Energetic Balance of the Total (and I mean Total) Oxidation of a Fatty Acid with an Odd number of Carbons.


In previous posts we have discussed how the fatty acids with an odd number of carbons chain, release 1 unit of Acetyl CoA and 1 unit of Propionyl CoA, instead of the two Acetyl CoA units released when a fatty acid with an even number of carbons is beta-oxidized.

 

Let’s use some examples, (we represent here just the carbons in the chains):

 

Example 1: a fatty acid with 6 carbons (Hexanoic acid)

 

C-C-C-C-C-C-C

 

During the Beta-oxidation, three units of Acetyl CoA are released (two carbons each):

 

C-C/C-C/C-C

 

Example 2: A fatty acid with 7 carbons (Heptanoic acid):

 

C-C-C-C-C-C-C

 

During the Beta-oxidation two units of Acetyl CoA and one unit of Propionyl CoA are released (two units of two carbons and one unit of three carbons):

 

C-C-C/C-C/C-C

 

As discussed previously in another post, the Acetyl CoA are oxidized in the Krebs Cycle, but the Propionyl CoA is used in the formation of Succinyl CoA, in a process that consumes 1 ATP (-1 ATP).

 

The Succinyl CoA can continue in the Krebs Cycle and form Oxalacetate. Oxalacetate will react with Acetyl CoA (Citrate Synthase reaction) to form Citrate, following the reactions in the Krebs Cycle. If it happens, we can consider that the atoms of carbons of the Propionyl CoA have followed an anaplerotic pathway (to be used in the Kreb’s Cycle without being consumed). 

 

BUT these carbons could also be completely oxidized if they follow this sequence of reactions:

 

Succinyl CoA + GDP + (P) – -> Succinate + CoA + GTP (it is equivalent to 1 ATP)

 

Succinate + FAD – – – – >Fumarate + FADH2 (It generates 2 ATP in the Respiratory Chain)

 

Fumarate + H2O—–> Malate

 

But the Malate can now diffuse from the matrix through the mitochondrial membranes and be decarboxylated (under the action of the cytoplasmatic malic enzyme) to Pyruvate (and production of 1 CO2).

 

Pyruvate can return to the interior of the mitochondria,  where another decarboxylation occurs, this time under the action of the  Pyruvate dehydrogenase complex, (with production of another CO2) and the formation of Acetyl CoA, whose Acetyl group will be oxidized in the Cycle producing other two molecules of CO2.

 

We can see that through this sequence of reactions it is possible the total oxidation of the three original carbons of the Propionate to 3 molecules of CO2! (To avoid confusions, observe that, yes, there are 4 decarboxylations, but one of the CO2 does not come originally from the Propionyl CoA, but from the carboxylation process in the conversion of Propionyl CoA to Succinyl CoA)

 

Which would be the energetic balance of the total oxidation of an odd chain fatty acid considering this sequence of reactions?

 

Let’s see:

 

Propionyl CoA to Succinyl Co A = -1 ATP

 

In the mitochondria, (following the reactions of the Kreb’s Cycle up to Malate):

 

Succinyl CoA + GDP + (P) –> Succinate +CoA + GTP (it is equivalent to 1 ATP)

 

Succinate + FAD ——– – – – > Fumarate + FADH2 (It generates 2 ATP in the Respiratory Chain)

 

Fumarate + H2O————–>Malate

 

In the cytoplasm:

 

Malate + NADP+ – – – >Pyruvate + NADPH.H+ + CO2 (we will not consider this  reduced cofactor in the balance since NADPH.H+ is not a source of energy, but a source of reduction equivalents for synthetic reactions)

 

In the mitochondria again:

 

Pyruvate + CoA + NAD+ —-> Acetyl CoA + CO2 + NADH.H+ (Observe that this NADH.H+ is generated inside the mitochondria, so it yields 3 ATP)

 

The Acetyl CoA produced in the previous reaction, when oxidized in the Krebs Cycle: 12 ATP

 

Therefore, considering this metabolic way,

 

-1 +1 +2 +3 + 12 = 17 ATP as a result of  the total oxidation of the Propionyl CoA generated by the beta-oxidation of a fatty acid of odd number of carbons.

 

 

Therefore, for calculating the energetic balance we should add 17 ATPs from the oxidation of the Propionyl CoA, to the ATPs generated in the Beta-oxidation, and the ATPs generated as a result of the oxidation in the Krebs Cycle  of the Acetyl CoA units formed during the Beta-oxidation of the odd chain fatty acid. ( We should recall also that 2 ATPs are consumed in the initial activation of the fatty acid)

 

In our next post we will analyze the oxidation of the heptadecanoic acid (17 carbons) as an example of the application of these calculations.

 

Oxidation of a fatty acid with 17 atoms of carbon


(This post analise the energetic balance considering that the Propionyl CoA follows an anaplerotic fate)

 

Apply the equations described in the previous post:

 

N= Number of Carbons

 

(N/2) -1.5 = Number of rounds in Beta-oxidation

 

(N/2) -1.5 = Number of acetyl CoA produced in Beta-oxidation

 

So, in terms of production and consumption of ATP of ATPs, the oxidation of a 17-carbons fatty acid will show the following energetic balance:

 

Activation of a fatty acid to Acyl CoA = -2 ATP

 

Number of rounds in Beta-Oxidation:

 

(17/2) – 1.5 = 8.5 -1.5 = 7

7 rounds x 5 ATP/round = 35 ATP

 

Number of produced Acetyl CoA: 7 Acetyl CoA

 

7 Acetyl CoA x 12 ATP/Acetyl CoA = 84 ATP

 

Additionally, the Beta-oxidation has produced 1 Propionyl CoA. The conversion of Propionyl CoA to Succinyl CoA, as described in a former post, will consume 1 ATP (Consider -1 ATP).

 

As described in a previous post:

 

We can consider the conversion of Propionyl CoA to Succinyl CoA as an anaplerotic pathway, in which case, the molecule of Succinyl CoA continue in the Krebs Cycle generating Oxalacetate in the following sequence of reactions:

 

Succinyl CoA + GDP + (P) —> Succinate + CoA + GTP (equivalent to 1 ATP)

 

Succinate   +  FAD ———-> Fumarate +  FADH2 (Generates 2 ATPs in the Respiratory Chain)

 

Fumarate +     H2O————– > Malate

 

Malate +   NAD+ —————->  Oxalacetate + NADH.H+ (Generates 3 ATPs in the Respiratory Chain) “

 

Total = (-1+1+2+3) = 5 ATPs

 

Total of ATPs produced (considering the anaplerotic fate of the Propionyl CoA turned into Succinyl CoA) = -2+35+84-1+6 = 122 ATP                        

 

BUT…

 

We may also consider a total oxidation that would include the carbon atoms of the Propionyl CoA!

 

In our next post, we will consider what happens if, instead of the Succinyl CoA following an anaplerotic pathway, it follows a path that allow the carbon atoms of Propionyl CoA end up being oxidized to CO2. It would allow a real  total oxidation of all the original carbons of the heptadecanoic acid or any other fatty acid with an odd number of carbons.

 

 

Inhibitors of the Electron Transport Chain


 

Answer to Question B-09

 

As described in a former post, the inhibitors of the Electron Transport Chain are substances that bind to some of the components of the ETC blocking its ability to change in a reversible form from an oxidized state to a reduced state.

 

This inhibition results in the accumulation of reduced forms before the inhibitor point, and oxidized forms of the components of the ETC downstream (ahead) the inhibition point.

 

 

Since energy is not released, the synthesis of ATP also stops. The most important known inhibitors of the ETC are Amytal, Rotenone, Antimycin A, CO, Sodium Azide, and Cyanides.

 

Amytal, a barbiturate, and Rotenone, a plant product used as insecticide and pesticide, block the ETC between NADH dehydrogenase (Complex I) and CoQ.

 

Consequently, they prevent the utilization of NADH as a substrate. On the contrary, electron flow resulting from the oxidation of Complex II is not affected, because these electrons enter through QH2, beyond the block.

 

The effect of Amytal has been observed in vitro, since the intoxication with amytal and other barbiturates in vivo affect mainly the CNS by acting on GABA-sensitive ion channels, an effect not related to the action of Amytal on Complex I.

 

Rotenone intoxications are very rare. In facts, some human tribes used to catch fishes by spreading plant extracts containing rotenone in the water, and this substance was easily absorbed by the fishes through the gills. These fishes were eaten later without notable side effects in humans, since rotenone is absorbed very difficult by the gastrointestinal tract. Usually, when taken in a concentrated form, irritating action in mucoses causes vomits.

 

It is interesting to note that Rotenone and MPTP (a neurotoxin), when administered in vein,  cause at the same time interference with the functioning of Complex I and a Parkinson-like disease. These substances affect primary neurons in substancia nigra; apparently the sequence is: impairment of Complex I, impairment of mitochondria metabolism, accumulation of free radicals, cell death, release of toxic compounds and destruction of other cells.

 

Antimycin A is an antibiotic produced by Streptomyces griseous that has been used as a piscicide for the control of some fish species. Antymicine A interferes with electron flow from cytochrome bH in Complex III (Q-cytochrome c oxidoreductase).  In the presence of this substance, cytochrome bH can be reduced but not oxidized, consequently,  in the presence of antimycin A cytochrome c remains oxidized, as do the cytochromes a and a3 that are ahead.

 

Carbon monoxide (CO) is responsible for more than 50 % of death by poisoning worldwide. It is colorless and odorless; high levels can result from incomplete combustion of fuels: engine and furnace exhausts are important sources. Tobacco smoking increases CarboxyHb levels.

 

Carbon monoxide intoxication causes impaired oxygen delivery and utilization at the cellular level. The affinity of Hb for CO is almost 300 times higher than for Oxygen. An environment in which there is 100 ppm of CO is enough to form 16 % carboxyhemoglobin. The situation is worsen since the binding of CO to one of the Hem groups of Hemoglobin increases the affinity of the other three Hem groups for Oxygen, so the delivery of Oxygen to  tissues is very affected. The brain and the heart, that has a high Oxygen consumption, are the most affected. Myoglobin has even a greater affinity for CO than Hemoglobin. As a consequence of the binding of CO to these molecules, the heart functioning is very impaired and the patient presents sever hypotension. As described above, this intoxication is an important cause of death worldwide.

 

The affinity of respiratory chain components for CO is lower than for Oxygen,

but since the clinical status does not correlate very well with the carboxyhemoglobin levels, it is considered that the inhibition of Cytochrome Oxidase by CO also plays a role in CO intoxication. CO binds to the reduced form of iron in Hem groups (Fe++) in cytochrome Oxidase

 

On the contrary, in cyanide intoxication the inhibition of the respiratory chain has a primary role. Intoxication by cyanide can be seen relatively frequent in patients with smoke inhalation from residential or industrial fires. Also in persons related professionally with cyanide or derivatives in certain industries.  Intentional poisoning can be seen in suicidal persons with access to cyanide compounds. Cyanide affects practically all metalloenzymes, but its principal toxicity derives from the binding to the Fe+++ in the Hem groups in cytochrome Oxidase, inhibiting the functioning of the Electron Transport Chain. As a consequence, redox reactions in the respiratory chain will stop, energy will not be released, proton pumps will not function, so they will not return through Complex V, and the production of ATP will cease (Related question here).

 

Azides have an action on the respiratory chain very similar to cyanide, inhibiting the Hem groups of cytochromes in Cytochrome Oxidase (Complex IV). Azides are used as propellants in airbags, in detonant (explosive) industry and as preservative of sera an reagents. Some cases of azide intoxication in humans have been reported.

 

You can find more information about these inhibitors of the Electron Transport Chain in these links:

 

Antimycin A: toxicity, ecological toxicity and regulatory information

 

 

Risk assessment for Piscicidal Formulations of Antimycin

 

Leybell, I: Toxicity: Cyanide

 

Cyanide poisoning

 

 

Azide Toxicity

 

Sodium Azide Toxicity effects

 

Shochat, G.N.: Toxicity, Carbon Monoxide

 

 

How to calculate QUICKLY the energetic balance of the total oxidation of a fatty acid


 

The basis for the calculation and how to do it have been explained in detail in other post.

 

Anyway, since time is an issue in exams, some readers are interested in knowing a method of doing the calculation in a real fast way.

 

For obtaining a quick answer when calculating the energetic balance of the total oxidation of a fatty acid (and also for verifying your answers if you use some other method of calculation) you can apply these formulas:

 

a) If your course use for the reduced cofactors these energetic yields

NADH.H+ = 2.5 ATP

FADH2 = 1.5 ATP

 

Use this formula:

 

[(n/2) -1] x (14) +8 = Number of ATP formed

 

Where n= Number of carbons

 

Example:

 

Balance of the total oxidation of palmitic acid (16 carbons):

(16/2)-1] x (14) +8 = 106 ATP

 

b) If the equivalence used for the energetic yields in your course are:

NADH.H+ = 3 ATP

FADH2 = 2 ATP

 

Then apply this formula:

 

[(n/2) -1] x 17 +10 = Number of ATP formed

 

For the total oxidation of palmitic acid, following the former energetic yielding criteria:

 

[(16/2)-1] x 17 + 10 = 129 ATP

 

Thanks for the questions and comments!

 

 

Substances which interfere with the Respiratory Chain: Overview


Recalling:

 

Respiratory Chain:

 

Set of reaction that transfers the Hydrogen and electrons from reduced cofactors to Oxygen, obtaining water and using the released energy for the synthesis of ATP

 

 

Sometimes, the terms Electron Transport Chain and Oxidative Phosphorylation are used indistinctly to refer to the Respiratory Chain. We prefer to use Respiratory chain for the whole process, in which we can distinguish two different parts:

 

         Electron transport chain: Set of reaction through which the Hydrogen and electrons are transfer from reduced cofactors to Oxygen, obtaining water and releasing energy. It allows that the energy derived from redox reactions be released little by little with a better use and without damaging the cell. It involves the transfer of electrons from complex I (or II) to Oxygen. (An excellent animation here)

          Oxidative phosphorylation: It’s the biosynthesis of ATP from ADP + (P) using the energy released in the electron transport chain. It occurs in Complex V (ATP synthase). The coupling of ATP synthesis and the energy released in the ETC is indirect (Animation here)

 

Substances that interfere with the Respiratory Chain function can be classified as:

 

Inhibitors of Electron Transport Chain:

Substances that bind to some of the components of the ETC blocking its ability to change in a reversible form from an oxidized state to a reduced state. It results in the accumulation of reduced forms before the inhibitor point, and oxidized forms of the components of the ETC ahead the inhibition point. Sites of action of some inhibitors (and some artificial electron acceptors) can be found in this graphic

Since energy is not released, the synthesis of ATP also stops.

Ex: Amital, Rotenone, Antimycin A, CO, Sodium Azide,  CN

 

Inhibitors of Oxidative Phosphorylation:

These compounds bind to the Complex V (ATP synthase), impeding the synthesis of ATP, by inhibiting the return of protons to the matrix. Since this process is coupled to the ETC these inhibitors also stop the function of the ETC.

         Ex Oligomycin

 

Uncouplers of respiratory chain:

Substances that dissipate the electro-chemical gradient by facilitating the entrance of protons to the matrix using “shortcuts” and by that reason the electron transport takes places but not the oxidative phosphorylation.

         Ex. 2,4 dinitrophenol

         Thermogenin – UCP-1, DNP

 

Inhibitors of ATP/ADP exchange

ATP is produced in the mitochondria but is used all over the cell, so it should be allowed to go from the production site (mainly, mitochondria) to the locations where it is going to be used. At the same time, the ADP resulting from the use of ATP all over the cell should be allowed to enter the matrix in order to be used in the formation of more ATP.  The inhibitors of ATP/ADP exchange inhibit the translocase that allows the entrance of ADP to the matrix and the output of recently synthesized ATP outside of the mitochondria.

         Ex Atractyloside

 

More information about these substances that interfere with the Respiratory Chain will be included in future posts dedicated to each specific group.

 

 

How to calculate the energetic balance of the total oxidation of a fatty acid


The total oxidation of a fatty acid comprehends different processes:

 

1. – The activation of the fatty acid

 

2. – Beta-Oxidation

 

3. – Krebs Cycle.

 

For being metabolized, a fatty acid should experiment activation:

 

Fatty acid + CoA + ATP —-à Acyl CoA + AMP + 2(P)

 

The activation of the fatty acid requires 1 molecule of ATP, but since two energy rich bonds are hydrolyzed (the ATP is hydrolyzed to AMP and 2 (P) ) for energetic balance purposes it is considered that 2 ATP have been consumed in this activation process)

 

The formed acyl CoA will experiment different oxidation reactions. These reactions occur in the Beta-carbon. That is why the process is called Beta-oxidation

 

Recalling:

 

       CH3 -………………………………..   -CH2 – CH2 – CH2 – CH2 -COOH

(Omega carbon)                                -Delta-Gamma-Beta-Alpha-Carboxyl

 

In Beta-oxidation (a mitochondrial process) the acyl CoA is totally oxidized to Acetyl groups in form of Acetyl CoA units.

 

Beta-Oxidation

Beta-Oxidation

 

 

 

 

How many Acetyl CoA units will be formed?

 

Since the Acetyl group of the acetyl coA is formed by two carbons, we should divide the number of carbons in the acyl group between two.

 

Miristic acid (14 carbons): 14 carbons /2 = 7 Acetyl CoA

 

Palmitic acid (16 carbons): 16 carbons/2 = 8 Acetyl CoA

 

In order to be completed degraded to Acetyl CoA, the fatty acid in form of acyl CoA should experiment several “rounds” in the Beta-oxidation process. En each round, an Acetyl CoA is released and, a NADH.H+  and a FADH2 are produced.

 

 

We know already how many acetyls CoA are formed from each fatty acid: n/2, where n  is the number of carbons.

 

Now, how many rounds are necessary for converting all the fatty acid to acetyl CoA?

 

Since in the last round we already obtain two Acetyl CoA, the number of necessary rounds is (n/2) -1

 

Observe:

 

Miristic acid (14 carbons)

 

 1st round:

Produce one acyl CoA of 12 carbons and one Acetyl CoA + NAD H.H+  +  FADH2

 

2nd round:

Produce one acyl CoA of 10 carbons and one Acetyl CoA + NAD H.H+  +  FADH2

 

3rd round:

Produce one acyl CoA of 8 carbons and one Acetyl CoA + NAD H.H+  +  FADH2

 

4th round:

Produce one acyl CoA of 6 carbons and one Acetyl CoA + NAD H.H+  +  FADH2

 

5th round:

Produce one acyl CoA of 4 carbons and one Acetyl CoA + NAD H.H+  +  FADH2

 

6th round:

Produce one acyl CoA of 2 carbons and one Acetyl CoA + NAD H.H+  +  FADH2

 

But the acyl CoA of 2 carbons is already an Acetyl CoA, so it is the last round! 

 

So, after 4 rounds, all the Miristic acid has been converted to Acetyl CoA.

 

Then, what we have obtained as a result of the beta-oxidation of Miristic acid?

 

7 acetyl CoA

And 6 NADH.H+ y 6 FADH2

 

The acetyl CoA units are oxidized up to CO2 and H2O in the Krebs Cycle.

 

In terms of  ATP, the yielding depends on the kind of yielding that is used for reduced cofactors:

 

a) If during your course it is considered that each NADH.H+ yields 2.5 ATP and each FADH2 yields 1.5 ATP, then

7 acetyl CoA x 10 ATP/AcetylCoA in the Krebs Cycle: 70 ATP

6  NADH x 2.5 ATP/NADH = 15 ATP

6 FADH2 x 1.5 ATP/FADH2 = 9 ATP

Minus 2 ATP used in the activation (Miristic acid to miristyl CoA)

70+11+9-2 =  92 ATP

 

b) If during your course it is considered that each NADH yields 3 ATP and each FADH2 yields 2 ATP, then

7 acetyl CoA x 12 ATP/AcetylCoA in the Krebs Cycle: 84 ATP

6 NADH x 3 ATP/NADH = 18 ATP

6 FADH2 x 2 ATP/FADH2 = 12 ATP

Minus 2 ATP used in the activation (Miristic  acid to Miristyl coA)

84+18+12-2 = 112 ATP

 

How to calculate the energetic balance of any fatty acid?

 

Step 1.- Number of Carbons/2 = Number of Acetyl CoA formed.

 

Step 2.- Number of rounds in the Beta-oxidation necessary for converting the whole fatty acid to Acetyl Co A units:  Number of Acetyl CoA minus 1 [(n/2)-1]

 

Step 3 (Option a) If you consider that each NADH yields 2.5 ATP and each FADH2 yields 1.5 ATP then multiply the number of rounds times 4 and multiply the number of Acetyl CoA times 1o

 

OR

 

Step 3 (Option b).-  If you consider that each NADH yields 3 ATP and each FADH2 yields 2 ATP then multiply the number of rounds times 5 and multiply the number of Acetyl CoA times 12.

 

Step 4.- Take two ATP that were used for the activation of the Fatty Acid

 

 

Example:

 

Fatty acid with 12 Carbons

 

– Option (a):

 

Step 1:  12/2 = 6 Acetyl CoA

 

Step 2: 6-1 = 5 rounds

 

Step 3 (Option a): (5 x 4) + (6 x10)

 

Step 4 = -2

 

Total: 78 ATP

 

– Option (b):

 

Step 1:  12/2 = 6 Acetyl CoA

 

Step 2: 6-1 = 5 rounds

 

Step 3 (Option b): (5 x 5) + (6 x12)

 

Step 4 = -2

 

Total: 95 ATP

 

I would like now that the reader calculates the energetic balance of the total oxidation of a fatty acid with 18 carbons. Assume that the oxidation of each NADH.H+ yields 3 ATP and that each FADH2 yields 2 ATP.

 

I am looking forward to read your answers in the comments!

 

 

Energetic Balance of the total oxidation of one mol of glucose up to CO2 and H2O: Understanding the contradictions.


 

For understanding the process of total oxidation of glucose, it is necessary to consider the different steps and metabolic pathways involved as well as the cellular location of these processes:

 

   

STEPS

M. PATHWAY

CELLULAR LOCATION

Glucose to  Pyruvate

Aerobic Glycolysis

Cytosol

Pyruvate to Acetyl CoA

Oxidative Decarboxylation of Pyruvate

Mitochondria

Acetyl Co A to CO2

Krebs Cycle

Mitochondria

  

 

Aerobic Glycolysis describes the oxidation of one mol of Glucose (6 carbons)  up to the formation of two moles of pyruvate (3 carbons each).

This conversion involves different reactions where ATP is produced or consumed:

Glucose to Glucose-6-(P)                                                                          – 1 ATP

 

Fructose-6-(P) to Fructose 1,6- bisphosphate                                 – 1 ATP

 

Since Fructose 1,6 bisphosphate becomes two trioses phosphate, the reactions after the aldolase reaction occurs twice (one for each triose that continues the glycolysis). In one reaction, NADH.H+  is produced; in other two reactions, a Substrate Level Phosphorylation (SLP) occur

 (2) Gliceraldehide 3 (P) to (2) 1,3 bisphosphoglycerate           +(2) NADH.H+

 

(2) 1,3 bisphosphoglycerate to (2) 3 phosphoglycerate (SLP*)     + 2 ATP

 

(2) Phosphoenol pyruvate to Pyruvate (SLP*)                                    + 2 ATP

 

(*Maybe it is necessary to recall now that there are two different ways of synthesizing ATP:  (a)SLP, in which ATP is synthesized using energy from some reactions of metabolism, like these reactions, and (b) Oxidative Phosphorylation, synthesis of ATP using the energy released in the Respiratory chain, from the oxidation of reduced cofactors)

 

Total energetic Balance from Glucose to (2) Pyruvate

(Aerobic Glycolysis): 

   _ 2 ATP  +  2 NADH.H+  + 4 ATP  = 2 ATP + 2 NADH.H+ in cytosol

 

 

An excellent animation of this process up to pyruvate can be found here.

 

Pyruvate will enter the mitochondria and will experiment Oxidative decarboxylation, in a reaction catalyzed by the pyruvate dehydrogenase complex.

The global reaction is:

2 Pyruvate + 2NAD+  +2 CoA —à 2 Acetyl CoA + 2 CO2 + 2 NADH.H+

This reaction occurs twice since each glucose (6 carbons) produce 2 pyruvates (3 carbons each), consequently these process produce

2 NADH.H+ in the mitochondria

 

Each Acetyl Co A is oxidized  in the Krebs Cycle yielding:

 

2 Isocitrate to 2 alfaketoglutarate            (+2CO2)                     2 NADH.H+

2 alfaketoglutarate to 2 Succinyl CoA (+2CO2)                          2 NADH.H+

2 Succinyl CoA to 2 Succinate (SLP)                                               2 GTP

2 Succinate to 2 Fumarate                                                                 2 FADH2

2 malate to 2 oxalacetate                                                                   2 NADH.H+

 

An animation with these reactions can be found in this link. 

Observe that at the end of the Kreb Cycle the 6 carbons of glucose have been oxidized to 6 CO2

 

At the same time, from the energetic point of view:

4 ATP have been obtained through Substrate level Phosphorylation (ATP synthesis without intervention of the energy of respiratory chain): 2 were obtained during the Aerobic Glycolysis and 2 were obtained in the Krebs Cycle as GTP (1 GTP is equivalent, from the energetic point of view,  to 1 ATP).

2 FADH2 have been obtained from the Krebs Cycle

8 NADH.H+ have been obtained inside the mitochondria (2 from Oxidative decarboxylation of Pyruvate and 6 from the Krebs cycle)

2 NADH.H+have been obtained in the cytosol through the Aerobic Glycolysis.

 

It is important to do these distinctions about the cellular location of the NADH.H+. since those produced in the cytosol should enter the mitochondria to be oxidized. Since the internal mitochondria membrane is impermeable to these nucleotides, (the mitochondria has their own pool of NAD) the NADH.H+ produced in the cytosol should enter using one of the shuttles already described for transporting the reduction equivalents of cytosolic NADH.H+  through the internal membrane of the mitochondria:

 

a)     the malate aspartate shuttle.

b)     The glycerophosphate shuttle

 

As described in other post, the malate-aspartate shuttle regenerates NADH.H+  inside the mitochondria, the energy yielding of the cytoplasmatic NADH.H+  is the same as if it was generated directly in the mitochondria

 

With the glycerophosphate shuttle, the reduction equivalents of the cytosolic NADH.H+  are transferred to FAD in the inner membrane. It means that the cofactor that will be oxidized in the respiratory chain when this shuttle is used, is FADH2 (see the explanation in this related post)

 

In conclusion, when the malate aspartate shuttle is used for transporting the reduction equivalents from the cytosolic NAD+ inside the mitochondria, we can consider that the t oxidation of glucose has produced:

4 ATP

10 NADH.H+  to be oxidized in the Respiratory chain

2 FADH2 to be oxidized in the Respiratory Chain.

 

If we use the convention that each NADHH+ produce approximately 3 ATP in the Respiratory chain, and each FADH2 produce 2 ATP, the total ATP production is:

 

Substrate Level Phosphorylation (SLP)                           04 ATP

10 NADH.H+  x 3 ATP/NADH.H                                          30 ATP

02 FADH2  x  2 ATP/FADH2                                                04 ATP

 Total                                                                                           38 ATP

 

Using the same convention (each NADHH+ produce approximately 3 ATP in the Respiratory chain, and each FADH2 produce 2 ATP,), but now assuming that the shuttle use is the glycerophosphate shuttle:

 

Substrate Level Phosphorylation (SLP)                         04 ATP

08 NADH.H+  x 3 ATP/NADH.H                                        24 ATP

04* FADH2  x  2 ATP/FADH2                                            04 ATP

 Total                                                                                         36 ATP

(*02 from the use of the glycerophosphate shuttle and 02 from the Krebs Cycle)

 

It explains that some textbooks say that the energetic Balance of the Total Oxidation a a mol of Glucose is 36-38 moles of ATP (since it depends on the shuttle that is used for entering the reduction equivalents of the NADH.H+ produced in the cytosol through glycolysis).

 

Other possible results:

 

As described in other post, some books use the convention that each mol of NADH.H+, when oxidized in the respiratory chain, produce approximately 2.5 moles of ATP, while each mol of FADH2 produce 1.5 moles of ATP. Using this convention:

When the malate-aspartate shuttle is used:

Substrate Level Phosphorylation (SLP)                         04 ATP

10 NADH.H+  x 2.5 ATP/NADH.H                                     25 ATP

02 FADH2  x  1.5 ATP/FADH2                                           03 ATP

 Total                                                                                         32 ATP

 

When the glycerophosphate shuttle is used:

Substrate Level Phosphorylation (SLP)                         04 ATP

08 NADH.H+  x 2.5 ATP/NADH.H                                    20 ATP

04* FADH2  x  1.5 ATP/FADH2                                        06 ATP

 Total                                                                                        30 ATP

(*02 from the use of the glycerophosphate shuttle and 02 from the Krebs Cycle)

 

It explains that some textbooks say that the energetic Balance of the Total Oxidation a a mol of Glucose is 30-32 moles of ATP

 

An advice: When solving a problem of this kind is absolutely necessary to know the conventions used for the yielding of the reduced cofactors (2.5 or 3 ATP/ NADH.H+ ? 1.5 or 2 ATP/ FADH2?) and the kind of shuttle that has been used for entering the reduction equivalents from the cytosol to the mitochondria.  A fair question will have both information. If not information is provided in the question, use the conventions followed by your professor during the lectures.

For students preparing for USMLE exams, the most used review books, like Harvey and Champe, in the “Lippincott Illustrated Reviews” of Biochemistry, Dawn B. Marks in “Biochemistry, Board Review Series”, Kaplan Biochemistry Lecture Notes for USMLE and “First Aid for the USMLE Step I”, agree in using the equivalence of  ‘approximately” 3 ATP for each NADH.H+  that is oxidized and ‘approximately” 2 ATP per FADH2. 

 

Related post:

To understand the mechanism of the shuttles and their difference in yielding ATP, I strongly recommend to read this post.