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8-2: Glycolysis
Cellular Respiration: An Overview
3 Stages:
1) Glycolysis
 Occurs in the cytoplasm
 Splits glucose (6 C) into two pyruvate (3 C) molecules
2) Krebs Cycle
 Occurs in the mitochondrial matrix
 Breaks down a pyruvate derivative (Acetyl CoA) into CO2
 Both glycolysis and the Krebs Cycle produce:
o A small amount of ATP
o NADH by reducing NAD+
o Use SUBSTRATE-LEVEL PHOSPHORYLATION = ATP production by
the direct enzymatic transfer of phosphate from an intermediate substrate
in catabolism to ADP.
3) Electron Transport Chain
 Occurs along the inner membrane of the mitochondria
 Accepts energized electrons (e-s) from reduced coenzymes (NADH and FADH2)
 Couples the exergonic slide of e-s to ATP synthesis or…
OXIDATIVE PHOSPHORYLATION = ATP production that is coupled to the
exergonic transfer of e-s from food to oxygen
_______________________________________________________________________
GLYCOLYSIS = catabolic pathway during which 6-C glucose is split into two 3-C sugars,
called pyruvate
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Occurs in the cytoplasm
No CO2 is released
Occurs whether or not oxygen is present
Energy-Investment Phase:
1) 2 ATP are used to activate glucose by phosphorylating it
 This is endergonic
2) Glucose is split into two 3-C molecules known as Glyceraldehyde-3-Phosphate (G3P).
 After this, each G3P goes through the same series of steps
Energy-Harvesting Phase:
3) G3P is oxidized  e-s are removed, along with two H+ ions
 These are passed to NAD+ to form NADH as follows:
2 NAD+ + 4 e- + 2 H+  2 NADH


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2 NADH’s are made total, one from each G3P
This is very exergonic
G3P is phosphorylated by inorganic phosphate, increasing the energy of the
molecule again
4) ATP is produced by substrate-level phosphorylation
 Highly exergonic
5) Molecule is rearranged
6) ATP is produced again by substrate-level phosphorylation
 Highly exergonic
In Summary:
Glucose + 2 ATP + 2 NAD+  2 pyruvic acid + 4 ATP + 2 NADH + 2 H+
Net Gain: 2 ATP + 2 NADH
FERMENTATION
Cellular respiration is an aerobic process, but some organisms can oxidize their food under
anaerobic conditions = existing in the absence of free oxygen
Fermentation = anaerobic catabolism of organic nutrients
 Begins with Glycolysis
 Still gets a net gain of 2 ATP
 Instead of being further oxidized (as it is in respiration), the NADH hands the two
electrons back to the organic molecule they came from, reducing it again.
Two Main Types:
1) Alcohol Fermentation
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Final product is ethanol
Releases CO2
Many yeasts and bacteria carry out alcoholic fermentation under anaerobic conditions
2) Lactic Acid Fermentation
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Final product is lactate (lactic acid)
When O2 is scarce (a.k.a. oxygen debt), vertebrate muscle cells switch from
aerobic respiration to lactic acid fermentation
Lactate accumulates and the lower pH it provides:
o Causes pain
o Slows muscle contractions (a.k.a. muscle fatigue), allowing O2 to build
back up again  “2nd wind”
The lactate is gradually carried to the liver where it is converted back to pyruvate.
Advantages:
 Makes FOOD!! Like cheese, yogurt, sauerkraut, soy sauce, etc.
 Makes Chemicals: isopropanol, acetic acid, etc.
 Alcoholic beverages: wine, beer, etc.
Disadvantage: Less ATP per glucose 
 The 2 ATP net gain in fermentation (from glycolysis) = 14.6 kcal.
 Complete breakdown of glucose to CO2 and H2O = 686 kcal.
 Efficiency rate of fermentation = 14.6 / 686 (x100%) = 2.1%
 Fermentation will only produce 2 ATP per glucose, but aerobic respiration can produce
36-38 ATP per glucose!
8-3 Notes: Cellular Respiration
Recall: Glycolysis involves glucose being broken down into 2 pyruvate molecules.
The remainder of Cellular Respiration occurs in the mitochondrion. Review its structure:
The Preparatory (Prep) Reaction
The 2 pyruvates cannot directly enter the next phase (nor the mitochondrion), but must be
modified first.

The molecule is oxidized by transferring two e-s to NAD+  NADH

One carbon is removed, forming CO2

Coenzyme A is added, making the final product acetyl CoA

This reaction happens twice for each molecule of glucose first entered.

Final Tally: 2 pyruvate  2 acetyl CoA + 2 CO2 + 2 NADH
The Citric Acid (Krebs) Cycle

Occurs in the mitochondrial matrix

Requires 2 turns for one glucose molecule
Many steps are involved, but here are the ones you need to know:
1) Acetyl CoA (2 C) enters and combines with oxaloacetate (C4) to form Citric Acid (C6)
2) The compound is oxidized a total of 4 times, losing two e-s each time
o Forms a total of 3 NADH and 1 FADH2
3) The compound is phosphorylated by an inorganic phosphate, which it then transfers by
substrate-level phosphorylation to ATP
4) During the cycle, the compound also loses a total of 2 C’s as CO2
o This completes the breakdown of the original 6-C glucose molecule
Net Gain from Citric Acid Cycle (per glucose or 2 turns of the cycle)
2 ATP
6 NADH
2 FADH2
THE ELECTRON TRANSPORT CHAIN

Series of electron carrier (protein) molecules embedded in the inner mitochondrial
membrane (cristae) of eukaryotes (or the plasma membrane invaginations of prokaryotes)

NADH and FADH2 pass their high energy e-s to the E.T.C., becoming oxidized again
o They can now be reused

Each carrier in the chain is successively more electronegative (pulls on electrons harder)
than the one before it, so electrons passed from one to the next in series

Most carriers in the chain are forms of cytochrome

1st carrier = FMN (Flavin mononucleotide)  becomes reduced when it accepts the
electrons, but immediately becomes oxidized when the next carrier takes the electrons
from it.

This pattern continues the length of the chain until the final electron acceptor – O2 – is
reduced.
o As molecular oxygen is reduced, it also picks up H+ ions from the matrix to form
H2O
o For every 2 NADHs, 1 O2 is reduced to 2 H2O
o O2 is so important, that if it is not present, the chain does not function and NO
ATP is produced by the mitochondria.

At any given time, the human body only contains enough ATP to sustain
life for ~1 minute!

Cellular respiration must be done constantly to prevent death. (That’s why
suffocation is quick).

Estimated that our mitochondria produce our body weight in ATP every
day!

The E.T.C. does NOT create ATP. It generates an electrochemical gradient across the
inner mitochondrial membrane, which stores potential energy that can be used to
phosphorylate ADP  ATP.

How it works: The Energy-Coupling Mechanism
o Chemiosmosis = the coupling of exergonic e- flow down an e- transport chain to
endergonic ATP production by the creation of a proton gradient across a
membrane
o Proposed by Peter Mitchell (1961)
o The term chemiosimosis emphasizes the coupling between (1) chemical reactions
(phosphorylation) and (2) transport processes (H+ transport)
o Site of oxidative phosphorylation = the Inner Mitochondrial Membrane

cristae = the infoldings of the inner mitochondrial membrane

These increase the surface area available for chemiosmosis to
occur

Contain ATP synthase = protein complexes that function as
enzymes to catalyze the production of ATP
o Use the existing proton gradient from the ETC

Process:
o 3 of the carriers in the chain are also H+ pumps
o NADH drops its electrons off at the first one, and they pass through all three on
their way to oxygen.
o FADH2 drops its e-s off at a different carrier after the first one, so its electrons
only pass through two of the pumps.
o When each of these three pick up the electrons, they pump a H+ out of the matrix
(LOW [H+]) to the intermembrane space (HIGH [H+]).
o This creates a proton gradient, which is maintained because the membrane is
impermeable to H+ and prevents them from leaking back across the membrane by
diffusion
o This creates potential energy
o ATP Synthase uses the potential energy stored in the proton gradient to make
ATP by allowing H+s to diffuse through it back across the membrane
o The drop in potential energy can then be captured in the bonds that attach the last
phosphate to ADP  ATP.
The process is similar to a battery:
(We’ll draw it in class)
The proton gradient that results is called the Proton Motive Force = potential energy stored in the
proton gradient created across biological membranes that are involved in chemiosmosis

This is an electrochemical gradient with:
o Concentration gradient of protons (chemical gradient)
o Voltage across the membrane b/c of a higher concentration of positively charged
protons on one side (electrical gradient)

It tends to drive protons across the membrane into the matrix
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For every one H+ pumped out in the ETC, one H+ is allowed to diffuse back in
through an ATP synthase, creating one ATP

Therefore, for every pair of e-s dropped off by:
o NADH leads to ATP synthase creating 3 ATP
o FADH2 leads to ATP synthase creating 2 ATP
Final Tallies of ATP
From Glycolysis: 2 ATP (net gain)
From Citric Acid Cycle: 2 ATP
ATP yield from the ETC is often slightly lower than predicted because the electrons from NADH
created in glycolysis must be transported across the membrane by one of several “shuttle”
carriers. Depending on which is working, they are either transferred to NAD+ or FAD. If FAD
is used, the yield is lower.
(Complete on your own or wait until we do this in class…)
Process
ATP Produced
Directly by
Substrate-Level
Phosphorylation
Reduced
Coenzyme
ATP Produced by
Oxidative
Phosphorylation
ATP
NADH 
ATP
Prep Step
ATP
NADH 
ATP
Citric Acid Cycle
ATP
NADH 
ATP
FADH2 
ATP
Glycolysis
(Net)
TOTAL:
Total ATP
8-4 Notes
We learned yesterday how ATP is made through Oxidative Phosphorylation in the
mitochondrion. The key is the coupling of the proton gradient created by the ETC and the
exergonic diffusion of protons back into the matrix by the ATP synthase complex.
Even with this awesome process, only about 34% of the energy released from the proton gradient
is captured in the bonds of ATP. The rest is lost to the cell/organism as heat.
Occasionally, it is beneficial to actually decouple the creation of ATP from the diffusion of H+s
back down their electrochemical gradient.

If that happens, none of the energy is captured in the bonds of ATP and all of the
potential energy is converted to heat.

This is beneficial in thermoregulation of animals, as seen in:
o Brown fat in newborns and other species
o Hibernating mammals

If they didn’t do this, they would generate so much ATP, cellular
respiration would shut down completely
CATABOLISM
We don’t eat just glucose, so how do we get energy (ATP) from other food sources?
Things our body does:

Carbohydrate digestion:
o Starch is hydrolyzed into individual glucose molecules in digestion
o In between meals, glycogen is hydrolyzed into individual glucose molecules by
glucagon
o In the small intestine, carbohydrates are broken down into glucose

Protein digestion:
o Proteins are hydrolyzed into amino acids in the stomach and small intestine

Amino acids are used as monomers to make new proteins OR

Deaminated (have the amino group removed) to a carbon skeleton, which
can be converted into acetyl groups (like acetyl CoA) or can enter the
citric acid cycle at some juncture

Fat digestion:
o Fats can be hydrolyzed in the small intestine into glycerol and fatty acids
o Glycerol can be converted to pyruvate and enter at the end of glycolysis
o Fatty acids can be broken down into 2-C acetyl CoA’s that enter the citric acid
cycle
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Ex. A single 18-C fatty acid chain  9 acetyl CoA molecules

These can enter the Citric Acid Cycle and form:
o 27 NADH
o 9 FADH2
o 9 ATP in the Citric Acid Cycle

The NADH can create a total of 27 x 3 = 81 ATP in the ETC
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The FADH2 can create a total of 9 x 2 = 18 ATP in the ETC
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Added together with the ATP from the Citric Acid Cycle = 108 ATP!!!
o This is why fats are an efficient form of stored energy: one triglyceride can
produce a lot of ATP when needed
ANABOLISM
Building new molecules often requires the use (breakdown) of ATP. These catabolic pathways
we’ve discussed explain how to replace those ATP molecules.
Biosynthetic Needs:

Photosynthesis uses ATP to help build glucose from CO2 and H2O (next unit).

Excessive carbohydrate intake results in fat formation
o Extra G3P molecules from glycolysis  glycerol
o Extra acetyl groups from glycolysis  fatty acids
o Put together = FAT

Some substrates from the citric acid cycle can be transaminated into amino acids
o 9 amino acids are “essential”  we can’t make them
o The other 11 we can created by altering the others through metabolic pathways
Control of Cellular Respiration
The process of cellular respiration, like all other pathways of the cell, must be finely controlled.

Uncontrolled, your body would burn through all your food very quickly, without
anywhere to put the excess energy.
o This energy would then be converted to heat and lost from the cell.
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By shutting down the pathway at times, it allows the cell to control the amount of ATP
produced and not waste precious food energy.
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Although there are several control points in the process, the one you need to know the
best is an enzyme in the glycolysis pathway called phosphofructokinase.
o It is involved with the third step in the glycolytic pathway, in which it acts as an
enzyme that phosphorylates the original glucose molecule for the 2nd time by
transferring a phosphate from ATP to the substrate.
o It is an ALLOSTERIC enzyme
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It is activated by the presence of AMP
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It is inhibited by excess ATP and by citric acid (from the citric acid cycle)
This is a form of feedback inhibition