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Chemistry 20 Chapter 19 & 20 Metabolic pathway & Energy production Metabolism Chemical reactions in cells that break down or build molecules. It produces energy and provide substances to cell growth. Catabolic reactions: Complex molecules Simple molecules + Energy Anabolic reactions: Simple molecules + Energy (in cell) Complex molecules Metabolism in cell Mitochondria Proteins Urea NH4+ Amino acids e Carbohydrates Polysaccharides Glucose Fructose Galactose Glucose Pyruvate Acetyl CoA Citric Acid cycle e CO2 & H2O Glycerol Lipids Fatty acids Step 1: Digestion and hydrolysis Step 2: Degradation and some oxidation Step 3: Oxidation to CO2, H2O and energy Cell Structure Nucleus Membrane Mitochondria Cytoplasm (Cytosol) Cell Structure Nucleus: consists the genes that control DNA replication and protein synthesis of the cell. Cytoplasm: consists all the materials between nucleus and cell membrane. Cytosol: fluid part of the cytoplasm (electrolytes and enzymes). Mitochondria: energy producing factories. Enzymes in matrix catalyze the oxidation of carbohydrates, fats , and amino acids. Produce CO2, H2O, and energy. ATP and Energy - Adenosine triphosphate (ATP) is produced from the oxidation of food. - Has a high energy. - Can be hydrolyzed and produce energy. ph os phoric ester O - O O O-P-O-P-O-P-O-CH2 O O O- O H H H ph os phoric 3 Phosphates anh yd rides HO OH NH2 N N N aden ine N -N -glycos idic b on d H -D-ribofuranose Ribose ATP and Energy O O O-P-O-P-O-AMP + H2 O O O- ATP O O-P-O-AMP + H2 PO4 - + 7.3 kcal/mol O AD P (adenosine triphosphate) Pi (adenosine diphosphate) (inorganic phosphate) - We use this energy for muscle contraction, synthesis an enzyme, send nerve signal, and transport of substances across the cell membrane. - 1-2 million ATP molecules may be hydrolysis in one second (1 gram in our cells). - When we eat food, catabolic reactions provide energy to recreate ATP. ADP + Pi + 7.3 kcal/mol ATP Step 1: Digestion Convert large molecules to smaller ones that can be absorbed by the body. Carbohydrates Lipids (fat) Proteins Digestion: Carbohydrates Salivary amylase Mouth Dextrins + Polysaccharides + Maltose Stomach Small intestine pH = 8 pH = 2 (acidic) Dextrins α-amylase (pancreas) Maltose Lactose Sucrose Bloodstream Glucose Maltase Lactase Sucrase Glucose Glucose + Galactose Glucose + Fructose Liver (convert all to glucose) Glucose + Digestion: Lipids (fat) Small intestine H2C Fatty acid HC Fatty acid H2C Fatty acid + 2H2O Triacylglycerol H2C lipase (pancreas) OH H2C OH HC Fatty acid + 2 Fatty acids Monoacylglycerol Intestinal wall Monoacylglycerols + 2 Fatty acids → Triacylglycerols Protein Lipoproteins Chylomicrons Lymphatic system Bloodstream Cells Enzymes hydrolyzes Glycerol + 3 Fatty acids liver Glucose Digestion: Proteins Pepsinogen HCl Pepsin Stomach Proteins denaturation + hydrolysis Polypeptides Small intestine Typsin Chymotrypsin Polypeptides Intestinal wall Bloodstream Cells hydrolysis Amino acids Some important coenzymes oxidation Coenzyme + Substrate Coenzyme(+2H) + Substrate(-2H) Reduced 2 H atoms 2H+ + 2e- NAD+ Coenzymes Oxidized FAD Coenzyme A NAD+ Nicotinamide adenine dinucleotide The p lus sign on N A D + represents th e positive ch arge on this n itrogen O CNH2 O - O-P-O-CH2 O ADP AMP H N+ O H H H HO N icotinamide; derived from niacin (vitamin) OH Ribose a -N-glycosidic bond NAD+ - Is a oxidizing agent. - Participates in reactions that produce (C=O) such as oxidation of alcohols to aldehydes and ketones. O CH3-CH2-OH + NAD+ CH3-C-H + NADH + H+ NAD+ + 2H+ + 2e- NADH + H+ H O C NH2 + H+ + 2 e- NH2 : + H H O C N Ad NAD+ N Ad N AD H FAD Flavin adenine dinucleotide O H3 C N H3 C N N N Riboflavin CH2 (Vitamin B2) H C OH H C OH H C OH CH2 O O=P-O-AMP OADP H Flavin O Ribitol (sugar alcohol) FAD - Is a oxidizing agent. - Participates in reaction that produce (C=C) such as dehydrogenation of alkanes. H H R-C-C-R + FAD HH R-C=C-H + FADH2 H H O H3 C H3 C N N N Ad FAD NH O H3 C H N O + 2 H+ + 2 e H3 C N N Ad H FAD H2 NH O Coenzyme A (CoA) HS-CoA Coenzyme A Aminoethanethiol ( vitamin B5) Coenzyme A (CoA) - It activates acyl groups, particularly the acetyl group. O O CH3-C- + HS-CoA CH3-C-S-CoA Acetyl group Coenzyme A Acetyl CoA Metabolism in cell Mitochondria Proteins Urea NH4+ Amino acids e Carbohydrates Polysaccharides Glucose Fructose Galactose Glucose Pyruvate Acetyl CoA Citric Acid cycle e CO2 & H2O Glycerol Lipids Fatty acids Step 1: Digestion and hydrolysis Step 2: Degradation and some oxidation Step 3: Oxidation to CO2, H2O and energy Step 2: Glycolysis - We obtain most of our energy from glucose. - Glucose is produced when we digest the carbohydrates in our food. - We do not need oxygen in glycolysis (anaerobic process). 2 ADP + 2Pi 2 ATP C6H12O6 + 2 NAD+ O 2CH3-C-COO- + 2 NADH + 4H+ Glucose Pyruvate Inside of cell Pathways for pyruvate - Pyruvate can produce more energy. Aerobic conditions: if we have enough oxygen. Anaerobic conditions: if we do not have enough oxygen. Aerobic conditions - Pyruvate is oxidized and a C atom remove (CO2). - Acetyl is attached to coenzyme A (CoA). - Coenzyme NAD+ is required for oxidation. OO O CH3-C-C-O- + HS-CoA + NAD+ pyruvate Coenzyme A CH3-C-S-CoA + CO2 + NADH Acetyl CoA Important intermediate product in metabolism. Anaerobic conditions - When we exercise, the O2 stored in our muscle cells is used. - Pyruvate is reduced to lactate. - Accumulation of lactate causes the muscles to tire and sore. - Then we breathe rapidly to repay the O2. - Most lactate is transported to liver to convert back into pyruvate. OO CH3-C-C-O- NADH + H+ NAD+ HO O CH3-C-C-OH pyruvate Lactate Reduced Glycogen - If we get excess glucose (from our diet), glucose convert to glycogen. - It is stored in muscle and liver. - We can use it later to convert into glucose and then energy. - When glycogen stores are full, glucose is converted to triacylglycerols and stored as body fat. Metabolism in cell Mitochondria Proteins Urea NH4+ Amino acids e Carbohydrates Polysaccharides Glucose Fructose Galactose Glucose Pyruvate Acetyl CoA Citric Acid cycle e CO2 & H2O Glycerol Lipids Fatty acids Step 1: Digestion and hydrolysis Step 2: Degradation and some oxidation Step 3: Oxidation to CO2, H2O and energy Step 3: Citric Acid Cycle - Is a central pathway in metabolism. - Uses acetyl CoA from the degradation of carbohydrates, lipids, and proteins. - Two CO2 are given off. - There are four oxidation steps in the cycle provide H+ and electrons to reduce FAD and NAD+ (FADH2 and NADH). 8 reactions Reaction 1 Formation of Citrate O Acetyl CoA CH3-C-S-CoA + COOC=O Oxaloacetate CH2 COO- COOCH2 H2O HO C COO- + CoA-SH CH2 COOCitrate Coenzyme A Reaction 2 Isomerisation to Isocitrate - Because the tertiary –OH cannot be oxidized. (convert to secondary –OH) HO COO- COO- CH2 CH2 C COO- CH2 COOCitrate Isomerisation H C COO- HO C H COOIsocitrate Reaction 3 First oxidative decarboxylation (CO2) - Oxidation (-OH converts to C=O). - NAD+ is reduced to NADH. - A carboxylate group (-COO-) is removed (CO2). H HO COO- COO- COO- CH2 CH2 CH2 C CH2 -COO- - NAD + NADH + H+ COO- H C-COO H COO- C isocitrate H COO - dehydrogenase O CHO CHC Isocitrate -COOCOO - CO CH -COO CH2 -COO 2 2 Isocitrate H C-COO - CH2 CO2 O C COO- α-Ketoglutrate H C-H - Reaction 4 Second oxidative decarboxylation (CO2) - Coenzyme A convert to succinyl CoA. - NAD+ is reduced to NADH. - A second carboxylate group (-COO-) is removed (CO2). COOCH2 2 CHCH -COO 2 O CHC 2 COO-O C-COO α-Ketoglutrate -Ketoglutarate COOCH2 CoA -SH N AD + N ADH -ketoglutarate dehydrogenase complex CH2 CH2 -COO + CO2 O C CH + CO 2 2 S-CoA O C SCoA Succinyl CoA Succinyl-CoA Reaction 5 Hydrolysis of Succinyl CoA - Energy from hydrolysis of succinyl CoA is used to add a phosphate group (Pi) to GDP (guanosine diphosphate). - Phosphate group (Pi) add to ADP to produce ATP. COO- COO- CH2 CH2 -COO + Pi FAD - ADP + Pi CH2 + H2O + GDP CH2 -COO O C Succinate HCH COOC2 ATPH2 FAD succinate dehydrogenase - C OOC CH H 2 Fumarate COO- S-CoA Succinyl CoA Succinate + GTP + CoA-SH Reaction 6 Dehydrogenation of Succinate - H is removed from two carbon atoms. - Double bond is produced. - FAD is reduced to FADH2. COOCH2 CH2 -COO CHCH 2 -COO 2 COO Succinate Succinate COOFAD H FAD H2 succinate dehydrogenase - C CH COO C CH OOC H COOFumarate Fumarate Reaction 7 Hydration - Water adds to double bond of fumarate to produce malate. COOCH CH COOFumarate H 2O COOHO C H CH2 COOMalate Reaction 8 Dehydrogenation forms oxaloacetate - -OH group in malate is oxidized to oxaloacetate. - Coenzyme NAD+ is reduced to NADH + H+. COOHO CHCOO H HO C CH2 -COO CH2 L-Malate COOMalate COON AD + N AD H + HO+ C-COO C=O CH2CH -COO malate 2 dehydrogenase Oxaloacetate COO- Oxaloacetate Summary The catabolism of proteins, carbohydrates, and fatty acids all feed into the citric acid cycle at one or more points: Proteins Carbohydrates Fatty Acids Pyruvate Acetyl-CoA Oxaloacetate -Ketoglutarate Succinyl-CoA Fumarate Malate intermediates of the citric acid cycle Summary Acetyl -CoA CoA H + + N AD H N AD + Citric acid cycle (8 steps) CoA FAD H2 N AD + + N AD H + H CO 2 N AD + FAD GTP GDP N AD H + H + CO 2 O CH3 C-SCo A + GD P + Pi + 3 N AD + + FAD + 2 H2 O 2 CO 2 + CoA + GT P + 3 N AD H + FAD H2 + 3 H+ 12 ATP produced from each acetyl-CoA Electron Transport H+ and electrons from NADH and FADH2 are carried by an electron carrier until they combine with oxygen to form H2O. FMN (Flavin Mononucleotide) Fe-S clusters Electron carriers Coenzyme Q (CoQ) Cytochrome (cyt) FMN (Flavin Mononucleotide) H O Riboflavin (Vitamin B2) H3 C N H3 C N N N O H Flavin O 2H+ + 2e- CH2 H C OH H C OH H C OH CH2 H3 C N H3 C N Riboflavin Ribitol (sugar alcohol) N N CH2 H H C OH H C OH H C OH CH2 O O=P-O-AMP O- O O=P-O-AMP O- FMN + 2H+ + 2e- → FMNH2 Reduced H Flavin O Ribitol Fe-S Clusters Cys S S S Cys S + 1 e- Fe3+ Cys Cys S Cys Fe3+ + 1e- S Cys S Cys Fe2+ Cys S Fe2+ Reduced Coenzyme Q (CoQ) OH 2H+ + 2e- OH Coenzyme Q Reduced Coenzyme Q (QH2) Q + 2H+ + 2e- → QH2 Reduced Cytochromes (cyt) - They contain an iron ion (Fe3+) in a heme group. - They accept an electron and reduce to (Fe2+). - They pass the electron to the next cytochrome and they are oxidized back to Fe3+. Fe3+ + 1eOxidized Fe2+ Reduced cyt b, cyt c1, cyt c, cyt a, cyt a3 Electron Transfer Mitochondria Electron Transfer Complex I NADH + H+ + FMN → NAD+ + FMNH2 FMNH2 + Q → QH2 + FMN NADH + H+ + Q → QH2 + NAD+ Complex II FADH2 + Q → FAD + QH2 Electron Transfer Complex III QH2 + 2 cyt b (Fe3+) → Q + 2 cyt b (Fe2+) + 2H+ Complex IV 4H+ + 4e- + O2 → 2H2O Oxidative Phosphorylation Transport of electrons produce energy to convert ADP to ATP. ADP + Pi + energy → ATP Chemiosmotic model - H+ make inner mitochondria acidic. - Produces different proton gradient. - H+ pass through ATP synthase (a protein complex). ATP synthase Total ATP Glycolysis: 6 ATP Pyruvate: 6 ATP Citric acid cycle: 24 ATP Oxidation of glucose 36 ATP C6H12O6 + 6O2 + 36 ADP + 36 Pi → 6CO2 + 6H2O + 36 ATP Metabolism in cell Mitochondria Proteins Urea NH4+ Amino acids e Carbohydrates Polysaccharides Glucose Fructose Galactose Glucose Pyruvate Acetyl CoA Citric Acid cycle e CO2 & H2O Glycerol Lipids Fatty acids Step 1: Digestion and hydrolysis Step 2: Degradation and some oxidation Step 3: Oxidation to CO2, H2O and energy Oxidation of fatty acids α O CH3-(CH2)14-CH2-CH2-C-OH oxidation - Oxidation happens in step 2 and 3. - Each beta oxidation produces acetyl CoA and a shorter fatty acid. - Oxidation continues until fatty acid is completely break down to acytel CoA. Oxidation of fatty acids Fatty acid activation - Before oxidation, they activate in cytosol. O O R-CH2-C-OH + ATP + HS-CoA Fatty acid R-CH2-C-S-CoA + H2O + AMP + 2Pi Fatty acyl CoA -Oxidation: 4 reactions Reaction 1: Oxidation (dehydrogenation) HHO O H R-CH2-C-C-C-S-CoA + FAD H H R-CH2-C=C-C-S-CoA + FADH2 H Fatty acyl CoA Reaction 2: Hydration O H R-CH2-C=C-C-S-CoA + H2O H HO H O R-CH2-C-C-C-S-CoA H H Reaction 3: Oxidation (dehydrogenation) HO H O O R-CH2-C-C-C-S-CoA + NAD+ O R-CH2-C-CH2-C-S-CoA + NADH+ H+ H H Reaction 4: Cleavage of Acetyl CoA O O R-CH2-C-CH2-C-S-CoA + CoA-SH O O R-CH2-C-S-CoA + CH3-C-S-CoA Fatty acyl CoA Acetyl CoA Oxidation of fatty acids One cycle of -oxidation O R-CH2-CH2-C-S-CoA + NAD+ + FAD + H2O + CoA-SH O O R-C-S-CoA + CH3-C-S-CoA + NADH + H+ + FADH2 Fatty acyl CoA # of Acetyl CoA = Acetyl CoA # of fatty acid carbon 2 = 1 + oxidation cycles Ketone bodies - If carbohydrates are not available to produce energy. - Body breaks down body fat to fatty acids and then Acetyl CoA. - Acetyl CoA combine together to produce ketone bodies. - They are produced in liver. - They are transported to cells (heart, brain, or muscle). O CH3-C-S-CoA O CH3-C-S-CoA Acetyl CoA Acetone O O O CH3-C-CH2-C-O- CH3-C-CH3 + CO2 + energy OH Acetoacetate O CH3-CH-CH2-C-O-Hydroxybutyrate Ketosis (disease) - When ketone bodies accumulate and they cannot be metabolized. - Found in diabetes and in high diet in fat and low in carbohydrates. - They can lower the blood pH (acidosis). - Blood cannot carry oxygen and cause breathing difficulties. Fatty acid synthesis - When glycogen store is full (no more energy need). - Excess acetyl CoA convert to 16-C fatty acid (palmitic acid) in cytosol. - New fatty acids are attached to glycerol to make triacylglycerols. (are stored as body fat) Metabolism in cell Mitochondria Proteins Urea NH4+ Amino acids e Carbohydrates Polysaccharides Glucose Fructose Galactose Glucose Pyruvate Acetyl CoA Citric Acid cycle e CO2 & H2O Glycerol Lipids Fatty acids Step 1: Digestion and hydrolysis Step 2: Degradation and some oxidation Step 3: Oxidation to CO2, H2O and energy Degradation of amino acids - They are degraded in liver. Transamination: - They react with α-keto acids and produce a new amino acid and a new α-keto acid. + NH3 CH3-CH-COO- O + + NH3 O pyruvate 2-CH2-COO α-ketoglutarate alanine CH3-C-COO- -OOC-C-CH + -OOC-CH-CH -CH -COO2 2 glutamate Degradation of amino acids Oxidative Deamination + NH3 -OOC-CH-CH -CH -COO2 2 + H2O + NAD+ glutamate dehydrogenase glutamate O -OOC-C-CH 2-CH2-COO α-ketoglutarate + NH4+ + NADH + H+ Urea cycle - Ammonium ion (NH4+) is highly toxic. - Combines with CO2 to produce urea (excreted in urine). - If urea is not properly excreted, BUN (Blood Urea Nitrogen) level in blood becomes high and it build up a toxic level (renal disease). - Protein intake must be reduced and hemodialysis may be needed. O 2NH4+ + CO2 H2N-C-NH2 + 2H+ + H2O urea Energy from amino acids - C from transamination are used as intermediates of the citric acid cycle. - amino acid with 3C: pyruvate - amino acid with 4C: oxaloacetate - amino acid with 5C: α-ketoglutarate - 10% of our energy comes from amino acids. - But, if carbohydrates and fat stores are finished, we take energy from them.