Overview

of Metabolism

Catabolism - breakdown of large particles into a small particle that is useful.

Anabolism - small metabolites produce a large product

ATABOLISM PROCESS
C
Catabolism is the breakdown of large molecules to smaller molecules.
● Carbohydrates,
● Fats,
● and Proteins need to be catabolized

Metabolite - products of metabolism

Catabolism is an exergonic reaction

Exergonic reaction sustains.
● ATP
● NADH
● NAD(P)H

Most important metabolites produced by catabolism

● ATP
● NAD(P)H
Catabolism produces energy-poor metabolites, 2CO2, H2O, NH3

NABOLISM PROCESS
A
Anabolism is the use of small molecules as building blocks to create larger molecules.

Endergonic reaction uses ATP and NAD(P)H

ATP and NAD(P)H are vital in maintaining the continuous cellular processes.

Anabolism needs ATP, NAD(P)H , and NADH to change Amino Acids, Sugars, Fatty Acids,
Nucleotides to Proteins, Polysaccharides, Lipids, Nucleic Acids.

NAD(P)H provides Phosphorus if phosphorylation is needed.

Phosphorylation is the addition of a phosphoryl group to a molecule.

HE FATE OF GLUCOSE
T
Glucose molecular formula (C6H12O6)

Pyruvate is the end product of Glycosylation

If pyruvate,
● undergoes fermentation, it produces yeasts (Ethanol).
● Pyruvate is converted to lactate depending on the needs of the body.
The fate of glucose in exercising muscle varies with
● physiological conditions
● Tissues
● And organisms.
 GLYCOLYSIS (EMBDEN-MEYERHOF PATHWAY)
● a set of reactions that converts glucose to pyruvate or lactate.
● irst metabolic pathway that has been elucidated and considered a paradigm for
the structure of metabolic pathways.
● Glycolysis reaction happens in the cytoplasm of every animal cell
● Does not require the presence of a molecular oxygen
● Generates 4 gross ATP but the process consumes 2 ATP, producing 2 net ATP.
● Generates 2 NADH molecules
GLYCOLYSIS PROCESS
 rythrocytes , cornea , and lens of the eyes do not have mitochondria. Cells without a
E
mitochondria convert pyruvate to lactate. Lactate is used by the RBC, cornea, and lens to
produce ATP

Cells with mitochondria undergo two conditions:

● Anaerobic - does not use oxygen
● Aerobic - uses oxygen
Cells with mitochondria undergoing anaerobic conditions convert pyruvate to lactate.
Cells with mitochondria undergoing aerobic conditions convert pyruvate to Carbon
Dioxide and Water molecule (CO2 + H2O).

For Glycolysis to continue, NAD needs to be regenerated. NAD is produced in the

mitochondria.
Cells without mitochondria get NAD from NADH.

The production of NADH is produced during the conversion of pyruvate and lactate.

HASES OF GLYCOLYSIS
P
1st Phase - glucose is broken down to two molecules of glyceraldehydes.
2nd Phase - produce ATP and NADH

STAGE OF GLYCOLYSIS
Stage 1
● Investment of ATP. Starting point: glucose.
● Upon the action of hexokinase, phosphorylates glucose converting it to
glucose-6-phosphate. ATP turns to ADP at this stage

Glucose-6-phosphate means the phosphate is attached to the carbon 6 of glucose.

The negative charge concentrates glucose in the cell and glucose becomes less stable
(glucose becomes open for several chemical reactions).

Normally, the body has to activate phosphoglucose isomerase when glucose-6-phosphate

is present converting it to fructose-6-phosphate. Glucose-6-phosphate and
fructose-6-phosphate are interchangeable/reversible with phosphoglucose isomerase.

hosphofructokinase phosphorylates the carbon 1 (1st carbon) of fructose-6-phosphate

P
converting it to fructose-1,6-bisphosphate.
 Step-by-Step reaction of 1st Stage:

st reaction : The Phosphorylation of glucose (Investment of ATP)

1
Also uses magnesium. The phosphorylation of Glucose into glucose-6-phosphate traps it
in the cell. Phosphorylation of glucose is irreversible.

Hexokinase is an isoenzyme which catalyzes phosphorylation of glucose.

nd reaction : The conversion of Glucose-6-phosphate to Fructose-6-phosphate

2
Reaction is catalyzed by phosphoglucose isomerase . These reactions are reversible and
interchangeable meaning that Glucose-6-phosphate can be converted to
Fructose-6-phosphate , and Fructose-6-phosphate can also be converted into
Glucose-6-phosphate . This reaction occurs in glycolysis and gluconeogenesis.

Glucose-6-phosphate is an aldose while Fructose-6-phosphate is a ketose .

rd reaction : The conversion of Fructose-6-phosphate to Fructose-1,6-bisphosphate

3
Rate-limiting step of glycolysis. This reaction is irreversible.

Phosphofructokinase is the enzyme that catalyzes the conversion of fructose-6-phosphate

by the enzyme phosphofructokinase.
The second ATP is invested during this reaction.

tage 2
S
● The 6-carbon sugar is split into two 3-carbon fragments.
● In stage 2, two phosphorylated trioses/triose phosphates are produced.

Phosphorylated trioses/triose phosphate - molecule with three phosphates

ructose-1,6 bisphosphate to Glyceraldehyde 3-phosphate

F
Fructose-1,6 bisphosphate split into Glyceraldehyde 3-phosphate and
Dihydroxyacetone phosphate.

Aldolase catalyzes the conversion of Fructose-1,6 bisphosphate to Glyceraldehyde

3-phosphate and Dihydroxyacetone phosphate.

Glyceraldehyde 3-phosphate can be converted to Dihydroxyacetone phosphate and vice

versa. Triose phosphate isomerase catalyzes the interchangeable conversion of
glyceraldehyde 3-phosphate to dihydroxyacetone phosphate.
 tage 3 (Energy Yielding Phase) (Oxidation of the 3 carbon fragments yields ATP)
S
1st Reaction:
Glyceraldehyde 3-phosphate is converted to 1,3-Diphosphoglycerate and vice versa by
the enzyme glyceraldehyde 3-phosphate dehydrogenase. This reaction converts NAD to
NADH.

nd Reaction:
2
1-3-bisphosphoglycerate is converted to 3-phosphoglycerate and vice versa by the
enzyme phosphoglycerate kinase. This reaction converts an ADP molecule to the 1st ATP
produced in glycolysis.

rd Reaction:
3
3-phosphoglycerate is converted to 2-phosphoglycerate and vice versa by the enzyme
phosphoglycerate mutase.

th Reaction:
4
2-phosphoglycerate is converted to phosphoenolpyruvate and vice versa by the
enzyme enolase. This reaction also produces H2O.
5th Reaction:
Phosphoenolpyruvate is converted to pyruvate by the enzyme pyruvate kinase. This
reaction converts an ADP molecule to produce the 2nd ATP produced by glycosylation.

Phosphoryl Transfer Reaction requires Magnesium(Mg2)

Kinases transfer phosphate from ATP to an acceptor.
Hexokinase has a more general speci icity in that it can transfer phosphate to other
sugars such as mannose.

Conversion of an aldose to a ketose is catalyzed by phosphohexose isomerase and Mg2.

Phosphofructokinase-1 (PFK)
-important allosteric enzyme regulates the rate of glucose catabolism and plays a role in
integrating metabolism.

llosteric enzymes are enzymes that contain a small region to where molecules bind to
A
create a reversible alteration of the enzyme's active site, thus, changing the catalytic
behavior of the enzyme.

is - means two phosphate groups on two different carbon atoms.

B
Di- means two phosphate groups linked together on the same carbon atom.
 PFK reaction
● Is the irst unique and irreversible step in the glycolytic pathway.
● It is the "committed" in the pathway
● In general, the enzyme catalyzing the committed step in a metabolic pathway is the
most important control component in the pathway.

Aldolase converts ketose to acetone and aldose

All Dihydroxyacetone phosphate (DHAP) is converted to glyceraldehyde 3-phosphate.

Although it is reversible it is shifted to the right since glyceraldehyde 3-phosphate is a
substrate for the next reactions of glycolysis. Thus, both 3 carbon fragments are
subsequently oxidized. However, when there is an "excess" amount of ATP, glyceraldehyde
3-phosphate is converted to DHAP by triose phosphate isomerase. As such, DHAP acts as
possible energy in stored form.

Under anaerobic conditions, pyruvate is converted to lactate or lactic acid . Examples are
exercising muscles.

EMEMBER!
R
NAD+ is consumed in the glyceraldehyde 3-phosphate reaction but is produced in the
lactate dehydrogenase (DH) reaction. Thus, The redox balance is maintained through this
reaction. The activities of glyceraldehyde 3-phosphate DH and lactate DH are linked
metabolically.

Glucose + 2 P + 2ADP -> 2 lactate + 2 ATP + 2 H2O

RUCTOSE AND GALACTOSE FEED INTO THE GLYCOLYTIC PATHWAY

F
FRUCTOSE
Fructose is converted to Fructose 1-phosphate by the enzyme Fructokinase. This
reaction uses ATP changing it to ADP.

ructose 1-phosphate is converted to Glyceraldehyde by the enzyme Fructose

F
1-phosphate aldolase.

lyceraldehyde is then converted to Glyceraldehyde 3-phosphate or dihydroxyacetone

G
phosphate by Triose kinase .
 ALACTOSE
G
Galactose is converted to glucose-6p via a four step reaction involving UDP-glucose .
1. Galactose is converted to glucose-6-phosphate (glucose-6p)
2. Glucose-6p converted to fructose-6-phosphate (fructose-6p)
3. Fructose-6p converted to fructose-1,6-bisphosphate (F-1,6-BP)
4. F-1,6-BP is converted to two trioses: DHAP or glyceraldehyde-3-phosphate (GAP)
5. GAP to pyruvate

Three points of control:

1. Hexokinase and Glucokinase
● Hexokinase is strongly inhibited by its product. If there are many G-6P, hexokinase
will stop its function.
● Although liver parenchymal cells contain hexokinase, this is where glucokinase is
found.
● Hexokinase is inhibited by the absence or presence of glucose-6p. However,
glucokinase is not inhibited by G-6P but is inhibited by fructose-6p and stimulated
by fructose-1p.
● Glukokinase is decreased by Cyclic adenosine monophosphate (cAMP.) Present in
liver and pancreatic beta cells.
2. PFK-1
● also known as 6-phosphofructo-1-kinase, controlled by fructose-2,6-bisphosphate
● ATP and Citrate is an allosteric inhibitor of PFK-1.

3. Pyruvate kinase

Disease and Clinical Considerations

Lactic Acidosis
● high blood lactate levels through strenuous exercises
● Accumulation of plasma lactate may be secondary to tissue hypoxia, severe anemia,
or problems in mitochondrial enzymes. Inhibitors of oxygen transport like CO or
cyanide poisoning, liver disease, and excessive alcohol drinking.

Diabetes
● insulin activity is low, glucagon level increases. the glucagon ratio is higher in
diabetes. There is no increase in glucose uptake in the liver because liver tissue
does not express GLUT 4. GLUT 4 is a glucose transporter.

GLUT 4 breakdown of name:

● GLU-Glucose
● T-Transporter
In skeletal muscles and adipocytes, glucose uptake decreases. Instead, glucose is excreted
in urine. If insulin is not able to maintain glucose levels, GLUT 4 is activated to transport
excess glucose to the liver.

Glucokinase de iciency
● Glucokinase is an enzyme that phosphorylates glucose.
● This may develop Non-insulin dependent diabetes mellitus type 2 is called Maturity
Onset Diabetes of the Young(MODY) due to the absence of glucokinase.
● Can cause hyperglycemia

Pyruvate Kinase de iciency

● production of pyruvate is below normal
● production of ATP is low in RBC, leading to hemolytic anemia.

Congenital de iciency of Glycolysis enzymes

 LUCONEOGENESIS
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Breakdown of the Gluconeogenesis term
Gluco-glucose
neo-new
genesis-formation

Gluconeogenesis
● is the synthesis of glucose from non-carbohydrate precursors when the body lacks
or needs glucose to create ATP.
● usually, pyruvate is converted to glucose
● happens in the liver since the liver has stored pyruvate which can be converted to
glucose.

*It is possible that gluconeogenesis can provide the energy for a whole but the brain
requires 120g/d of glucose to perform normally.

Anything that can be converted to pyruvate is considered glucogenic.

Glucogenic:
● Lactate and alanine - converted to lactate
● Glycerol - converted to DHAP

Irreversible glycolytic enzymes

● Hexokinase
● Phosphofructokinase
● Pyruvate kinase

Enzymes of gluconeogenesis are

1. Pyruvate carboxylase (1st reaction)
Reacts with pyruvate with CO2 to produce oxaloacetate, ADP, free phosphate group, and 2
Hydrogen atoms. This reaction takes place in the mitochondrial matrix and requires ATP.

Pyruvate + CO2 + ATP + H2O -> Oxaloacetate + ADP + Pi + 2H+

Pyruvate carboxylase ixes CO2.

 IOTIN
B
-is a vitamin that is always involved in CO2 ixation.
-is a cofactor required by enzymes that ix CO2.

. Phosphoenolpyruvate carboxykinase (2nd reaction)

2
Converts oxaloacetate to phosphoenolpyruvate (PEP). Uses GTP and also produces GDP
and CO2

Oxaloacetate + GTP to phosphoenolpyruvate + GDP + CO2

GTP - guanosine triphosphate

Reaction takes place in the cytosol

Since PEP is now synthesized, the sum of the irst and second reaction will be:
Pyruvate + ATP + GTP +H2O -> PEP + ADP + GDP + Pi + H+

Pyruvate is carboxylated in the mitochondria and is converted to oxaloacetate.

Oxaloacetate can't pass out of the mitochondria. For it to pass through, it is converted to
malate by the enzyme malate dehydrogenase (DH). Once malate has exited the
mitochondria and entered the cytosol, it is converted back into oxaloacetate by malate DH.
Oxaloacetate is decarboxylated and phosphorylated in the cytosol by the
phosphoenolpyruvate carboxykinase to produce phosphoenolpyruvate.

. Fructose 1,6-bisphosphatase (3rd Reaction)

3
An important allosteric enzyme that regulates gluconeogenesis.
Converts Fructose-1,6BP to Fructose-6P.

Fructose-1,6BP + H2O -> F-6P + Pi

Fructose-6P is easily converted to glucose-6P by phosphoglucose isomerase.

. Glucose 6-phosphatase (4th Reaction)

4
Converts Glucose-6P to Glucose

Glucose-6p + H2O -> Glucose + Pi

Liver can send glucose to blood to maintain homeostasis.

Glucose-6p is also a precursor to glycogen.

lucose-6p
G
-is valuable;precursor for glycogen synthesis
-glucose 6-phosphatase is present only in tissues responsible for maintaining blood
glucose levels, liver and kidney.
-in liver, glucose 6-phosphatase is highly regulated

In Liver
Lumen of the ER
-It takes 5 proteins to convert glucose-6-phosphate to glucose.

luconeogenesis stoichiometry
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2 pyruvate + 4ATP + 2GTP + 2NADH + 6H2O -> Glucose + 4ADP + 2GDP + 6Pi + 2NAD+ +
2H+;Go’ = -9 kcal mol-1

Just the reverse of glycolysis, Go’ = 20 kcal mol-1

ote : It takes 6 nucleotide triphosphate molecules to synthesize glucose in

N
gluconeogenesis. Only 2 nucleotide triphosphate molecules are generated from glycolysis.

It takes four extra high phosphoryl-transfer potential molecules to drive the unfavorable
gluconeogenesis.

Glycolysis and gluconeogenesis are reciprocally regulated.

Glycolysis is stimulated and regulated by insulin, gluconeogenesis is stimulated by

glucagon.

If there is a high [AMP], that will signal for the need of ATP which signals the conversion of
glucose to pyruvate and ATP.

*AMP - Adenosine Monophosphate

High [ATP] and [citrate] indicate the energy charge is high and intermediates are
abundant which inhibits glycolysis.
 The Cori Cycle

In muscle, glucose is converted to pyruvate and lactate.

The lactate passes through the blood and into the liver, where it is converted to pyruvate.
Pyruvate is converted to glucose. and the cycle repeats.

*Lactate from active muscles is converted to glucose in the liver.

arl and Gerty Cori won the Nobel Prize in Physiology and Medicine in 1947 for their
C
discovery of the course of the catalytic conversion of glycogen.

Lactate and Alanine are Glucogenic

In muscle, alanine is produced from pyruvate by transamination

pyruvate + glutamate -> alanine + alpha-ketoglutarate

In the liver, alanine is converted back to pyruvate

In active muscle, lactate builds up, passes through the blood and is converted to pyruvate
in the liver.

Thus, part of the metabolic burden of active muscle is shifted to the liver.

Diagram of the Glucose, Pyruvate, and Lactate Metabolism

Left Side: Glycolysis

1. Glucose to G-6P
2. G-6P to Pyruvate, produces CO2 + H2O in aerobic conditions; produces lactate in
anaerobic conditions.
3. Pyruvate to Lactate in muscles and RBCs.
Right Side: Gluconeogenesis
1. Lactate is transported into the liver
2. Lactate back to pyruvate
3. Pyruvate to Glucose-6P
4. Glucose-6P is a precursor to glycogen, thus can be converted to either glycogen or
glucose. Glucose is transported back into the blood.