA+3NAD++FAD+GDP+Pi+2H2O 2CO2 + 3NADH + FADH2 +GTP+2H++CoA One high energy compound made Four pairs of electrons are made available to the respiratory chain and oxidative phosphorylation. These are used to generate most of the ATP needed. What is the maximum yield of high energy ATP in the aerobic catabolism of glucose? Glycolysis: glucose 2pyruvate + 2NADH+2ATP 8 ATPs Pyruvate Dehydrogenase: 2pyruvate 2acetyl CoA + 2NADH 6 ATPs TCA cycle: acetyl CoA2CO2+3NADH+FADH2+GTP 2x12ATPs OVERALL YIELD FROM GLUCOSE 38 ATPs ENERGY RELATIONSHIPS This represents 41% conservation of the potential energy available in glucose as ATP REGULATION OF CITRIC ACID CYCLE FOUR WAYS 1- PYRUVATE DEHYDROGENASE -- Inhibited by acetyl-CoA and NADH 2- CITRATE SYNTHASE -- Substrate = oxaloacetate -- limited 3- ISOCITRATE DEHYDROGENASE -- Activated allosterically by ADP -- Inhibited allosterically by NADH 4- - KETOGLUTARATE DEHYDROGENASE -- Inhibited allosterically by products = succinyl-CoA and NADH REGULATION OF CITRIC ACID CYCLE Major regulator is intramitochondrial NAD+/NADH ratio REPLACEMENT OF INTERMEDIATES Intermediates are removed for biosynthesis 1- AMPHIBOLIC reactions (Removal of intermediates) 2- ANAPLEROTIC reactions (Replacing cyclic intermediates) AMPHIBOLIC PATHWAYS A- TRANSAMINASES oxaloacetate Asp removes 4C -ketoglutarate Glu removes 5C pyruvate Ala removes 6C B- FATTY ACID BIOSYNTHESIS citrate Acetyl CoA and oxaloacetate acetyl CoA can build fatty acids C- HEME BIOSYNTHESIS succinyl CoA + glycine Porphyrins ANAPLEROTIC REACTIONS A- PYRUVATE CARBOXYLASE – Replaces oxaloacetate- most important, especially in liver and kidney O CH3-C-COO- + CO2 + ATP O -OOC-CH C-COO- + ADP + P 2 i oxaloacetate B- MALIC ENZYME Replaces malate-- pyruvate + CO2 +NADPHmalate + NADP+ C- FROM AMINO ACIDS Reversals of transaminations--restores oxaloacetate or a-ketoglutarate with abundant Asp or Glu Glutamate dehydrogenase Glu + NAD(P)+ a-ketoglutarate + NAD(P)H + NH4+ NADH acetyl CoA NAD+ oxalocitrate synthase MDH acetate l-malate citrate H2O fumarase aconitase H2O fumarate 2-step FADH2 succinate dehydrogenase isocitrate FAD NAD+ succinate TCA IDH NADH CoASH GTP succinate-CoA synthetase CO2 GDP+ Pi succinyl CoA NADH NAD+ CO2 -ketoglutarate -KGDH CoASH
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