Metabolism2 1

METABOLIC
PATHWAY
Copyright © 2022 Saint Mary’s University, Bayombong, Nueva Vizcaya

Introduction
• Metabolism is the sum total of all the reactions that take place in a
living cell. These reactions are used to extract energy and materials
from the environment (catabolism), and to use this energy and these
materials to produce new molecules (anabolism ) that will sustain the
cell and allow it to propagate itself. There are literally thousands of
reactions involved in metabolism, but we will focus our attention on a
core set of reactions that will allow us to understand some of core
principals that define metabolism.

Introduction
• There are literally thousands of chemical reactions
that take place in a living cell
• If you wrote the chemical equations for all of these
reactions down on a single piece of paper, it would
look something like this:
Copyright © 2022 Saint Mary’s University, Bayombong, Nueva Vizcaya 3

Introduction
• The reactions are arranged into pathways, where the product
for one reaction is the reactant (substrate) for the next
reaction.
• The arrangement of reactions looks very much like a wiring
diagram, but instead of tracing the flow of electrons, the
metabolic pathways trace the flow of atoms and molecules.
• Every chemical reaction in metabolism is catalyzed by an
enzyme.
• The enzymes are used like valves to control the flow of
material through the pathways.
• Nonspontaneous reactions are driven by coupling them to
spontaneous reactions.
• An outside source of energy is needed drive metabolism

Pathways, Energy, and Coupled Reactions
• Metabolic reactions are arranged in pathways
• The product of one reaction is the substrate for the
next reaction in the pathway.
• There are different topologies for metabolic pathways.

• The molecules that are placed along the pathway are the
intermediates in the reactions
• Other reactants and products are usually represented
by side arrows
•This reaction equation could also be written as

• When two reactions are
connected through a
common intermediate,
they are said to be
coupled.
• The coupling of
reactions allows
spontaneous
reactions to drive
nonspontaneous
reactions.
Pathways, Energy, and Coupled
Reactions
• The phosphorylation of ADP can be coupled to the
dephosphorylation of 1,3-Bisphosphoglycerate:

Overview of Metabolism
• Metabolism
• The sum of all reactions that take place in a living
organism.
Metabolism = Catabolism + Anabolism
• Catabolism - larger molecules are broken down into
smaller ones in a process that usually releases energy
• Anabolism - larger molecules are made from small
ones in a process the usually requires energy

• One of the common links between catabolism and
anabolism is ATP.
• ATP is used to shuttle chemical energy from
catabolism to anabolism.

• This is done by coupling the spontaneous reactions in
catabolism to the phosphorylation of ADP to produce
ATP:
• And then coupling the unfavorable reactions in

anabolism to the hydrolysis of ATP:

• The biological oxidation/reduction agents NAD + and FAD
are also used to shuttle energy from the favorable
oxidations that take place in catabolism, to the
unfavorable reductions that take place in anabolism
catabolism anabolism
A is B is reduced
oxidized

Overview of
Metabolism
• Catabolism
• Occurs in stages.
• Occupies the
center of the
metabolic chart.

• The reactions from Acetyl-Co and below require
molecular oxygen (O2).
• These reactions take place in a specialized organelle
called the mitochondria.

Digestion
• Digestion is the first stage of metaboism in which large
molecule are broken done in small molecules that can be
absorbed into the blood in the small intestine.
• Most of these reactions are hydrolysis reactions
•Proteins are hydrolyzed in to amino acids
•Polysaccharides are hydrolyzed into
monosaccharides
•Triglycerides are hydrolyzed into fatty acids and
glycerol.
Glucose is synthesized in
the tissues of the liver
and kidneys.
Tissues that use glucose
as their main energy
source are the brain,
skeletal muscles, and red
blood cells.

Utilization of Glucose
Glucose is the primary energy source for the brain,
skeletal muscle, and red blood cells. Glucose
deficiency can impair the brain and nervous system.
If our glycogen stores are depleted,

•liver cells synthesize glucose by gluconeogenesis.
•glucose is synthesized in the cytosol of the liver cells,
and some is synthesized in the kidneys.

Glycogen
•can supply us with about one day’s requirement of
glucose.
•is made from glucose, most of which is
synthesized in the cytosol of liver cells.
To begin gluconeogenesis, carbon atoms from
noncarbohydrate food sources are converted to
pyruvate.

Glycolysis
• Glycolysis is a series of 10 coupled reactions
• The pathway starts with glucose that comes into a cell
from the blood and is immediately phosphorylated to
glucose-6-phosphate.
•The phosphorylation traps the glucose in the cell.
• The pathway then goes on to split (lyse) the the 6-carbon
glucose molecule into two 3-carbon molecules and to
oxidize these to α-keto acids (Pyruvic acid).
• The energy released in the pathway is used to produce
two types of energy rich molecules:
•Two molecules of ADP are phosphorylated to ATP.
•Two molecules of NAD+ are reduced to NADH/H+.
Glycolysis
• Step 1: Glucose is brought
into the cell and
phosphorylated.
• The phosphorylation is
coupled to the hydrolysis
of ATP.

Glycolysis
• Step 2: Glucose-6-phosphate
(an aldohexose) is isomerized
to fructose-6-phosphate (a
ketohexose).
• This reaction occurs near
equilibrium, which allows it
to go in either direction.

Glycolysis
• Step 3: Fructose-6-phosphate
is phosphorylated to fructose-
1,6-bisphosphate.
• This reaction is coupled to
the hydrolysis of ATP.
• This sets things up for the
cleavage, which occurs in
the next step.
• So far 2 ATP’s have been
used instead of produced.

Glycolysis
• Step 4: Fructose-1,6-
bisphosphate splits into two three
carbon monosaccharides
•Glyceraldehyde-3-phophate.
•Dihydroxyacetone phosphate

Glycolysis
• Step 5: Dihydroxyacetone phosphate is isomerized to glyceraldehyde-
3-phosphate.
• The last five reactions in glycolysis start with glyceraldehyde-
phosphate.
• The remaing reactions will couple the oxidation of glyceraldhyde-3-
phosphate to the production of ATP and NADH/H+.

Glycolysis
• Step 6: Glyceraldehyde-3-
phosphate is oxidized to
1,3-Bisphosphoglycerate.
• The oxidation of the
aldehyde to an acid is
coupled to the reduction
of NAD+ to NADH/H+
and the phosphorylation
of the acid to a mixed
phosphate anhydride.
• The hydrolysis of a
phosphate anhydride
has a large negative ΔG.
Glycolysis
• Step 7: The hydrolysis of the
phosphate from 1,3-
bisphosphoglycerate is coupled to
the phosphorylation of ADP to
generate ATP
• Since two 1,3-
bisphosphoglycerates are
produced per glucose molecule,
the two ATP’s that were
invested in the first part of
glycolysis have now been
recovered.

Glycolysis
• The remaining three steps will convert the phosphate
ester in 3-phosphoglycerate into a phosphate whose
hydrolysis can be coupled to the phosphorylation of ADP
to produce ATP.
• Phosphate esters do not have a large enough
negative ΔG to be coupled to the phosphorylation of
ADP.

Glycolysis
• Step 8: 3-Phosphoglycerate
is isomerized to 2-
phosphoglycerate.
• The phosphate ester is
moved form carbon 3 to
carbon 2.
• Like most isomerization
reactions, this reaction
can go in either direction.

Glycolysis
• Step 9: 2-Phosphoglycerate
is dehydrated to form
phosphoenolpyruvate.
• The dehydration of the
alcohol produces a double
bond between carbons 2
and 3.
• This produces a
phosphate with a large
negative free energy for
hydrolysis, which can now
be coupled to the
phosphorylation of ADP.
Glycolysis
• Step 10: The hydrolysis of the
phosphate from
phosphoenolpyruvate is
coupled to the
phosphorylation of ADP.
• The hydroxyl group that is
produced next to the
carbon-carbon double-bond
spontaneously isomerizes
to a ketone.
Glycolysis
• The net reaction for coupling all ten steps in glycolysis:
• The energy released in the pathway is used to
produce two types of energy rich molecules:
•Two molecules of ADP are phosphorylated to ATP.
•Two molecules of NAD+ are reduced to NADH/H+.

Glycolysis
• Fates of pyruvate when molecular oxygen cannot be
used to reoxidize the NADH/H+ back to NAD+.
• The fermentation pathways provide away of
reoxidizing NADH/H back to NAD , so that it can be
+ +
used to keep glycolysis going.

Gluconeogenesis
• Gluconeogenesis is the
synthesis of glucose from
pyruvate
• It uses 7 out of the 10
reactions from glycolysis.
• The remaining three
have too large a negative
free energy to be
reversed.
•These include steps
• 1, 3 and 10
• Alternative reactions are
used to get around these
falls. Copyright © 2022 Saint Mary’s University, Bayombong, Nueva Vizcaya 38
Regulation of Gluconeogenesis
Gluconeogenesis is
•not utilized when the diet is high in carbohydrates.
•very active when the diet is low in carbohydrates.
When conditions in a cell favor glycolysis, there is no

synthesis of glucose.
When the cell requires the synthesis of glucose,

glycolysis is turned off.

Glycolysis and Gluconeogenesis

Glycogen Metabolism
• When glucose is not needed to meet energy needs, it
can be stored as the polysaccharide glycogen and used
for future energy needs.
• The liver and the muscles are where glycogen is
synthesized and stored.
•The muscles store it for future muscular activity.
•The liver stores it to help regulate blood glucose
levels.

Glycogen Metabolism

Lactate and the Cori Cycle
The Cori cycle
• is the flow of lactate and glucose between the
muscles and the liver.
• occurs when anaerobic conditions occur in active
muscle, and glycolysis produces lactate.
• operates when lactate moves through the blood
stream to the liver, where it is oxidized back to
pyruvate.
• converts pyruvate to glucose, which is carried back to
the muscles.

Lactate and the Cori Cycle

Regulation, Glycolysis, and Gluconeogenesis

Metabolic Reactions of Glucose
Glycolysis involves the breakdown of glucose, and gluconeogenesis involves the synthesis of glucose from
noncarbohydrates. The pentose phosphate pathway converts glucose to ribose and provides NADPH.
Glycogenolysis degrades glycogen to glucose whereas glycogenesis produces glycogen from glucose.

Concept Map

Citric Acid Cycle
• If an organism can utilize molecular oxygen to accept
electrons from the reduced nucleotides NADH/H + and
FADH2, then the pyruvate from glycolysis can be
completely oxidized to CO2 and H2O.
• These reactions occur within a cellular organelle
called the mitochondria.
• The first step in the complete oxidation is the
decarboxylation of pyruvate to produce Acetyl-S-CoA.

Citric Acid Cycle
• The Acetyl-CoA is fed into the citric acid cycle, where its
two carbons are oxidized to CO2.
• In the process
•3 more NAD+ are reduced to NADH/H+
•1 FAD is reduced to FADH2
•1 GDP is phosphorylated to GTP

Citric Acid
Cycle/Krebs
Cycle

Citric Acid Cycle
• The net reaction for coupling all 8 steps in glycolysis:

REACTIONS OF THE TCA CYCLE
 In the TCA cycle, oxaloacetate is first condensed with
an acetyl group from acetyl coenzyme A (CoA), and then
is regenerated as the cycle is completed.
 Thus, the entry of one acetyl CoA into one round of the
TCA cycle does not lead to the net production or
consumption of intermediates.
 Two carbons entering the cycle as acetyl CoA are
balanced by two CO2 exiting.

Oxidative decarboxylation of
pyruvate
 Pyruvate, the end product of aerobic glycolysis, must be
transported into the mitochondrion before it can enter the TCA
cycle.
 This is accomplished by a specific pyruvate transporter that
helps pyruvate cross the inner mitochondrial membrane.
 Once in the matrix, pyruvate is converted to acetyl CoA by the
pyruvate dehydrogenase complex, which is a multienzyme
complex.
 The pyruvate dehydrogenase complex is not part of the TCA
cycle, but is a major source of acetyl CoA which is substrate for the
cycle.

Oxidative decarboxylation of
pyruvate
 The pyruvate dehydrogenase complex (PDH complex) is a
multimolecular aggregate of three enzymes, pyruvate dehydrogenase
(PDH or E1 , also called a decarboxylase), dihydrolipoyl transacetylase
(E2 ), and dihydrolipoyl dehydrogenase(E3 ).
 In addition to the enzymes participating in the conversion of pyruvate
to acetyl CoA, the complex also contains two tightly bound regulatory
enzymes, pyruvate dehydrogenase kinase and pyruvate
dehydrogenase phosphatase.
 The PDH complex contains five coenzymes that act as carriers or
oxidants for the intermediates of the reactions. E1 requires thiamine
pyrophosphate (TPP), E2 requires lipoic acid and CoA, and E3
requires FAD and NAD+.

Regulation of the PDH complex
• Covalent modification by the two regulatory enzymes that are part
of the complex alternately activate and inactivate E1 (PDH).
• The cyclic AMP-independent PDH kinase phosphorylates and,
thereby, inhibits E1 , whereas PDH phosphatase
dephosphorylates and activates E1 .
• Pyruvate is a potent inhibitor of PDH kinase.
• Although covalent regulation by the kinase and phosphatase is
main, the complex is also subject to product (NADH, acetyl CoA)
inhibition.

Synthesis of citrate from acetyl
CoA and oxaloacetate
 The condensation of acetyl CoA and oxaloacetate to form citrate
(a tricarboxylic acid) is catalyzed by citrate synthase.
 It is inhibited by its product, citrate.
 Substrate availability is another means of regulation for citrate
synthase.

Isomerization of citrate
 Citrate is isomerized to isocitrate by aconitase, an Fe-S
protein.
 Aconitase is inhibited by fluoroacetate, a compound that

is used as a rat poison.

Oxidation and decarboxylation of
isocitrate
• Isocitrate dehydrogenase catalyzes the irreversible oxidative
decarboxylation of isocitrate, yielding the first of three NADH
molecules produced by the cycle, and the first release of CO2 .
• This is one of the rate-limiting steps of the TCA cycle.
• The enzyme is allosterically activated by ADP (a low-energy
signal) and Ca2+, and is inhibited by ATP and NADH.

Oxidative decarboxylation of α-
ketoglutarate
The conversion of α-ketoglutarate to succinyl CoA is catalyzed by
the α-ketoglutarate dehydrogenase complex, a multimolecular
aggregate of three enzymes.
 The reaction releases the second CO2 and produces the second
NADH of the cycle.
 The coenzymes for the enzyme complex are thiamine
pyrophosphate, lipoic acid, FAD, NAD+, and CoA

Cleavage of succinyl CoA
 Succinate thiokinase (also called succinyl CoA synthetase)
cleaves the high-energy thioester bond of succinyl CoA.
 This reaction is coupled to phosphorylation of guanosine
diphosphate (GDP) to guanosine triphosphate (GTP).
 The generation of GTP by succinate thiokinase is another
example of substrate-level phosphorylation.

Oxidation of succinate
 Succinate is oxidized to fumarate by succinate dehydrogenase,
as FAD is reduced to FADH2 .
 The reaction is inhibited by malonate.
 Succinate dehydrogenase is the only enzyme of the TCA cycle
that is embedded in the inner mitochondrial membrane.
 It functions as Complex II of the electron transport chain.

Hydration of fumarate
Fumarate is hydrated to malate in a freely reversible reaction
catalyzed by fumarase (also called fumarate hydratase).
Fumarate is also produced by the urea cycle, in purine synthesis,

and during catabolism of the amino acids, phenylalanine and
tyrosine.

Oxidation of malate
 Malate is oxidized to oxaloacetate by malate dehydrogenase.
 This reaction produces the third and last NADH of the cycle.
 The ΔG0 of the reaction is positive, but the reaction is driven in
the direction of oxaloacetate by the highly exergonic citrate
synthase reaction.
 Oxaloacetate is also produced by the transamination of aspartic
acid.

ENERGY PRODUCED BY THE TCA
CYCLE
Ten ATP are formed per turn of the citric acid cycle.
 As a result of oxidations catalyzed by the dehydrogenases of the
citric acid cycle, three molecules of NADH and one of FADH2 are
produced for each molecule of acetyl-CoA catabolized in one turn
of the cycle.
 These reducing equivalents are transferred to the respiratory
chain, where reoxidation of each NADH results in formation of ∼2.5
ATP, and of each FADH2 results in formation of ∼1.5 ATP.
 In addition, 1 ATP (or GTP) is formed by substrate-level
phosphorylation catalyzed by succinate thiokinase.
REGULATION OF THE TCA
CYCLE
 The TCA cycle is controlled by the regulation of several enzyme
activities.
 The most important of these regulated enzymes are those that
catalyze reactions with highly negative ΔG0 : citrate synthase,
isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase
complex.
 Reducing equivalents needed for oxidative phosphorylation are
generated by the pyruvate dehydrogenase complex and the TCA
cycle, and both processes are upregulated in response to a surge
in ADP

THE CITRIC ACID CYCLE PLAYS A
CRUCIAL ROLE IN METABOLISM
 The citric acid cycle is not only a pathway for oxidation of two
carbon units, but it is also a major pathway for
 interconversion of metabolites arising from transamination
and deamination of amino acids,
 providing the substrates for amino acid synthesis by
transamination,
 providing the substrates for gluconeogenesis and fatty acid
synthesis.
 Because it functions in both oxidative and synthetic processes,
it is amphibolic

BIOMEDICAL IMPORTANCE
 The tricarboxylic acid cycle (the TCA cycle, also called the Krebs cycle or the
citric acid cycle) plays several roles in metabolism.
 The TCA cycle is the final common pathway for the oxidation of
carbohydrate, lipid, and protein because glucose, fatty acids, and most amino
acids are metabolized to acetyl-CoA or intermediates of the cycle.
 This oxidation provides energy for the production of the majority of ATP in
most animals, including humans.
 It also has a central role in gluconeogenesis, lipogenesis, and
interconversion of amino acids.
 The cycle occurs totally in the mitochondria and is, therefore, in close
proximity to the reactions of electron transport, which oxidize the reduced
coenzymes produced by the cycle.

Electron Transport Chain and
Oxidative Phosphorylatioin
• The reoxidation of the NADH/H+ to NAD+ and FADH2 to
FAD using molecular oxygen (O2) as the oxidizing agent,
is carried out by the electron transport chain.
• The electron transport chain is located within the inner
membrane of mitochondria.


• The reoxidation of the NADH/H+ to NAD+ and FADH2 to FAD
using molecular oxygen (O2) as the oxidizing agent, is
carried out by the electron transport chain.
• The energy released in the reoxidation is coupled to the
synthesis of ATP from ADP and Pi by the enzyme ATP
synthase.
•The coupling involves the creation of a hydrogen ion
concentration gradient across the inner mitochondrial
membrane.
•The energy for synthesizing the ATP comes from
allowing the hydrogen ions to flow back across the
membrane.

Metabolism2 1

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METABOLIC

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• And then coupling the unfavorable reactions in

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If our glycogen stores are depleted,

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used to keep glycolysis going.

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When conditions in a cell favor glycolysis, there is no

When the cell requires the synthesis of glucose,

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 Aconitase is inhibited by fluoroacetate, a compound that

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Fumarate is also produced by the urea cycle, in purine synthesis,

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