Outline

Introduction (Figure 14.1)

Overview of Pyruvate Oxidation and the Citric Acid Cycle

> The Three Stages of Respiration (Figure 14.2)

> Strategy of the Citric Acid Cycle (Figure 14.3)

> > Oxidation

> > > Dehydrogenases

> > > Oxidases

> > > Oxygenases

> Discovery of the Citric Acid Cycle (Structures)

Pyruvate Oxidation: A Major Entry Route for Carbon into the Citric Acid Cycle (Reaction, Figure 14.4)

> Acetyl-CoA sources

> > Pyruvate - oxidative decarboxylation by pyruvate dehydrogenase

> > Fatty Acids

> > Amino Acids

Coenzymes Involved in Pyruvate Oxidation and the Citric Acid Cycle

> Thiamine Pyrophosphate (Figure 14.6)

> > Role in Decarboxylation

> Lipoic Acid

> > Role as Acyl Carrier and Electron Carrier

> Flavin Coenzymes (Figure 14.7, Figure 14.8)

> > Role as Electron Acceptor

> Coenzyme A and the Activation of Acyl Groups (Reaction, Figure 14.9)

> > Free thiol end of Coenzyme A used to linked to acetyl and acyl groups

> > High energy thioesters

Action of the Pyruvate Dehydrogenase Complex (Reactions, mechanisms, Figure 14.10)

The Citric Acid Cycle (Figure 14.3)

> Enzymes / Intermediates / Summary / of the citric acid cycle

> Phase 1: Introduction and Loss of Two Carbon Atoms

> > Step 1: Introduction of Two Carbon Atoms as Acetyl-CoA (Reaction, Figure 14.11)

> > Step 2: Isomerization of Citrate (Reactions, Reaction, specificity of aconitase, fluoroacetate.

> > Step 3: Generation of CO 2 by an NAD+ Linked Dehydrogenase (Reaction, Figure 14.13)

> > Step 4: Generation of a Second CO 2 by a Multienzyme Complex (Reaction, Figure 14.14, Figure 14.10)

> Phase 2: Regeneration of Oxaloacetate

> > Step 5: A Substrate-Level Phosphorylation (Reaction, Reaction 2, Figure 14.15, more)

> > Step 6: A Flavin-Dependent Dehydrogenase (Reaction, structure)

> > Step 7: Hydration of a Carbon-Carbon Double Bond (Reaction)

> > Step 8: A Dehydrogenation That Regenerates Oxaloacetate (Reaction)

Stoichiometry and Energetics of the Citric Acid Cycle (Table 14.1, Reaction, Reaction 2)

Regulation of Pyruvate Dehydrogenase and the Citric Acid Cycle (Figure 14.16)

> Control of Pyruvate Oxidation (Figure 14.10, Figure 14.17)

> > Regulation of the Pyruvate Dehydrogenase Complex

> Control of the Citric Acid Cycle (Figure 14.3) (Summary)

> > NAD+/NADH ratio

> > Citrate Levels

> > Isocitrate dehydrogenase (Activated by ADP, inactivated by NADH)

> > -Ketoglutarate dehydrogenase (Inhibited by Succinyl-CoA and NADH)

> > Substrate availability for Citrate Synthase

Anaplerotic Sequences: The Need to Replace Cycle Intermediates (Figure 14.18)

> Reactions that Replenish Oxaloacetate (Reaction, Figure 14.19, Reaction)

> > Pyruvate Carboxylase (allosterically activated by acetyl-CoA)

> > Phosphoenolpyruvate Carboxylase

> The Malic Enzyme (Reaction)

> Reactions Involving Amino Acids (Reaction, Reaction 2)

> > Transamination (Glutamate and Aspartate)

> > Glutamate dehydrogenase

Glyoxylate Cycle: An Anabolic Variant of the Citric Acid Cycle (Figure 14.21, Reaction, Reaction 2, Reaction 3, Reaction 4)

> Enzymes / Intermediates / Summary / of the Glyoxylate Cycle

> Bypasses decarboxylations of Citric Acid Cycle (Figure 14.20)

> Allows net synthesis of glucose from acetyl-CoA

> Occurs in plants (glyoxysomes) and some microorganisms

A Biosynthetic Pathway That Oxidizes Glucose: The Pentose Phosphate Pathway (Figure 14.22)

> Enzymes / Intermediates / Summary / of the Pentose Phosphate Pathway

> Functions

> > Provide NADPH for biosynthetic reactions

> > Provide Ribose-5-phosphate for nucleotide biosynthesis

> > Provide means of metabolizing dietary pentoses

> > Variant of pathway functions in plants to fix carbon in photosynthesis

> The Oxidative Phase: Generation of Reducing Power as NADPH (Figure 14.23)

> The Nonoxidative Phase: Alternative Fates of Pentose Phosphates

> > Production of Six-Carbon and Three-Carbon Sugar Phosphates (Reaction #1, #2, #3, #4, #5, #6, #7, #8, Figure 14.24)

> > Tailoring the Pentose Phosphate Pathway to Specific Needs (Figure 14.25)

> > > When nucleotide biosynthesis is needed, ribose-5-phosphate is the primary product.

> > > When NADPH is needed, cycling of fructose and glucose phosphates is favored

> > > When energy is the primary need, glycolysis and citric acid cycle intermediates are favored products.

> Human Genetic Disorders Involving Pentose Phosphate Pathway Enzymes (Structure, Reaction, Reaction 2, Reaction 3)

> > Prone to Oxidative Stress (Due to deficiency of glucose-6-phosphate dehydrogenase

> > Wernicke-Korsakoff syndrome (transketolase deficiency)