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4. Oxaloacetate. 6. Citrate. 4. Malate. Isocitrate. 6. CH 3 C. S-CoA. ~. O. CO 2. CO 2. 4. Fumarate. 5. a -ketoglutarate. 4. 4. Succinate. Succinyl-CoA. ENERGY YIELD. NADH + H +. 3 ATP. 3 ATP. 1 ATP. 2 ATP. NADH + H +. 3 ATP. FADH 2. Total = 12 ATP. NADH + H +. GTP.
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4 Oxaloacetate 6 Citrate 4 Malate Isocitrate 6 CH3C S-CoA ~ O CO2 CO2 4 Fumarate 5 a-ketoglutarate 4 4 Succinate Succinyl-CoA ENERGY YIELD NADH + H+ 3 ATP 3 ATP 1 ATP 2 ATP NADH + H+ 3 ATP FADH2 Total = 12 ATP NADH + H+ GTP
CH2-COO HO-C-COO CH2-COO CH2COO CH2COO C C OH HO Aconitase Prochirality Symmetrical OOC COO CH2COO CH2-COO Ogston’s 3 Point Attachment Theory
Ogston’s Three-point Attachment Theory of Aconitase Test this yourself Middle Index Right Hand Thumb Only your right hand will fit the pattern. Therefore, only one of the isomers of citrate will fit on the enzyme surface in the correct orientation
Glyoxylate Cycle (germinating plant seeds) H Starch H-C-COO Oxaloacetate Citrate H-C-COO .. HO-C-COO H Malate Isocitrate CH3C S-CoA ~ O CO2 CO2 CHO Fumarate a-ketoglutarate COO COO- Bypass CH2 CH2 Succinate Succinyl-CoA COO- Glyoxysomes (plant organelles) Malate Synthase Isocitrate Lyase Glyoxylate All 6 carbons are preserved Mitochondria
Glyoxysome FADH2 NADH Acetyl-CoA NAD+ FAD HS-CoA Acetyl-CoA HS-CoA NAD+ NADH Mitochondria Aspartate Aspartate -Ketoglutarate -Ketoglutarate Glutamate Glutamate Oxaloacetate Oxaloacetate Malate Citrate Fumarate Isocitrate Isocitrate lyase Glyoxylate Succinate Succinate Malate synthase Malate P 625 OAA Gluconeogenesis Starch
9 ATPs 2 ATPs 1 ATP 6 4 2
4 Carbons to Citrate Where do we get all that energy? 1. How energetic is citrate? 6 Carbons = 3 Cycle Turns = 3 x 12 ATP per cycle = 36 ATPs 2. How energetic is oxaloacetate = 2 Cycle turns = 24 ATPs 3. How energetic is malate 4 Carbons = 2 Cycle turns + 1 NADH = 27 ATPs
Regulators-Activators Regulators- Inhibitors Regulation of the Kreb’s Cycle Pyruvate Dehydrogenase complex Pyruvate + TPP Acetal-TPP + CO2 Acetal-TPP + S-S Ac-S ^ SH + TPP Ac-S ^ SH + HS-CoA AcS-CoA + HS ^ SH HS ^ SH + FAD S-S + FADH2 FADH2 + NAD+ FAD + NADH + H+ Pyruvate + HS-CoA + NAD+ Acetyl-CoA + NADH + H+ Fatty acids and ATP and AMP
NADH [NAD+] Acetyl-CoA HS-CoA Key Regulatory Points: 1. Pyruvate dehydrogenase Complex Inhibited by NADH and Acetyl-CoA High NADH means that the cell is experiencing a surplus of oxidative substrates and should not produce more. Carbon flow should be redirected towards synthesis. High Acetyl-CoA means that carbon flow into the Krebs cycle is abundant and should be shut down and rechanneled towards biosynthesis
Mechanism: Active TPP FAD HPO4= ATP E1-OH 3 1 2 PDH phosphatase PDH kinase Cyclic-AMP protein kinase Insulin E1-OPO3 ADP ATP H2O Inactive Text p621 1. Competitive Inhibition NADH and acetyl-CoA reverse the pyruvate dehydrogenase reaction by competing with NAD+ and HS-CoA 2. Covalent Modification (second level regulation) E-1 subunits of PDH complex is subject to phosphorylation Epinephrine Glucagon
Regulation of Cycle Enzymes Go’ (kJ/mol) Enzyme Citrate Synthase -31.5 Aconitase ~5 Isocitrate dehydrogenase -21 -Ketoglutarate dehydrogenase -33 Succinyl-CoA Synthase -2.1 Succinate dehydrogenase +6 Fumarase -3.4 Malate dehydrogenase +29.7 All regulatory enzymes occur in the first half of the cycle
Regulation of the Citric Acid Cycle Primary modes: 1. Substrate availability (key enzymes are subsaturated) Allostery is not a primary mode 2. Product inhibition 3. Feedback inhibition (competitive) Key regulators: 1. Acetyl-CoA (controls citrate synthase) 2. OAA (controls citrate synthase, regulated by NADH) 3. NADH (controls citrate synthase, isocitrate dehydrogenase 4. Calcium (stimulates NADH production)
Equilibria to Consider O2 consumption NADH oxidation Controls NADH and is controlled by NADH ATP production Tightly coupled: affect one is to affect all OAA + NADH Malate + NAD+ A working muscle will increase respiration and oxidize NADH. This stimulates OAA synthesis which stimulates citrate synthase and isocitrate dehydrogenase reactions.
OAA + NADH Malate + NAD+ K = [OAA][NADH] Citrate Isocitrate dehydrogenase [Malate][NAD+] -Kg dehydrogenase K [Malate][NAD+] [OAA][NADH] Respiration (O2) Substrate limited Respiration Increases
P 621 Pyruvate Dehydrogenase Citrate Synthase No Regulation Isocitrate Dehydrogenase -Ketoglutarate Dehydrogenase