KEY CONCEPTS: Section 14-1

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Presentation transcript:

KEY CONCEPTS: Section 14-1 The pyruvate dehydrogenase complex includes three types of enzymes that collectively remove a carboxylate group from pyruvate and produce acetyl-CoA and NADH. © 2014 John Wiley & Sons, Inc. All rights reserved.

The Pyruvate Dehydrogenase Reaction Surface View Cutaway View Model of the pyruvate dehydrogenase complex from B. stearothermophilus © 2014 John Wiley & Sons, Inc. All rights reserved.

The whole 60 subunit complex 24 subunit E2 core 24 E1 (orange) + 12 E3 subunits (red) Pyruvate Dehydrogenase: Bacterial, 4.6 Megadaltons larger than a ribosome. Mammalian, ~twice as large Vitamin rich. (thiamine pyrophosphate (TPP), lipoic acid, NAD, FAD, CoA)

The pyruvate dehydrogenase complex works in 5 steps. E1 decarboxylates pyruvate; CO2 is released. A leftover hydroxyethyl group is transferred to E2. An acetyl group is transferred to CoA. E2 is restored. E3 is restored and NADH is produced. © 2014 John Wiley & Sons, Inc. All rights reserved.

E1 of pyruvate dehydrogenase uses thiamine pyrophosphate. Thiamin = Vitamin B1 Cofactor for several decarboxylation reactions © 2014 John Wiley & Sons, Inc. All rights reserved.

Step 1: Decarboxylation of Pyruvate © 2014 John Wiley & Sons, Inc. All rights reserved.

E2 uses a lipoamide cofactor. Disulfide bond = active portion © 2014 John Wiley & Sons, Inc. All rights reserved.

Step 2: Transfer from E1 to E2 © 2014 John Wiley & Sons, Inc. All rights reserved.

Step 3: Acetyl Transfer to CoA © 2014 John Wiley & Sons, Inc. All rights reserved.

© 2014 John Wiley & Sons, Inc. All rights reserved. Step 4: Restoration of E2 E3 uses a disulfide bond and an FAD cofactor Lipoamide is oxidized by E3’s disulfide © 2014 John Wiley & Sons, Inc. All rights reserved.

© 2014 John Wiley & Sons, Inc. All rights reserved. Step 5: Restoration of E3 Electrons move to FAD to form FADH2. Electrons move from FADH2 to NAD+ to form NADH and H+. E3 is restored to its oxidized state. © 2014 John Wiley & Sons, Inc. All rights reserved.

Summary of the Pyruvate Dehydrogenase Reactions © 2014 John Wiley & Sons, Inc. All rights reserved.

G ~ -30kJ/mol for hydrolysis of acetyl-CoA, so net reaction is about zero.

KEY CONCEPTS: Section 14-2 The citric acid cycle is a set of eight reactions in which an acetyl group is condensed with oxaloacetate, two CO2 are lost, and oxaloacetate is regenerated. Each round of the citric acid cycle generates three NADH, one QH2, and one GTP or ATP. Flux through the citric acid cycle is regulated primarily by feedback inhibition at three steps. The citric acid cycle likely evolved by the combination of oxidative and reductive pathways. © 2014 John Wiley & Sons, Inc. All rights reserved.

Overview of the Citric Acid Cycle © 2014 John Wiley & Sons, Inc. All rights reserved.

Reaction 1: Citrate Synthase Adds an Acetyl Group to Oxaloacetate © 2014 John Wiley & Sons, Inc. All rights reserved.

© 2014 John Wiley & Sons, Inc. All rights reserved. Citrate synthase undergoes a conformational change upon binding oxaloacetate, allowing for binding of acetyl-CoA. No Substrates Bound Substrates Bound © 2014 John Wiley & Sons, Inc. All rights reserved.

© 2014 John Wiley & Sons, Inc. All rights reserved. Citrate synthase is one of a few enzymes that can synthesize a C-C bond without a metal ion cofactor. Let’s look at the mechanism of citrate synthase… © 2014 John Wiley & Sons, Inc. All rights reserved.

Citrate Synthase Mechanism © 2014 John Wiley & Sons, Inc. All rights reserved.

Citrate Synthase Mechanism © 2014 John Wiley & Sons, Inc. All rights reserved.

Citrate Synthase Mechanism © 2014 John Wiley & Sons, Inc. All rights reserved.

Citrate Synthase Mechanism © 2014 John Wiley & Sons, Inc. All rights reserved.

Reaction 2: Aconitase Isomerizes Citrate to Isocitrate © 2014 John Wiley & Sons, Inc. All rights reserved.

Reaction 3: Isocitrate Dehydrogenase Releases the First CO2 © 2014 John Wiley & Sons, Inc. All rights reserved.

Reaction 4: α-Ketoglutarate Dehydrogenase Releases the Second CO2 © 2014 John Wiley & Sons, Inc. All rights reserved.

Fates of Carbons in the Citric Acid Cycle The two carbons released in the 1st round of the citric acid cycle did not come from acetyl-CoA. Carbon from Acetyl-CoA © 2014 John Wiley & Sons, Inc. All rights reserved.

© 2014 John Wiley & Sons, Inc. All rights reserved. Reaction 5: Succinyl-CoA Synthetase Catalyzes Substrate Level Phosphorylation © 2014 John Wiley & Sons, Inc. All rights reserved.

Reaction 6: Succinate Dehydrogenase Generates Ubiquinol © 2014 John Wiley & Sons, Inc. All rights reserved.

Reaction 7: Fumarase Catalyzes a Hydration Reaction © 2014 John Wiley & Sons, Inc. All rights reserved.

Reaction 8: Malate Dehydrogenase Regenerates Oxaloacetate © 2014 John Wiley & Sons, Inc. All rights reserved.

The citric acid cycle is an energy-generating cycle. 1 NADH = 2.5 ATP 1 QH2 = 1.5 ATP © 2014 John Wiley & Sons, Inc. All rights reserved.

Regulation occurs at the three irreversible steps. © 2014 John Wiley & Sons, Inc. All rights reserved.

KEY CONCEPTS: Section 14-3 The citric acid cycle supplies precursors for the synthesis of other compounds. Citric acid cycle intermediates can be replenished. © 2014 John Wiley & Sons, Inc. All rights reserved.

Citric acid cycle intermediates are precursors of other molecules. © 2014 John Wiley & Sons, Inc. All rights reserved.

© 2014 John Wiley & Sons, Inc. All rights reserved. An Example of Amino Acid Formation from a Citric Acid Cycle Intermediate © 2014 John Wiley & Sons, Inc. All rights reserved.

Citrate Transport System Citrate and pyruvate can cross the mitochondrial membrane via specific transport proteins. © 2014 John Wiley & Sons, Inc. All rights reserved.

Intermediates that are diverted to other pathways can be replenished. © 2014 John Wiley & Sons, Inc. All rights reserved.

Anaplerotic reactions replenish citric acid cycle intermediates. © 2014 John Wiley & Sons, Inc. All rights reserved.

© 2014 John Wiley & Sons, Inc. All rights reserved. During exercise, some pyruvate can be converted to α-ketoglutarate to boost the activity of the citric acid cycle. © 2014 John Wiley & Sons, Inc. All rights reserved.