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Topic : GLYCOLYSIS Now that we have a general picture of what glycolysis

Lecturer: Dra. Uy is, we will be discussing the glycolytic pathway step by


step.
GLYCOLYSIS
-breakdown of GLUCOSE to 2 moles of PYRUVATE REVIEW on Carbohydrate structure
(and LACTATE in RBCs remember, in the absence of To fully understand and appreciate the enzymes, the structures and
oxygen) the biochemical processes, it might be necessary to discuss some
structure and concepts about carbohydrates and glucose.
-occurs in the CYTOSOL of ALL CELLS
-yields a total of 40 ATP under AEROBIC CONDITIONS Carbohydrates are simply Carbon (C) plus
(uses 2 in the process so NET ATP is 38) Water(hydrate, H2O)
-yields 2 ATP under ANAEROBIC CONDITIONS
-requires Magnesium ion as cofactor C + H2O = C-H2O

Here’s the big picture of what Glycolysis, aerobic and So if we have a carbohydrate compound, we sort of like
anaerobic conditions are and why these are important: have a compound with lots of Carbon and Water joined
After eating rice or any other food which is essentially together.
CARBOHYDRATES, it is converted to GLUCOSE.
C-H2O- C-H2O C-H2O- C-H2O C-H2O- C-H2O C-H2O- C-H2O
Glucose then undergoes GLYCOLYSIS. The important C-H2O- C-H2O C-H2O- C-H2O C-H2O- C-H2O C-H2O- C-H2O
products of this glycolysis are :

ATP, NADH and PYRUVATE. Glucose is a simple carbohydrate. That means glucose
must also be composed of Carbon and Water as well.
Let’s analyze the products of Glycolysis. Glucose has six carbons. Six carbons means we also
have six water molecules. So,
(1)ATP: ATP is already a final product, meaning it’s
1 C-H
already functional and will be used by the cell for 2O
I
2 C-H2O
energy-requiring activities. Notice that we have not yet
involved the electron transport chain to generate ATP 3 I
C-H2O
and this is what is meant by the term substrate-level 4 I
C-H2O
phosphorylation. 5 I
C-H2O
6 I
C-H2O
(2)NADH: NADH, in the presence of oxygen (aerobic
condition) will be used in the ELECTRON TRANSPORT Also, glucose, as we learned previously, is a
CHAIN (ETC) to generate ATP. Each mole of NADH is carbohydrate sugar with an Aldehyde and an Alcohol
equivalent to 3 ATP. Since we already enter the ETC, group. So to complete the structure of glucose, we need
this is now called oxidative phosphorylation. to show these groups.

(3) PYRUVATE, by the action of pyruvate


dehydrogenase complex will be converted to acetyl- Let’s take care of the alcohol group first.
coA. Acetyl-coA will then enter the carboxylic acid Alcohol is a compound with a functional group
cycle/Krebs cycle. The Krebs cycle will generate 12 represented as R-OH.
moles of ATP per cycle and will involve oxidative R here can be substituted with any organic compounds
phosphorylation. like CH3-, CH2CH3-. For example, in R-OH, if we replace R
with CH3, (methyl),we get
Notice that in the absence of Oxygen, NADH and CH3-OH or what we commonly known as methyl
Pyruvate cannot be utilized as products of glycolysis and alcohol. If we replace R with CH3CH2 (ethyl) we get
we can only produce 2 ATP via the substrate level CH3CH2-OH or ethyl alcohol, the alcohol you use in your
phosphorylation. This is known as anaerobic hand sanitizers and rubbing alcohol.
respiration and occurs in states like heavy exercise
where oxygen is already depleted because of too much
cellular activity.
In our illustration in the previous page, notice that if we be attached on the sixth carbon, it is specifically called
place an additional Hydrogen in carbon number 6, we glucose-6-phosphate.
will arrive at a structure similar to this :
1 C-HO
1 C-H
2O
I
2 C-H2O
I
2 C-H2O 3 I
3 I
C-H2O
C-H2O 4 I
4 I
C-H2O
C-H2O 5 I PO4 on Carbon 6
5 I C-H2O
C-H2O additional H 6 I
6 I C-H2O-PO4
C-H2O-H
If an additional phosphate group is added just beside
It follows the alcohol pattern of R-OH right? the phosphate group already attached, then our
What about the aldehyde group? Aldehydes are compound is called glucose-6-diphosphate. But if an
compounds which follows the pattern R-CHO. additional phosphate is attached in another carbon, say
Again, R can be any compound. For example if we Carbon number 1, then our compound will be called,
replace R with CH3 we get CH3-CHO or methyl aldehyde. glucose-1,6-bisphosphate.
If we replace R with Hydrogen, we get H-CHO or what
we commonly know as formaldehyde, or the formalin
we use in the cad room.  Glycolysis : the steps.

So what happens if we take one Hydrogen from the first (1)So the carbohydrate from the rice we ate was
carbon in our illustration above? We get a structure digested to glucose, glucose in turn will be acted upon
similar to this : by our first enzyme HEXOKINASE. From our review
remove H
above, we know that hexokinase will convert glucose to
1 C-HO
glucose-6-phosphate (G6P).
I
2 C-H2O
3 I HEXOKINASE
C-H2O GLUCOSE GLUCOSE-6-Phosphate
4 I R group ATP  ADP
C-H2O
5 I What you need to know about this step:
C-H2O
6 I -Hexokinase has a low Km (very high affinity for
C-H2O-H
glucose) and will be inhibited by high concentrations of
If you consider the boxed structure as the R group, we Glucose-6-phosphate as a regulatory mechanism. When
now follow the aldehyde pattern R-CHO. Notice that this happens, another enzyme, glucokinase (GCK), not
the Hydrogen we removed from the first carbon to inhibited by G6P, will act on excess glucose to prevent
make the aldehyde group is the same hydrogen we add hyperglycemia.
in the sixth carbon to make the alcohol group. So we
have the carbon, the hydrate (water), the aldehyde, the -remember that glucokinase activity REQUIRES
alcohol and so we have the final glucose structure. ENERGY in preparation for conversion to glycogen, the
storage form of glucose. You store only when there is
Now what if a certain HEXOKINASE enzyme acts on our abundant supply. So during the starved state, you do
glucose? not store, because there is nothing to store in the first
If we breakdown the name of the enzyme, we will have place, and the activity of glucokinase decreases.
a clue as to what it does. HEXO means 6, so probably,
this enzyme acts on compounds with 6 carbons. -genetic defect in GLUCOKINASE is present in a disease
KINASE, remember, always transfers a PHOSPHATE called MODY (Maturity-Onset Diabetes of the Young)
group usually from ATP to the compound it is acting on. Type 2 whose primary symptom is hyperglycemia

So if a HEXOKINASE acts on our glucose what will (2) The next step is the conversion of glucose-6-
happen? Hexokinase will transfer one phosphate group phosphate to fructose-6-posphate via the enzyme
from ATP to our glucose. Since ATP loses a phosphate phosphoglucose isomerase
group it now becomes a diphosphate or ADP. And our
glucose after receiving the phosphate from ATP will Phosphoglucose isomerase
become glucose-phosphate. And since phosphate will GLUCOSE-6-phosphate fructose-6-Phosphate
(3) Fructose-6-phosphate will then be Phosphorylated After the splitting stage, we are now ready to collect
again. Since this is phosphorylation we have a clue that the ATPs. 
the enzyme involved is a KINASE. This KINASE will act on
a substrate which is fructose that has a phosphate (6) Each GADPs we produce will undergo
attached to its 6th carbon. The name of the enzyme dehydrogenation and addition of inorganic phosphate
therefore is PHOSPHOFRUCTOKINASE 1 (PFK1). This using the enzyme glyceraldehyde-3-phosphate
enzyme will add phosphate to the first carbon of dehydrogenase (GADPH). This step yields 1,3-
fructose-6-phosphate so we would end up with a bisphosphoglycerate (1,3-BPG) and NADH.
compound named fructose-1,6-bisphosphate.
GADPH
PHOSPHOFRUCTOKINASE GADP 1,3-BPG + NADH
FRUCTOSE-6-phosphate FRUCTOSE-1,6-bisphosphate
ATP  ADP *GADPH is inhibited by SULFHYDRYL AGENTS

What you need to know about this step: (7) Notice that on our previous product, 1,3-BPG*, we
have two phosphate groups. In the next reaction we will
- this is an IRREVERSIBLE and the REGULATORY STEP of transfer one of these phosphate group to ADP which
glycolysis means we will generate ATP from ADP via the enzyme
- deficiency in phosphofructokinase leads to Phosphoglycerate Kinase(PGK). Because 1,3-BPG loses
accumulation of glycogen and manifests as HEMOLYTIC a phosphate group it now called 3-phosphoglycerate
anemia an muscle cramping (3-PG)

PGK
Notice that in steps 1 and 3 we’ve used a total of 2
1,3-BPG 3-PG
ATPs. This is known as the preliminary or the ADP  ATP
investment stage of glycolysis. This means that we are
investing ATP to produce more ATPs. *1,3-BPG can also be converted to 2,3-BPG via the a
MUTASE enzyme. 2,3-BPG binds greatly in
(4) The next step is known as the splitting stage. deoxygenated Hgb. It can be converted to 3-PG to
Splitting means we will split our 6-carbon sugar into two enter the glycolytic pathway again via the enzyme
3-carbon sugar (triose). Fructose-1,6-bisphosphate will Phosphatase.
be split to 2 triose sugars namely D-glyceraldehyde-3-
phosphate (GADP) and dihydroxyacetone phosphate (8) 3-PG will undergo isomerization and will be
(DHAP)by the enzyme ALDOLASE. These two sugars are converted to 2-Phosphoglycerate (2-PG)
ISOMERS.
(9) 2-PG under the action of Enolase will be converted
ALDOLASE
FRUCTOSE-1,6-bisphosphate GADP + DHAP
to Phosphoenol Pyruvate (PEP).

*ENOLASE is INHIBITED by FLUORIDE.


(5) DHAP can be converted to GADP by the enzyme
Triose Phosphate Isomerase. So in essence, we produce (10) Finally, PEP by the action of the enzyme pyruvate
2 GADPs. kinase will be dephosphorylated and its phosphate
group will be donated to ADP to form ATP. This is our
What you need to know about this step: second substrate level phosphorylation.

-Aldolase A is found in muscles and RBCs and deficiency Pyruvate kinase


PEP Pyruvate
of which causes nonspherocytic hemolytic anemia ADP  ATP

-deficiency in Triose phosphate isomerase leads to


neonatal hemolytic anemia and progressive neurologic Deficiency in Pyruvate Kinase leads to poor production
inolvement of ATP (ADP has higher concentrations than ATP) and
consequently affecting the ion pumps (esp Na-K
ATPase) which causes the cells to swell and lyse leading
to hemolytic anemia.
ATP COUNT Regulation of Glycolysis:

For one glucose molecule : -Under the FED STATE, there is HIGH LEVEL of INSULIN
and LOW LEVEL OF GLUCAGON. This causes decreased
ATP Loss : cAMP and consequently decreased level of protein
In step 1, we used 1 ATP. kinase A. This decreased level of protein kinase A
In step 3, we used another ATP. causes dephosphorylation or activation of PFK2 in the
Total ATP used : 2 bifunctional enzyme PFK2/FBP2. Activation of PFK2
causes formation of Fructose-2,6-bisphosphate.
ATP Gained : Elevated levels of Fructose-2,6-bisphosphate leads to
In Step 6, we generated 1 NADH. Remember that increased glycolysis because it is a POTENT ACTIVATOR
Glucose was split into two triose? of Phosphofructokinase 1.
So that means 1NADH x 2 = 2NADH
Total NADH generated : 2 This NADH can enter the Bottomline : Fed state, insulin and Fructose-2,6-
Krebs cycle under aerobic conditions. bisphosphate favors GLYCOLYSIS.
Each NADH is equal to 3ATP.
So 2 NADH x 3 = 6 Inhibitors of Phosphofructokinase :
Total ATP generated = 6 - Citrate
- ATP
In Step 7, we generated 1 ATP. (x2 since we split - Hydrogen ions (low pH/acidic environment)
glucose into two)
In Step 10, we generated 1 ATP. (x2 since we split Activators of Phosphofructokinase:
glucose into two) - AMP
Total ATP Generated = 4 - Fructose 2,6-bisphosphate

Our final product is pyruvate (x2). Pyruvate will enter


the Krebs cycle. But before that, it should be converted
to acetyl-coA first by pyruvate dehydrogenase
complex. This step produces 1 NADH (x2).
Each NADH is equal to 3ATP.
So 2NADH x 3 =6
Total ATP Generated : 6

When the 2 pyruvates we have had been converted to


acetyl-coA, each oh these two acetyl-coA will generate
12 ATP after entering the Krebs Cycle. So 12 X 2 =24
Total ATP generated : 24

TOTAL ATP Generated for 1 glucose molecule : 40


TOTAL ATP used : 2
NET ATP Generated : 38

Under anaerobic conditions, we do not have oxygen


which means we cannot proceed with the Krebs cycle
and the only way we can generate ATP is via steps 7 and
10. That means we generate 4 ATPs but since we use 2
ATPs in steps 1 and 3, our NET ATP gain for anaerobic
condition is only 2.