CHEM  30 B   Dr. R. Rinehart  
Chapters 21.1-21.3 and 22.1-22.6
ENERGY PRODUCTION I: AEROBIC METABOLISM

 The bottom-up order in which I cover the critically-important subject of cellular energy production is much different from the sequence in which it is done in most textbooks, so you’ll need to skip back and forth between parts of several chapters to develop a working picture. We’ll begin with a general introduction to what metabolism is, cellular organization, and the importance of energy in the overall scheme of things and the role of the magical compound ATP in cellular energy. ATP is primarily produced by a process called oxidative phosphorylation, so we’ll next dissect this process into its components and examine their operation individually.  Finally, we’ll look at the metabolic pathway called the Krebs Cycle, which is the major feeder pathway to oxidative phosphorylation.

 I.  METABOLISM: the sum total of all the chemical reactions taking place in an organism at any
    given time
            A. Anabolism: conversion of small simple molecules to large complex molecules;
                     requires input of chemical energy
            B. Catabolism: breakdown of molecules with liberation of energy
                        1.  Stage I:  digestion = hydrolysis;  macromolecules à monomers
                        2.  Stage II:  “simplification”:  formation of Acetyl-Coenzyme A
                                        carbohydrates:  glycolysis
                                        fatty acids:  b-oxidation
                                        amino acids:  transamination, deamination, C-skeleton “trimming”
                        3.  Stage III:  “common pathway”
                                         Krebs cycle: complete (but indirect) oxidation of Acetyl-CoA
                                        oxidative phosphorylation: electron flow & ATP production

            C. Metabolic pathway
                        1.  Series of linked chemical reactions where product of one reaction becomes
                              substrate for next reaction
                        2.  Starting and ending points chosen for our convenience
                        3.  Each and every reaction in a pathway is catalyzed by an enzyme
                                    reasons: speed, specificity, and control
                        4.  Four major patterns of pathways
                                    • linear:  glycolysis
                                    • branched: pyrimidine synthesis
                                    • cyclic: Krebs cycle, urea cycle, b-oxidation
                                    • cascade [tiered]:  blood coagulation, hormonal activation of glycogenolysis
                        5.  Control of  pathways can be exercised by:
                                    • regulation of one or more key enzymes in pathway
                                    • cellular compartmentation, which can control delivery of substrates,
                                                local pH, etc.
            D.   Mitochondrial structure, organization, and function
                        outer membrane: “leaky,” contains enzymes
                        intermembrane space: contains enzymes, including creatine kinase
                        inner membrane: contains the electron transport system and many “translocases”
                                    or shuttle systems
                        matrix: a soup of enzymes, location of: the Krebs cycle,  fatty acid b-oxidation,
                                  amino acid oxidation, mtDNA, mt tRNA,  mt ribosomes

II.  ENERGY: the basics

A. The ability to do work
                        1.  Forms of energy: light, kinetic, potential, chemical, electrical, heat
                        2.  Energy flow in the biosphere
                        3.  The need for energy in living systems
                                    biosynthesis
                                    active transport  
                                    motility

            B.  ATP and “Free Energy” 
                        1.  “Free energy” from chemical reactions  [it ain’t free] 
                        2.  The ATP/ADP cycle
                        3.  High-energy bonds

              4. The vast majority of ATP in most of our cells is generated by a complex
                                mitochondrial process called “oxidative phosphorylation,” in
                                which the formation of water from O₂ and “H₂” abstracted from
                                organic substrates [the oxidation] yields energy, which is used to
                                drive the formation of ATP from ADP + P_i [the phosphorylation]

C.  Energy production from redox reactions
                        1.  Oxidation and Reduction: definitions and examples [see table]
            D. Alternative forms of hydrogen that can be oxidized [see table]
                        “H₂” = 2H⁺ + 2 e^- = 2H• = H• + H⁺ + e^- = H:^- + H⁺

E.  Redox Coenzymes [hydrogen or electron acceptors]  and prosthetic groups 
                        1. NAD⁺  nicotinamide-adenine dinucleotide
                        2. FAD and FMN   flavin-adenine dinucleotide and flavin mononucleotide
                        3. CoQ  coenzyme Q₁₀  
                        4. Hemin  ferriprotoporphyrin IX

 III. Oxidative phosphorylation
            A.  Oxidation of “H₂” by the electron transport system [ETS, “respiratory chain”]
                        1.  ETS organization: in inner mitochondrial membrane
                        2. Energy conservation in the form of a transmembrane electrochemical gradient of H⁺
                                    [the “Mitchell hypothesis”]

            B.  Phosphorylation:  synthesis of ATP from ADP + P_i by the mitochondrial “ATPase”
                         using energy supplied by the transmembrane electrochemical gradient of H⁺
                        1. The ATPase has multiple subunits; the “F₁” “head” contains a₃b₃gde and the
                                “F₀” membrane channel has multiple copies of a short hydrophobic peptide
                        2.  The F₀ proton channel can be blocked by oligomycin and DCCD, while the
                                F₁ activity can be blocked by aurovertin or rutamycin  

             C.  Oxidation and phosphorylation are normally “coupled” – if one process is blocked for
                    any reason, so is the other.  Certain compounds called “uncouplers” disconnect the
                     two processes by collapsing the transmembrane proton gradient. This causes 
                    respiration rate to maximize, while ATP synthesis ceases. Uncouplers include
                     2,4-dinitrophenol and pentachlorophenol.    

IV.  The Krebs Cycle [citric acid cycle, tricarboxylic acid cycle, TCA]
            A.  Acetyl CoA, the major product of Stage II catabolism
                    can be formed from sugars, fatty acids, amino acids

             B. Reactions of the cycle [see table with additional references]
                            Net reaction for the cycle:
                        Acetyl-CoA + 3 NAD⁺ + FAD + GDP + Pi à 2CO₂ + 3(NADH + H⁺) + FADH₂ + GTP
                    ATP yield per AcCoA:  3NADH + 1 FADH₂ + GTP = 3x3 + 1x2 +1 = 12 ATP
                                    (in some texts you will see 3x2.5 + 1x1.5 +1 = 10 ATP)
  
            C. Control of Krebs Cycle activity
                        1. Rate of reoxidation of NADH and FADH2 ß à rate of ETS
                        2. Allosteric control of ICDH, aKGDH, and CitSyn

© Ronald W. Rinehart, 2002-2007