Energy Metabolism of Major Nutrients (Terminal Oxidation)

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*Purpose of terminal oxidation

As the final step of energy production from nutrients, ATP is produced from the reducing power delivered to terminal oxidation in the form of reduced coenzymes NADH and FADH.

As the final step of energy production from nutrients, ATP is produced from the reducing power delivered to terminal oxidation in the form of reduced coenzymes X and X.

NADH and FADH

Terminal oxidation = x and x

electron transport and oxidative phosphorylation

What is terminal oxidation?
1. Electron carriers transfer electrons and protons from reduced coenzymes x and x to oxygen. This is called electron transport
2. This reducing power is then converted into ATP energy by x

What is terminal oxidation?
1. Electron carriers transfer electrons and protons from reduced coenzymes NADH and FADH to oxygen. This is called electron transport.
2. This reducing power is then converted into ATP energy by oxidative phosphorylation

Differentiate between electron transport and oxidative phosphorylation. What are they a part of?

What is terminal oxidation?
1. Electron carriers transfer electrons and protons from reduced coenzymes NADH and FADH to oxygen. This is called electron transport.
2. This reducing power is then converted into ATP energy by oxidative phosphorylation

Where does terminal oxidation take place?

mitochondrial inner membrane

*Where do the reduced coenzymes NADH, FADH used in terminal oxidation come from?

1. NADH is produced in glycolysis or other cytosolic processes and transported to the mitochondrial matrix via one of the shuttles
2. NADH is produced by PDH (mitosol)
3. NADH and FADH are produced by the TCA (mitosol)
4. NADH and FADH are produced by the fatty-acid beta-oxidation (mitosol)

The mitochondrial electron transport system is a sequence of linked x reaction where either x or x are transferred stepwise to the final electron acceptor, molecular x (hence the alternative name -respiratory chain)

The mitochondrial electron transport system is a sequence of linked oxidation-reduction reaction where either electrons or electrons+protons are transferred stepwise to the final electron acceptor, molecular oxygen (hence the alternative name -respiratory chain)

Oxidation Reduction Reactions (Self study)
1.Oxidation reduction occurs when electrons are transferred from a suitable electron donor (the x, which becomes oxidized) to a suitable electron acceptor (the x, which becomes reduced)
2. The donor and acceptor together are called a x pair.
3. The capacity for a donor to give up its electrons to an acceptor is the x, as measured in volts as an electromotive force
4. The potential of the standard hydrogen electrode is set by convention at 0.0V at pH 0.0, but when corrected to pH 7.0, the standard value becomes -.x V
5. The sequence of electron transfer begins with components that x electrons more readily (larger negative potential) and ends with components with greatest affinity for electrons (higher positive potential)

Oxidation Reduction Reactions (Self study)
1.Oxidation reduction occurs when electrons are transferred from a suitable electron donor (the reductant, which becomes oxidized) to a suitable electron acceptor (the oxidant, which becomes reduced)
2. The donor and acceptor together are called a redox pair.
3. The capacity for a donor to give up its electrons to an acceptor is the oxidation-reduction potential, as measured in volts as an electromotive force
4. The potential of the standard hydrogen electrode is set by convention at 0.0V at pH 0.0, but when corrected to pH 7.0, the standard value becomes -0.42 V
5. The sequence of electron transfer begins with components that lose electrons more readily (larger negative potential) and ends with components with greatest affinity for electrons (higher positive potential)

Why does NADH generate 3 ATPs whereas FADH only generates 2 ATPs?

NADH starts earlier than FADH in the electron transport - and builds up higher proton gradient to power ATP synthase.

The mechanism of the electron transport system
1. The electron transport chain oxidizes reduced cofactors stepwise by x.

2. The oxidation-reduction potential differences between the redox pairs represent x changes. This energy is used to synthesize x molecules at the end of terminal oxidation.

The mechanism of the electron transport system
1. The electron transport chain oxidizes reduced cofactors stepwise by transferring electrons in a series of steps to O2, the terminal electron acceptor.

2. The oxidation-reduction potential differences between the redox pairs represent free energy changes. This energy is used to synthesize ATP molecules at the end of terminal oxidation.

In electron transport chain, electrons and protons are transported stepwise in a specific order to oxygen.

During the removal of the electrons, protons are also removed and pumped across the x membrane to the x space to create an electrochemical gradient that provides energy for ATP synthesis.

In electron transport chain, electrons and protons are transported stepwise in a specific order to oxygen.

During the removal of the electrons, protons are also removed and pumped across the inner mitochondrial membrane to the inter membrane space to create an electrochemical gradient that provides energy for ATP synthesis.

***The components of the electron transport chain

4 large multi subunit enzyme complexes with redox systems (Complex I-IV)

Free floaters Coenzyme Q and cytochrome c.

The electron transport complexes (I-IV) contain x enzymes, coenzymes, and x ions - all of which participate in the redox reaction.

redox enzymes, coenzymes, and metal ions

Vitamins (NAD, FAD, FMN) and minerals (iron and copper) have to be taken up by food to ensure that the x works properly

electron transport system

*****Explain the specific function of the four complexes and 2 free floating enzymes of electron transport system, where does NADH and FADH enter the system?

Complex I
Complex II
Coenzyme Q
Complex III
Cytochrome C
Complex IV

NADH enters the system at Complex I, which transfers electrons and protons to coenzyme Q.

FADH enters the system at Complex II, transfers electrons and protons to coenzyme Q.

Coenzyme Q also accepts electrons through FADH from ß-oxidation of fatty acids. Electrons are then transferred to Complex III

Complex III transfers electrons to cytochrome C

cytochrome C transports electrons to Complex IV

Complex IV transfers electrons to molecular oxygen which is the terminal electron acceptor.

Deficiency of copper and iron will mess up the electron transport system - T/F?

True

How do poisons act on the electron transport system?
1. fish poison, rotenone
2. barbiturate amytal
3. antibiotic antimycin A
4. Cyanide
5. Azide
6. Carbon Monoxide

1. inhibits complex I
2. Inhibits complex I
3. inhibits complex III
4. inhibits terminal step at complex IV
5. Inhibits terminal step at complex IV
6. inhibits terminal step at complex IV

Inhalation of hydrogen cyanide gas or ingestion of potassium cyanide causes a rapid and extensive inhibition of the x

Inhalation of hydrogen cyanide gas or ingestion of potassium cyanide causes a rapid and extensive inhibition of the mitochondrial electron transport chain at the Complex IV (cytochrome oxidase step)

Cyanide is one of the most potent and rapidly acting poisons known.
1. Cyanide binds to the Fe3+ in the heme a3 of cytochrome c oxidase enzyme in x that catalyzes the terminal step in the electron transport chain. Cyanide thus prevents the binding of x to the enzyme and thus the role of x as the final electron acceptor

2. Aftereffects - mitochondrial respiration and energy production cease, and cell death occurs rapidly.
3. Death due to cyanide poisoning occurs from x, most notably of the CNS.
4. An antidote to cyanide poisoning, if the poisoning is diagnosed rapidly, is the administration of various nitrites that convert x to x by oxidizing Fe3+ of hemoglobin to Fe3+. Methemoglobin Fe3+ competes with cytochrome a3 (Fe3+) for cyanide, forming a methemoglobin-cyanide complex
Administration of x causes the cyanide to react with the enzyme rhodanese, forming the nontoxic thiocyanate.

Convert cyanide to thiocyanate.

Cyanide is one of the most potent and rapidly acting poisons known.
1. Cyanide binds to the Fe3+ in the heme a3 of cytochrome c oxidase enzyme in Complex IV that catalyzes the terminal step in the electron transport chain. Cyanide thus prevents the binding of Oxygen to the enzyme and thus the role of Oxygen as the final electron acceptor

2. Aftereffects - mitochondrial respiration and energy production cease, and cell death occurs rapidly.
3. Death due to cyanide poisoning occurs from tissue asphyxia, most notably of the CNS.
4. An antidote to cyanide poisoning, if the poisoning is diagnosed rapidly, is the administration of various nitrites that convert oxyhemoglobin to methemoglobin by oxidizing Fe2+ of hemoglobin to Fe3+. Methemoglobin Fe3+ competes with cytochrome a3 (Fe3+) for cyanide, forming a methemoglobin-cyanide complex
Administration of thiosulfate causes the cyanide to react with the enzyme rhodanese, forming the nontoxic thiocyanate.

Convert cyanide to thiocyanate.

How is the electron transport chain connected to ATP synthesis?

While electrons are transferred through the electron transport chain, protons are ejected from the mitochondrial matrix into the intramembrane space at three points - Complexes I, III, IV. The protons are later translocated back into the matrix by the F1F0-ATPase that is also located in the inner membrane.

It has been shown experimentally that as electrons are transferred from NADH to oxygen, there occurs an oxidation-reduction potential decrease of x V and this occurs in discrete steps. Thus, energy is gain in increments and used to produce 2-3 ATP molecules in the oxidative phosphorylation step of terminal oxidation (Why 2 ATPs for FADH and 3 ATPs for NADH?)

It has been shown experimentally that as electrons are transferred from NADH to oxygen, there occurs an oxidation-reduction potential decrease of 1.14 V and this occurs in discrete steps. Thus, energy is gain in increments and used to produce 2-3 ATP molecules in the oxidative phosphorylation step of terminal oxidation (Why 2 ATPs for FADH and 3 ATPs for NADH? - Because FADH enters at coenzyme Q rather than complex I

Chemiosmotic-coupling mechanism
1. Establishment of proton gradient, high concentration of protons where?
2. What subunit of ATP synthase makes membranes permeable to protons?
3. What subunit of ATP synthase contains the ATPase enzyme? Where does the synthesis of ATP happen?

Chemiosmotic-coupling mechanism
1. Establishment of proton gradient - electron transport pumping protons from the mitosol to the intermembrane space
2. What subunit of ATP synthase makes membranes permeable to protons? The F0 portion - it's oligomycin sensitive too.
3. What subunit of ATP synthase contains the ATPase enzyme? A: F1 Where does the synthesis of ATP happen? ATP synthesis on the surface of F1

T/F - The F0F1 ATPase is a single protein capable of synthesizing ATP from ADP + Pi

false - the F01F1ATPase is a multi protein complex.

***Basic mechanism of F0F1ATPase in making ATP.

***Basic conformational mechanism of making ATP

The proton channel lets the protons go back to the intermembrane space to the mitosol. With proton going through the channel, the other proteins of the complex go through a conformational change and transfer the electrochemical energy to mechanical energy.

1. F1 head part of the multi protein complex binds ADP and Pi and synthesizes ATP

With proton going through the channel, the other proteins of the complex go through a conformational change, which is transferred to the head part and transforms the mechanical energy into chemical energy - high energy phosphate bond.

T/F - oxidative phosphorylation occurs independently of electron transport

false - oxidative phosphorylation is coupled to electron transport

Oxidative phosphorylation is coupled to electron transport
1. Oxygen consumption increases following addition of oxidizable substrate and ADP plus Pi, and then x is produced
2. T/F - lack of ADP and Pi stops ATP synthesis and electron transport
3. T/F - Poisoning the electron transport chain stops the process, but ATP still can be produced
4. What is the effect of adding oligomycin on the formation of ATP?

Oxidative phosphorylation is coupled to electron transport
1. Oxygen consumption increases following addition of oxidizable substrate and ADP plus Pi, and then ATP is produced
2. T/F - true
3. T/F - False, ATP production ceases
4. What is the effect of adding oligomycin on the formation of ATP? The F0 portion of ATP synthase that allows protons to pass from mitosol to intermembrane space is sensitive to oligomycin. Thus, oligomycin stops ATP synthesis, which then stops electron transport

Can respiration and phosphorylation be uncoupled?

yes

***Explain how respiration and phosphorylation can be uncoupled. What compound can uncouple these two processes? What does this mean for ATP production?

Why would uncoupling be a good thing in certain animals rather than a bad thing?

Uncouplers can dissipate the proton gradient (2,4 dinitrophenol) and cause a rapid initiation of oxygen consumption. Because respiration or electron transport is now uncoupled from ATP synthesis, electron transport continues without ATP synthesis

Brown fat for instance - the energy gained from oxidation of fat will not be used for ATP synthesis but for heat production. In this way, brown adipose cells play major role in non-shivering thermogenesis.

***What is Physiological Uncoupling Protein? Where is it found? What animals use it? What does it do?
Explain how the onset of winter triggers the activity of this protein.

Physiological uncoupling protein (UCP-1) is found in brown adipose tissue.
Newborns and hibernating animals have more brown adipose cells than adult humans.

Cold sensation stimulates triglycerise hydrolysis, which in turn stimulates UCP-1.

UCP-1 is located in the inner mitochondrial membrane and has a specific pore through which protons are transported back to the mitochondrial matrix. Thus, the energy gained from oxidation of fat will not be used for ATP synthesis but for heat production. In this way, brown adipose cells play a major role in non-shivering thermogenesis.

Leber's Hereditary Optic Neuropathy
1. Disease of the x
2. maternal inheritance, why?
3. affects what part of the body?
4. Cause of the disease?
5. Varying degrees of severity

Leber's Hereditary Optic Neuropathy
1. The first mitochondrial disease to be elucidated at the molecular leave.
2. maternal inheritance - you inherit mitochondria and mtDNA from your mother
3. affects the CNS, including the optic nerves, causing sudden onset blindness in early adulthood due to the death of the optic nerve.
4. In nearly all families, LHON results from SINGLE BASE CHANGES IN THE MITOCHONDRIAL GENES FOR THREE SUBUNITS OF COMPLEX I, resulting in a lowered activity for complex I
5. Patients with lower percentage of mutant mtDNA develop the sudden-onset blindness in early adulthood and other symptoms typical of LHON. Patients with a higher percentage of mutant mtDNA carrying the identical mutation develop dystonia, a severe disease characterized by early onset of generalized movement disorder, impaired speech, and mental retardation.

Single base changes in the mitochondrial genes for 3 subunits of complex I result in

Leber's Hereditary Optic Neuropathy

Mitochondrial Myopathies
1. Caused by what?
2. Two major diseases
3. How does it affect the electron transport chain?

Mitochondrial Myopathies
1. Due to mutations in tRNA genes
2. Point mutations in genes encoding mitochondrial tRNAs result in two of the most common mitochondrial diseases characterized by abnormalities of the CNS as well as mitochondrial myopathy with ragged-red fibers, an association known as mitochondrial encephalomyopathy.
3. The biochemical consequence of both of these tRNA mutations is impaired mitochondrial protein synthesis leading to decreased activities of complex I and complex IV.

Point mutations in genes encoding mitochondrial tRNAs result in

mitochondrial myopathies

Main consequence of mitochondrial myopathies

The biochemical consequence of both of these tRNA mutations is impaired mitochondrial protein synthesis leading to decreased activities of complex I and complex IV.

Exercise intolerance in Patients with Mutations in Cytochrome b
1. A mutation in cytochrome b resulting in lowered activity of x presents with exercise intolerance.
2. More recently, a patient with severe hypertrophic cardiomyopathy was shown to have a mutation in the x gene.
3. Most of the nonsense and deletion mutations often leads to severe exercise intolerance, lactic acidosis in the resting state, and occasionally myoglobinuria resulting from the decreased activity of the complex.
4. Most of these mutations have only been expressed in muscle tissues, suggesting that the mutations identified in the cytochrome b gene are x and occur during germ-layer differentiation of myogenic stem cells
5. Complex III myopathy has been treated with a mixture of vitamin C and vitamin K. This combo is able to oxidize x and reduce x, thus bypassing Coenzyme Q and complex III

Exercise intolerance in Patients with Mutations in Cytochrome b
1. A mutation in cytochrome b resulting in lowered activity of COMPLEX III presents with exercise intolerance.
2. More recently, a patient with severe hypertrophic cardiomyopathy was shown to have a mutation in the cytochrome b gene.
3. Most of the nonsense and deletion mutations often leads to severe exercise intolerance, lactic acidosis in the resting state, and occasionally myoglobinuria resulting from the decreased activity of the complex.
4. Most of these mutations have only been expressed in muscle tissues, suggesting that the mutations identified in the cytochrome b gene are somatic and occur during germ-layer differentiation of myogenic stem cells
5. Complex III myopathy has been treated with a mixture of vitamin C and vitamin K. This combo is able to oxidize NADH and reduce cytochrome c, thus bypassing Coenzyme Q and complex III

A mutation in cytochrome b can result in lowered activity of x and present with exercise intolerance.

complex III

How would you treat Complex III myopathy?

Complex III myopathy has been treated with a mixture of vitamin C and vitamin K. This combo is able to oxidize NADH and reduce cytochrome c, thus bypassing Coenzyme Q and complex III

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