MEDICAL BIOCHEMISTRY II

(M3611BB)

Theme II - OXIDATIVE METABOLISM

Dr D. Haiyambo
Dept. Human, Biological and Translational Medical Sciences
 Oxidative Metabolism

• Oxidation: the removal of

electrons

• Reduction: the addition of

electrons

• The affinity of an oxidation

reduction system for electrons
is referred to as oxidation –
reduction potential (or) redox
potential.

Fig 1. Redox diagram

 Oxidative Metabolism

• A biological system which has a strong tendency to donate electrons has a

negative redox potential.

• The redox potential is reference is the potential of hydrogen electrode at

pH 7. 0 with -0.42 volt in a biological system.

• Redox potential redox system (redox pair)

- 0.32 NADH/NAD+
+ 0.82 H2 / ½ O2

• The electrons flow from electro negative redox couple to more electro
positive system
 Oxidative Metabolism

Groups of oxidoreductases
• Enzymes that are involved in oxidation and reduction reactions are called oxido reductases.

• 1.Oxidases: use oxygen as hydrogen acceptor.

2.Dehydrogenases: involved in transfer of hydrogen from one substrate to another in a

coupled oxidation reduction reactions.

3.Hydroperoxidases: use hydrogen peroxide or an organic peroxide as substrate.

4.Oxygenases: catalyze the direct transfer and incorporation of oxygen into a substrate
molecule.
 Oxidative Metabolism

Phases of Energy transformations

1. oxidation of fuels (fat, carbohydrate, and

protein).

2. conversion of energy from fuel oxidation into

ATP.

3. use of ATP phosphate bond energy to drive

energy-requiring processes.

Fig 2. Energy transformations in fuel metabolism From Marks’ basic medical

biochemistry : a clinical approach 4 th Ed., Lieberman, Marks & Peet,
Lippincott Williams & Wilkins, 2013, Fig IV.1
Oxidative Metabolism

Fig 3. Cellular respiration

From Marks’ basic medical
biochemistry : a clinical
approach 4th Ed.,
Lieberman, Marks & Peet,
Lippincott Williams &
Wilkins, 2013, Fig IV.2
Oxidative Metabolism
 Oxidative Metabolism
Phases of Energy transformation
Phase 1
• electrons are transferred from the fuels to the coenzymes nicotinamide adenine
dinucleotide (NAD+) and flavin adenine dinucleotide (FAD), which are reduced to
NADH and FAD(2H).
Fig 4. Converging
catabolism. From Lehninger
Principles of Biochemistry
4th Ed., Nelson & Cox, W. H.
Freeman and Company,
2004, Fig 4

• The pathways for the oxidation of most fuels converge in the generation of acetyl
coenzyme A (acetyl-CoA).

• The complete oxidation of the acetyl group to CO2 occurs in the tricarboxylic acid
(TCA) cycle, which collects the energy mostly as NADH and FAD(2H).
 Oxidative Metabolism

Phase 2
• energy derived from fuel oxidation is converted to the high-energy phosphate
bonds of ATP by the process of oxidative phosphorylation.

• electrons are transferred from NADH and FAD(2H) to O2 by the electron-transport

chain in the inner mitochondrial membrane.

• NADH and FAD(2H) are oxidized by O2, this generates an electrochemical potential
(proton gradient [Δp]) across the inner mitochondrial membrane.

• The electrochemical potential drives the synthesis of ATP by a transmembrane

enzyme (ATP synthase or F0F1 ATPase).
 Oxidative Metabolism

Phase 3
• high-energy phosphate bonds of ATP are used for mechanical work, transport
work, biosynthetic work biochemical work.

Cellular respiration occurs in mitochondria.

• The mitochondrial matrix, which is the compartment enclosed by the inner

mitochondrial membrane, contains most of the enzymes for the TCA cycle and
oxidation of fatty acids.
 Oxidative Metabolism
Mitochondria

• The inner membrane forms invaginations known as cristae containing the

electron-transport chain and ATP synthase.

Fig 5. Mitochondria From Marks’ basic medical biochemistry : a Fig 6. Mitochondria From Marks’ basic medical biochemistry : a
clinical approach 4th Ed., Lieberman, Marks & Peet, Lippincott clinical approach 4th Ed., Lieberman, Marks & Peet, Lippincott
Williams & Wilkins, 2013, Fig 10.13 Williams & Wilkins, 2013, Fig 10.13
 Oxidative Metabolism

Mitochondria

• contains the pyruvate dehydrogenase complex

• enzymes of the CAC
• enzymes for fatty acid -oxidation pathway
• enzymes for pathways of amino acid oxidation

• all the pathways of fuel oxidation except glycolysis

 Oxidative Metabolism

Oxidative phosphorylation

• The process by which free energy is liberated when protons are pumped by the
respiratory chain is trapped in the form of ATP by phosphorylation of ADP with
phosphate.

• The process of oxidation coupled with phosphorylation is called oxidative

phosphorylation and it occurs in the mitochondria.
 Oxidative Metabolism

• Oxidative phosphorylation begins with the entry of electrons into the respiratory
chain.

• electrons are collected from catabolic pathways and transferred to universal

electron acceptors (nicotinamide nucleotides (NAD or NADP) or flavin nucleotides
(FMN or FAD).

• Nicotinamide nucleotide–linked dehydrogenases catalyse these reactions

 Oxidative Metabolism

Electrons Pass through a Series of Membrane-Bound Carriers

• In addition to NAD and flavoproteins

• a hydrophobic quinone (ubiquinone)
• cytochromes
• iron-sulfur proteins
 Oxidative Metabolism

Electrons Pass through a Series of Membrane-Bound Carriers

Ubiquinone (coenzyme Q /CoQ10/ Q)
• Fat soluble quinone compound

Cytochromes
• Have iron containing prosthetic groups and are able to absorb visible light.
• three classes of cytochromes, designated a, b, and c

Iron-sulfur proteins
• iron bound to inorganic sulfur atoms (or with the sulfur atoms of Cys).
Oxidative Metabolism

Cellular respiration
 Oxidative Metabolism

Electron Carriers Function in Multienzyme Complexes

• Each component of the electron-transfer chain accepts and passes the electrons to
the next part of the chain.

Fig 10 Components of the electron-transport chain From Marks’ basic medical biochemistry : a clinical approach
4th Ed., Lieberman, Marks & Peet, Lippincott Williams & Wilkins, 2013, Fig 21.5
 Oxidative Metabolism

Complex I - NADH:COQ OXIDOREDUCTASE

• NADH:CoQ oxidoreductase (NADH dehydrogenase) contains a binding site for
NADH, several FMN and Fe–S center-binding proteins, and binding sites for CoQ.

• An FMN accepts two electrons from NADH and passes single electrons to the Fe–S
centers

• Fe–S centers transfer electrons to CoQ.

 Oxidative Metabolism

Complex II - SUCCINATE DEHYDROGENASE (AND FLAVOPROTEINS)

• pass electrons to CoQ
 Oxidative Metabolism

Complexes III and IV - Cytochromes

• Small differences in the heme structure bring about different reduction potential.
• (Cu) ions facilitate the collection of the four electrons and the reduction of O2.
 Oxidative Metabolism

Mitchell’s chemiosomotic hypothesis

• Electron transport chain pumps protons into the inter membrane space across the
inner membrane which is not permeable to protons.

• This creates an electro chemical potential gradient.

The protons (H+) flow back across inner membrane through
ATP synthase resulting in trapping of free energy as ATP.

Fig 13 ATP synthase (F0F1 ATPase). From Marks’ basic medical biochemistry : a clinical approach
th
 Oxidative Metabolism

Fig 14 Oxidative phosphorylation. From Marks’ basic medical biochemistry : a clinical approach 4 th Ed., Lieberman,
Marks & Peet, Lippincott Williams & Wilkins, 2013, Fig 21.1
 Oxidative Metabolism

• P:O ratio
• It is the number of high energy phosphates produced per atom of oxygen used.
ie : for NADH+H+- 2.5 ATP
for FADH2 – 1.5 ATP
(For every 4 protons translocated one ATP is synthesized)

• Rate of respiration (O2 consumption) in mitochondria is tightly limited by the

availability of ADP as a substrate for phosphorylation.