BIOCHEMICAL ENERGY PRODUCTION
BioChemistry
By: Mrs. Teresa Maralle
METABOLISM
★ sum total of all chemical reactions in
a living organism
★ provide the source of energy we need
for all our activities such as thinking,
moving, breathing, walking, talking,
etc
★ Energy is also needed for many of the
cellular processes such as protein
synthesis, DNA replication, RNA
transcription and transport across
the membrane, etc.
CATABOLISM: all metabolic reactions in
which large biochemical molecules are
broken down to smaller ones
★ usually release energy
★ The reactions involved in the
oxidation of glucose
ANABOLISM: all metabolic reactions in which
small biochemical molecules are joined
together to form larger ones
★ usually require energy
★ synthesis of proteins
★ Knowledge of the cell structure is
essential for understanding
metabolism
Prokaryotic cell:
★ No nucleus and found only in
bacteria
★ Presence of a single circular DNA
molecule near the center of the cell
called nucleoid
Eukaryotic cell:
★ Cell where the DNA is found in a
membrane-enclosed nucleus
★ About 1000 times larger than
bacterial cells
Practice Exercise
Metabolic Pathway: Series of consecutive
biochemical reactions used to convert a
starting material into an end product
★ two types of metabolic pathways
○
Linear
○
Cyclic
★ The major pathways for all forms of
life are similar:
ANABOLIC: Synthesis of a protein from
amino acids
ANABOLIC: Formation of a triacylglycerol
from glycerol and fatty acids
CATABOLIC: Hydrolysis of a polysaccharide
to monosaccharides
ANABOLIC: Formation of a nucleic acid from
nucleotides
1
BIOCHEMICAL ENERGY PRODUCTION
BioChemistry
METABOLISM & CELL STRUCTURE
Eukaryotic Cell Organelles and Their Function
Nucleus: DNA replication and RNA synthesis
Plasma membrane: Cellular boundary
Cytoplasm: The water-based material of a
eukaryotic cell
Mitochondria: Generates most of the energy
needed for cells.
Lysosome: Contain hydrolytic enzymes
needed for cell rebuilding, repair and
degradation
Ribosome: Sites for protein synthesis
MITOCHONDRION
★ an organelle that is responsible for
the generation of most of the energy
for a cell
★ outer membrane: permeable to
small molecules: 50% lipid, 50%
protein
★ inner membrane: highly
impermeable to most substances:
20% lipid, 80% protein
★ inner membrane folded to increase
surface area
★ synthesis of ATP occurs on the inner
membrane
By: Mrs. Teresa Maralle
ADENOSINE PHOSPHATE (ATP, ADP, AND AMP)
Adenosine phosphate of interest:
★ Adenosine monophosphate
(AMP)-one phosphate group
○ Structural component of RNA
★ Adenosine diphosphate (ADP)-two
phosphate groups
○ key components of metabolic
pathways
★ Adenosine triphosphate (ATP)-three
phosphate groups
○ Key concept of metabolic
pathways
★ A phosphoryl group is derived from a
phosphate ion when it becomes part
of another molecule
★ The net energy produced in these
reactions is used for cellular
reactions
Important Nucleotide-Containing
Compounds in Metabolic Pathways
Adenosine Phosphates of interest: AMP,
ADP, ATP, cAMP
★ Monophosphate (AMP): one
phosphate group
★ Diphosphate (ADP): Two phosphate
groups
★ Triphosphate (ATP): Three phosphate
groups
★ Cyclic monophosphate (cAMP):
Cyclic structure of phosphate
2
BIOCHEMICAL ENERGY PRODUCTION
BioChemistry
★ AMP: Structural component of RNA
★ ADP and ATP: Key components of
metabolic pathways
○ Phosphate groups are connected
to AMP by strained bonds which
require less than normal energy
to hydrolyze them
★ ATP + H2O → ADP + PO43-+ Energy
★ ADP + H2O → AMP + PO43-+ Energy
★ Overall Reaction:
○ ATP+2H2O → AMP+2PO43-+Energy
★ The net energy produced in these
reactions is used for cellular
reactions
★ In cellular reactions ATP functions as
both a source of a phosphate group
and a source of energy.
○ E.g., Conversion of glucose to
glucose-6-phosphate
Role of Other Nucleotide Triphosphates in
Metabolism
★ Uridine triphosphate (UTP): involved
in carbohydrate metabolism
★ Guanosine triphosphate (GTP):
involved in protein and carbohydrate
metabolism
By: Mrs. Teresa Maralle
★ Cytidine triphosphate (CTP):
involved in lipid metabolism
Flavin Adenine Dinucleotide (FAD)
★ A coenzyme required in a numerous
metabolic redox reactions
○ Flavin subunit is the active
form-accepts and donates
electrons
○ Ribitol is a reduced form of
ribose sugar
★ FAD is oxidized form
★ FADH2 is reduced form
★ in enzyme reactions FAD goes back
and forth (equilibrium) from oxidized
to reduce form
★ a typical cellular reaction in which
FAD serves as oxidizing agent
involves conversion of an alkane to
an alkene
○ it is also a biological oxidizing
agent
Nicotinamide Adenine Dinucleotide (NAD
★ NAD+: coenzyme
★ NADH is reduced form
★ 3 subunit structure
○
○
Nicotinamide- ribose-ADP
6 subunit structure
3
BIOCHEMICAL ENERGY PRODUCTION
BioChemistry
★ A typical cellular reaction in which
NAD+ serves as the oxidizing agent is
the oxidation of a secondary alcohol
to give a ketone
By: Mrs. Teresa Maralle
Why is ATP the best energy source for
human beings? It has an intermediate
value in free energy, and it undergoes slow
hydrolysis in an aqueous environment.
Important Carboxylate Ions in Metabolic
Pathways
Coenzyme A
★ a derivative of vitamin B
★ 3 subunit structure
○ 2-Aminoethanethiolpanthothenic acidphosphorylated ADP
★ 6 sub unit structure
○ 2-Aminoethanethiol-pantotheni
c acid- phosphate-phosphate
phosphorylated ribose-adenine
★ Active form of coenzyme A is the
sulfhydryl group (-SH group) in the
ethanethiol subunit of the coenzyme
★ Acetyl-CoA (acetylated)
Classification of Metabolic Intermediate
Compounds
★ Metabolic intermediate compounds
can be classified into three groups
based on their functions
★ Carboxylate ions or Metabolic acids:
Polyfunctional acids formed as
intermediates of metabolic reactions.
★ There are 5 such acids that serve as
substrates for enzymes in metabolic
reactions:
★ 3 Succinic acid (C4 diacid)
derivatives: Fumarate, oxaloacetate,
and malate
★ 2 Glutaric acid (C5 diacid)
derivatives : a-ketoglutarate and
citrate
High-Energy Phosphate Compounds
What intermediate molecule in metabolic
reactions is responsible for producing
energy in the human body? ATP
★ Several phosphate containing
compounds found in metabolic
pathways are known as high energy
compounds
★ High energy compounds have
greater free energy of hydrolysis than
a typical compound:
○ They contain at least one reactive
bond -- called strained bond
4
BIOCHEMICAL ENERGY PRODUCTION
BioChemistry
○
○
○
○
Energy to break these bonds is less
than a normal bond -- hydrolysis
of high energy compounds give
more energy than normal
compounds
More negative the free energy of
hydrolysis, greater the bond strain
Typically the free energy release is
greater than 6.0 kcal/mole
(indicative of bond strain)
Strained bonds are represented by
sign ~ (squiggle bond)
How many “strained” bonds are present in
an ATP molecule? Two
By: Mrs. Teresa Maralle
An Overview of Biochemical Energy
Production
★ Energy needed to run human body is
obtained from food
★ Multi-step process that involves
several different catabolic pathways
aid in this process
★ There are four general stages in the
biochemical energy production
process:
○ Stage 1: Digestion
○ Stage 2: Acetyl group formation
○ Stage 3: Citric acid cycle
○ Stage 4: electron transport chain
and oxidative phosphorylation
★ Each stage also involves numerous
reactions
Stage 1. Digestion
★ Begins in mouth (saliva contains
starch digesting enzymes), continues
in the stomach (gastric juice),
completed in small intestine:
5
BIOCHEMICAL ENERGY PRODUCTION
BioChemistry
○
Results in small molecules that
can cross intestinal membrane
into the blood
★ End Products of digestion:
○ Glucose and monosaccharides
from carbohydrates
○ Amino acids from proteins
○ Fatty acids and glycerol from fats
and oils
★ The digestion products are absorbed
into the blood and transported to
body’s cells
Stage 2. Acetyl Group Formation
★ The small molecules from Stage 1 are
further oxidized.
★ End product of these oxidations is
acetyl CoA
★ Involves numerous reactions:
○ Reactions occur both in cytosol
(glucose metabolism) as well as
mitochondria (fatty acid
metabolism) of the cells.
Stage 3. Citric Acid Cycle
★ Takes place inside the mitochondria
★ First intermediate of the cycle is citric
acid – therefore designated as Citric
acid cycle (also known as Krebs
Cycle)
★ In this stage acetyl group is oxidized
to produce CO2 and energy
★ The carbon dioxide we exhale comes
primarily from this stage
★ Most energy is trapped in reduced
coenzymes NADH and FADH2
★ Some energy produced in this stage
is lost in the form of heat
Stage 4. Electron Transport Chain and
Oxidative Phosphorylation
★ Takes place in mitochondria
By: Mrs. Teresa Maralle
★ NADH and FADH2 are oxidized to
release H+ and electrons
★ H+ are transported to the
inter-membrane space in
mitochondria
★ Electrons are transferred to O2 and
O2 is reduced to H2O
★ H+ ions reenter the mitochondrial
matrix and drive ATPsynthase
reaction to produce ATP
★ ATP is the primary energy carrier in
metabolic pathways
What are the stages of energy production in
the order of occurrence? Digestion, acetyl
group formation, the citric acid cycle, and
electron transport and oxidative
phosphorylation
CITRIC ACID CYCLE
★ series of biochemical reactions in
which the acetyl portion of acetyl
CoA is oxidized to carbon dioxide and
the reduced coenzymes FADH2 and
NADH are produced
★ Also known as tricarboxylic acid
cycle (TCA) or Krebs cycle:
○ Citric acid is a tricarboxylic acid –
TCA cycle
○ Named after Hans Krebs who
elucidated this pathway
★ Two important types of reactions:
○ Reduction of NAD+ and FAD to
produce NADH and FADH2
○ Decarboxylation of citric acid to
produce carbon dioxide
○ The citric acid cycle also
produces 2 ATP by substrate level
phosphorylation from GTP
6
BIOCHEMICAL ENERGY PRODUCTION
BioChemistry
★ Summary of citric acid cycle
reactions:
Acetyl CoA+3NAD++FAD+GDP+ Pi+2H2O→2CO2+CoA-SH+3NADH+2H++ FADH2+GTP
Hans Adolf Krebs (1900–1981), a
German-born British biochemist, received
the 1953 Nobel Prize in medicine for
establishing the relationships among the
different compounds in the cycle that
carries his name, the Krebs cycle.
By: Mrs. Teresa Maralle
Step 5: Thioester bond cleavage in Succinyl
CoA and Phosphorylation of GDP to form
GTP
Step 6: Oxidation of Succinate. This is the
third redox reaction of the cycle. The
enzyme involved is succinate
dehydrogenase, and the oxidizing agent is
FAD rather than NAD.
Step 7: Hydration of Fumarate. The enzyme
fumarase catalyzes the addition of water to
the double bond of fumarate. The enzyme is
stereospecific, so only the L isomer of the
product malate is produced.
Step 8: Oxidation of L-Malate to Regenerate
Oxaloacetate
When one acetyl CoA is processed through
the citric acid cycle, how many times does
each of the following events occur?
a. A FAD molecule is a reactant. 1 (step 6)
b. A CoA-SH molecule is produced. 2 (steps
1 and 5)
c. A dehydrogenase enzyme is needed for
the reaction to occur. 4 (steps 3, 4, 6, and 8)
d. A C5 molecule is produced. 1 (step 3)
Reactions of the Citric Acid Cycle
Step 1: Formation of Citrate. Acetyl CoA
Step 2: Formation of Isocitrate. Citrate is
converted to its less symmetrical isomer
isocitrate in an isomerization process that
involves a dehydration followed by a
hydration, both catalyzed by the enzyme
aconitase.
Step 3: Oxidation of Isocitrate and Formation
of CO2. This step involves oxidation–
reduction (the first of four redox reactions in
the citric acid cycle) and decarboxylation.
Step 4: Oxidation of a-Ketoglutarate and
Formation of CO2.
Regulation of the Citric Acid Cycle
★ The rate at which the citric acid cycle
operates is controlled by ATP and
NADH levels
★ When ATP supply is high, ATP inhibits
citrate synthase (Step 1 of Citric acid
cycle)
★ When ATP levels are low, ADP
activates citrate synthase
★ Similarly ADP and NADH control
isocitrate dehydrogenase:
○ NADH acts as an inhibitor
○ ADP as an activator.
7
BIOCHEMICAL ENERGY PRODUCTION
BioChemistry
How many high-energy molecules are
formed in one turn of the citric acid cycle?
3 NADH, 1 FADH2 , and 1 GTP
The Electron Transport Chain
★ The electron transport chain (ETC)
facilitates the passage of electrons
trapped in FADH2 and NADH during
citric cycle
★ ETC is a series of biochemical
reactions in which intermediate
carriers (protein and non-protein)
aid the transfer of electrons and
hydrogen ions from NADH and FADH2
★ The ultimate receiver of electrons is
molecular oxygen
★ The electron transport (respiratory
chain) gets its name from the fact
that electrons are transported to
oxygen absorbed via respiration
★ The overall ETC reaction:
2 H++2e-+1/2 O2 → H2O+energy
★ Energy is used to synthesize ATP in
oxidative phosphorylation
★ Note that 2 hydrogen ions, 2
electrons, and one halfoxygen
molecule react to form the product
water
★ This relatively straight forward
reaction actually requires eight or
more steps
★ The reaction releases energy
(exothermic reaction)
★ The energy released is coupled with
the formation of three ATP molecules
per every molecule of NADH
processed through ETC
★ The enzymes and electron carriers
needed for the ETC are located along
inner mitochondrial membrane
By: Mrs. Teresa Maralle
★ They are organized into four distinct
protein complexes and two mobile
carriers
The four protein complexes tightly bound to
membrane:
★ Complex l: NADH-coenzyme Q
reductase
○ NADH from citric acid cycle is the
source of electrons for this
complex
○ It contains >40 subunits including
flavin mononucleotide (FMN) and
several iron-sulfur protein clusters
(FeSP)
○ Net result: Facilitates transfer of
electrons from NADH to
coenzyme Q
○ Several intermediate reactions
are involved in this electron
transfer
★ Complex II: Succinate-coenzyme Q
reductase
○ Smaller than complex I
○ Contains only four subunits
including two iron-sulfur protein
clusters (FeSP)
○ Succinate is converted to
fumarate by this complex
○ In the process it generates FADH2
○ CoQ is the final recipient of the
electrons from FADH2
★ Complex III: Coenzyme Q cytochrome C reductase
○ Complex III contains 11 different
subunits
○ Several iron-sulfur proteins and
cytochromes are electron carriers
in this complex
8
BIOCHEMICAL ENERGY PRODUCTION
BioChemistry
Cytochrome is a heme iron
protein in which reversible
oxidation of an iron atom occurs
○ Various cytochromes, e.g., cyt a,
cyt b, cyt c, differ from each other
by:
■ Their protein constituents
■ The manner in which the heme
is bonded to the protein
■ Attachments to the heme ring
★ Complex IV: Cytochrome C oxidase
○ Contains 13 subunits including two
cytochromes
○ The electrons flow from cyt c to
cyt a to cyt a3
○ In the final stage of electron
transfer, the electrons from cyt a3
, and hydrogen ion (H+ ) combine
with oxygen (O2 ) to form water
○ O2 + 4H+ + 4e- → 2 H2O
○ It is estimated that 95 % of the
oxygen used by cells serves as the
final electron acceptor for the ETC
★ Two mobile electron carriers are:
○ Coenzyme Q and cytochrome c
By: Mrs. Teresa Maralle
○
The electron transfer pathway through complex
IV (cytochrome c oxidase). Electrons pass
through both copper and iron centers and in the
last step interact with molecular O2 . Reduction
of one O2 molecule requires the passage of four
electrons through complex IV, one at a time.
Practice Exercise
With which of the four complexes in the electron
transport chains is each of the following events
associated? (There may be more than one
correct answer in a given situation.)
a.The metal iron is present in the form of Fe2+
and Fe3+ ions. Complexes I, II, III, and IV
b.FADH2 is needed as a reactant. Complex II
c.The metal copper is present in the form of Cu+
and Cu2+ ions. Complex IV
d.Cytochromes are needed as reactants.
Complexes III and IV
Which statement best describes the electron
transport chain? It is a series of biochemical
reactions in which electrons and hydrogen ions
from NADH and FADH2 are passed to
intermediate carriers that eventually react
with molecular oxygen to produce water.
OXIDATIVE PHOSPHORYLATION
★ process by which ATP is synthesized
from ADP and Pi using the energy
released in the electron transport
chain. - coupled reactions
Coupled reactions
★ are pairs of biochemical reactions
that occur concurrently in which
energy released by one reaction is
used in the other reaction
○ Example: oxidative
phosphorylation and the oxidation
reactions of the electron transport
chain are coupled systems
9
BIOCHEMICAL ENERGY PRODUCTION
BioChemistry
★ The coupling of ATP synthesis with the
reactions of the ETC is related to the
movement of protons (H+ ions)
across the inner mitochondrial
membrane
★ Complexes I, III and IV of ETC chain
have a second function in which they
serve as “proton pumps” transferring
protons from the matrix side of the
inner mitochondrial membrane to
the intermembrane space
★ For every two electrons passed
through ETC, four protons cross the
inner mitochondrial membrane
through complex I, four through
complex III and two more though
complex IV
★ This proton flow causes a buildup of
H+ in the intermembrane space
★ The gradient build-up would push the
H+ ions through membrane-bound
ATP synthase:
○ This high concentration of protons
passing through ATP synthase
becomes the basis for the ATP
synthesis
A Second Function for Protein Complexes I,
III, and IV. For every two electrons passed
through ETC, four protons cross the inner
mitochondrial membrane through complex
I, four through complex III and two more
though complex IV
By: Mrs. Teresa Maralle
What main event in oxidative
phosphorylation is responsible for ATP
production? The movement of protons
from a region of high to low concentration
through enzyme complexes called ATP
synthase, resulting in ATP formation
ATP Production for the Common
Metabolic Pathway
★ Formation of ATP accompanies the
flow of protons from the
intermembrane space back into the
mitochondrial matrix.
★ The proton flow results from an
electrochemical gradient across the
inner mitochondrial membrane
★ For each mole of NADH oxidized in the
ETC, 2.5 moles of ATP are formed.
★ For each mole of FADH2 Oxidized in
the ETC, only 1.5 moles of ATP are
formed.
★ For each mole of GTP hydrolyzed 1
mole of ATP is formed.
★ Ten molecules of ATP are produced
for each acetyl CoA catabolized
– 3 NADH → 7.5 ATP
– 1 FADH2 → 1.5 ATP
– 1 GTP → 1 ATP
– Total 10 ATP
How many moles of ATP are ultimately
produced from the “processing” of one
mole of acetyl CoA molecules through the
common metabolic pathway? 10
10
BIOCHEMICAL ENERGY PRODUCTION
BioChemistry
The Importance of ATP
★ The cycling of ATP and ADP in
metabolic processes is the principal
medium for energy exchange in
biochemical processes
Non-ETC Oxygen-Consuming Reactions
★ >90% of inhaled oxygen via
respiration is consumed during
oxidative phosphorylation.
★ Remaining O2 are converted to
several highly reactive oxygen
species (ROS) within the body.
Examples of ROS:
★ Hydrogen peroxide (H2O2 )
★ Superoxide ion (O2 - )
★ Hydroxyl radical (OH)
★ Superoxide ion and hydroxyl
radicals have unpaired electron and
are extremely reactive
★ ROS can also be formed due to
external influences such as polluted
air, cigarette smoke, and radiation
exposure
★ Reactive oxygen species (ROS) are
both beneficial as well a problematic
within the body
★ Beneficial Example: White blood cells
produce a significant amount of
superoxide free radicals via the
following reaction to destroy the
invading bacteria and viruses.
By: Mrs. Teresa Maralle
★ 2O2+NADPH → 2O2-+NADP++H+
★ > 95% of the ROS formed are quickly
converted to non toxic species :
★ About 5% of ROS escape destruction
by superoxide dismutase and
catalase enzymes.
★ Antioxidant molecules present in the
body help trap ROS species
★ Antioxidants present in the body:
○ Vitamin K
○ Vitamin C
○ Glutathione (GSH)
○ Beta-carotene
★ Plant products such as flavonoids
are also good antioxidants – Have
shown promise in the management
of many disorders associated with
ROS production
What happens to unused oxygen from the
electron transport chain? It is converted to
several highly reactive oxygen species
(ROS).
B Vitamins and the Common Metabolic
Pathway
★ Structurally modified B-vitamins
function as coenzymes in the
metabolic pathways
★ Four B Vitamins participate in various
reactions:
○ Niacin – NAD+ and NADH
○ Riboflavin – as FAD, FADH2 and
FMN
○ Thiamin – as TPP
11
BIOCHEMICAL ENERGY PRODUCTION
BioChemistry
○ Pantothenic acid - as CoA
★ Without these B-vitamins the body
would be unable to utilize
carbohydrates, proteins and fats as
energy sources.
By: Mrs. Teresa Maralle
Athletes have the ability to perform at high
levels of activity because of their systems’
ability to produce large amounts of energy.
How is this possible? They have an
increased number of mitochondria which
are able to produce large quantities of ATP.
CHEMICAL CONNECTIONS
B vitamin participation in chemical
reactions associated with the common
metabolic pathway.
Apples are the fruit that contains the
greatest amount of the antioxidant
quercetin; the skin (peel) contains the
majority of the quercetin.
Metabolism and Cell Structure
Practice Exercise
White blood cells are necessary for the
destruction of invading viruses and
bacteria. A significantly concentrated
species helps in this process. Identify the
species. Superoxide free radicals
Adenosine Phosphates and Muscle
Relaxation/Contraction
Important structural compounds in
muscle tissue are the filament proteins
myosin and actin. These two types of
muscle protein were previously considered
in animal and fowl muscle tissue (meat)
consumed as food. An additional aspect of
the structural chemistry of muscle tissue,
with its associated myosin and actin, is now
considered, that of muscle contraction and
relaxation.
A simplified diagram for a relaxed
muscle, in terms of myosin (which are thick
protein filaments) and actin (which are thin
protein filaments) present is In the process
of muscle contraction the thin filaments
(actin) slide inward between the thick
filaments
(myosin)
producing
a
"contracted" structural arrangement for the
filaments as shown in the following
diagram.
Two key substances must be present
for muscle contraction to occur. They are
Ca2+ ions and ATP molecules. Low cellular
Ca2+ concentration is associated with
relaxed
muscle
and
high
Ca2+
concentration is associated with contracted
muscle. An increase in Ca2+ concentration
is the trigger for muscle contraction. Nerve
impulses reaching muscle filament cells
12
BIOCHEMICAL ENERGY PRODUCTION
BioChemistry
cause cell membrane Ca2+ ion channels to
open with a resulting influx of Ca2+ ion in
the muscle filament cell. The Ca2+ ion
increase causes ATP molecules present in
the cells to hydrolyze to ADP molecules,
which provides the energy needed for
muscle
contraction--a
myosin-actin
interaction that pulls the actin molecules
inward. The ATP hydrolysis equation is
Contraction continues as long as both ATP
and Ca2+ ion filament levels are high.
Cessation of a nerve impulse causes the
calcium
channels
within
cellular
membranes to close. Then ATP-provided
energy is used to pump Ca2+ ions out of
filament cells resulting in muscle relaxation.
The process repeats itself when additional
nerve impulses are generated.
Brown Fat, Newborn Babies, and Hibernating
Animals
Ordinarily,
metabolic
processes
generate enough heat to maintain normal
body temperature. In certain cases,
however, including newborn infants and
hibernating animals, normal metabolism is
not sufficient to meet the body's heat
requirements.
In
these
cases,
a
supplemental method of heat generation,
which involves brown fat tissue, occurs.
Brown fat tissue, as the name implies,
is darker in color than ordinary fat tissue,
which is white. Brown fat is specialized for
heat production. It contains many more
blood vessels and mitochondria than white
fat. (The increased number of mitochondria
gives brown fat its color.)
Another difference between the two
types of fat is that the mitochondria in
By: Mrs. Teresa Maralle
brown fat cells contain a protein called
thermogenin, which functions as an
uncoupling agent. This protein "uncouples"
the ATP production associated with the
electron transport chain. The ETC reactions
still take place, but the energy that would
ordinarily be used for ATP synthesis is simply
released as heat.
Brown fat tissue is of major
importance for newborn infants. Newborns
are immediately faced with a temperature
regulation
problem.
They leave an
environment of constant 37°C temperature
and enter a much colder environment
(25°C). A supply of active brown fat, present
at birth, helps the baby adapt to the cooler
environment.
Very limited amounts of brown fat
are present in most adults. However, stores
of brown fat increase in adults who are
regularly exposed to cold environs. Thus the
production of brown fat is one of the body's
mechanisms for adaptation to cold.
Thermogenin, the uncoupling agent
in brown fat, is a protein bound to the inner
mitochondrial membrane. When activated,
it functions as a proton channel through the
inner membrane. The proton gradient
produced by the electron transport chain is
dissipated through this "new" proton
channel, and less ATP synthesis occurs
because the normal proton channel, ATP
synthase, has been bypassed. The energy of
the proton gradient, no longer useful for ATP
synthesis, is released as heat.
In 2013, a new hormone, whose
production is exercise induced, was
discovered by researchers. This hormone,
called irisin by its discoverers, is likely
responsible for some of the positive health
13
BIOCHEMICAL ENERGY PRODUCTION
BioChemistry
effects that come from exercise, including
weight loss and lower risk for type 2
diabetes. In effect, the hormone confers the
"heat-release" properties of brown fat cells
on white fat cells. Additional investigational
studies on the hormone are in progress.
Cyanide Poisoning
Inhalation of hydrogen cyanide gas
(HCN) or ingestion of solid potassium
cyanide (KCN) rapidly inhibits the electron
transport chain in all tissues, making
cyanide one of the most potent and rapidly
acting poisons known. The attack point for
the cyanide ion (CN) is cytochrome c
oxidase, the last of the four protein
complexes in the electron transport chain.
Cyanide inactivates this complex by
bonding itself to the Fe3+ in the complex's
heme portions. As a result, Fe3+ is unable to
transfer electrons to oxygen, blocking the
cell's use of oxygen. Death results from
tissue asphyxiation, particularly of the
central nervous system. Cyanide also binds
to the heme group in hemoglobin, blocking
oxygen transport in the bloodstream.
One treatment for cyanide poisoning
is to administer various nitrites, NO₂, which
oxidize the iron atoms of hemoglobin to
Fe3+. This form of hemoglobin helps draw
CN back into the bloodstream, where it can
be converted to thiocyanate (SCN) by
thiosulfate (S,O,2), which is administered
along
with
the
nitrite
(see
the
accompanying figure).
A number of plants (cassava, sugar
cane, white clover) and fruits (almonds,
peach and apricot pits, apple seeds) are
natural sources of HCN. Compounds known
as cyanoglycosides of which the best
By: Mrs. Teresa Maralle
known is - amygdalin, are the HCN source.
Amygdalin's molecular structure isThe
disaccharide part of amygdalin's structure
involves two D-glucose units joined via a
ẞ(1-6) linkage (Section 1-13).
Amygdalin is naturally present in the
pits of apricots, peaches, and plums (see
accompanying
photo).
Enzymatic
hydrolysis of amygdalin, as well as other
cyanoglycosides, produces HCN as one of
the hydrolysis products.
Amygdalin, produced primarily in
Mexico and sold under the name laetrile,
was once heavily promoted as a substance
useful in treating cancer. Studies have now
established that laetrile has little or no
effect in treating cancer. The HCN produced
when ingested laetrile is hydrolyzed affects
all cells rather than selectively targeting
cancer cells; the side effects produced
closely resemble those associated with
chronic HCN exposure: headache, vomiting,
and in some cases coma and death.
The United States Federal Drug
Administration (FDA) now seeks jail
sentences for vendors who sell laetrile
within the United States for cancer
treatment. In scientific literature, the use of
laetrile as an anticancer agent has been
described as the most sophisticated and
most remunerative example of medical
quackery in medical history.
Phytochemicals: Compounds with Color
and Antioxidant Functions
Compounds
identified
as
phytochemicals besides having positive
functions in the human body, obviously
have important roles to play in plants
themselves. In plants they can provide
14
BIOCHEMICAL ENERGY PRODUCTION
BioChemistry
protection against insect predators, against
infections (bacterial, viral, and fungal), and
against tissue damage associated with
oxidation processes. Some phytochemicals
are known to have plant hormone functions.
Plant pigmentation (color) is also a major
phytochemical function.
The following listing gives selected
color-active phytochemicals in specific
foods.
Sometimes the green chlorophyll
present in plants obscures phytochemical
color. Dark green leafy vegetables usually
contain yellow and orange pigments.
Numerous studies indicate that diets
high in fruits and vegetables are associated
with a healthy lifestyle. One reason for this is
the many phytochemicals that fruits and
vegetables
contain.
Each
fruit and
vegetable is a unique package of
phytochemicals, so consuming a wide
variety of fruits and vegetables provides the
body with the broadest spectrum of
benefits.
In
this
situation,
many
phytochemicals are consumed in small
amounts. This approach is much safer than
taking supplemental doses of particular
phytochemicals; in larger doses some
phytochemicals are toxic.
The major function in the human
body for the majority of phytochemicals is
that of an antioxidant (Section 6-11). A major
family of antioxidant phytochemicals are
the flavonoids, of which more than 4000
individual compounds are known. All
flavonoids are antioxidants, but some are
stronger
antioxidants
than
others,
depending on molecular structure. About 50
flavonoids are present in foods and
By: Mrs. Teresa Maralle
beverages obtained from plants (tea
leaves, grapes, oranges, and so on).
The core flavonoid structure is The
most widespread flavonoid in food is
quercetin (queer-sah-tin).
It is predominant in fruits, vegetables,
and the leaves of various vegetables. In
fruits, apples contain the highest amounts
of quercetin, the majority of it being found in
the outer tissues (skin, peel). A small peeled
apple contains about 5.7 mg of the
antioxidant vitamin C. But the same amount
of apple with the skin contains flavonoids
and other phytochemicals that have the
effect of 1500 mg of vitamin C. Onions are
also major dietary sources of quercetin.
In addition to their antioxidant
benefits, flavonoids may also help fight
bacterial infections. Recent studies indicate
that flavonoids can stop the growth of some
strains of drug-resistant bacteria.
15
CARBOHYDRATE METABOLISM
BioChemistry
Digestion and Absorption of
Carbohydrates
Digestion:
★ Breakdown of food molecules by
hydrolysis into simpler chemical units
that can be used by cells in their
metabolic processes
Carbohydrate digestion:
★ Begins in the mouth
★ Salivary enzyme “Alpha-amylase”
catalyzes the hydrolysis of
alpha-glycosidic linkages of starch
and glycogen to produce smaller
polysaccharides and disaccharide maltose
By: Mrs. Teresa Maralle
★ The final step in carbohydrate
digestion occurs on the outer
membranes of intestinal mucosal
cells
★ Disaccharidase enzymes present in
the intestinal mucosa convert
disaccharides (maltose, sucrose and
lactose) to monosaccharides
(glucose, fructose and galactose)
★ Maltase – converts maltose to
glucose
★ Sucrase – Converts sucrose to
glucose and fructose
★ Lactase – Converts lactose glucose
and galactose
★ The carbohydrate digestion products
(glucose, galactose, and fructose)
are absorbed into the bloodstream
★ Only a small amount of carbohydrate
digestion occurs in the mouth
because food is swallowed so quickly
into the stomach.
★ In stomach very little carbohydrate is
digested:
○
No carbohydrate digestion
enzymes present in stomach
○
Salivary amylase gets
inactivated because of stomach
acidity
★ The primary site for the carbohydrate
through the intestinal wall.
★ The intestinal villi are rich in blood
capillaries into which the
monosaccharides are actively
transported.
★ ATP hydrolysis and protein carriers
mediate the passage of the
monosaccharides through cell
membranes.
★ Galactose and Fructose are
converted to products of glucose
metabolism in the liver.
digestion is within the small intestine
★ Pancreatic alpha-amylase breaks
down polysaccharide chains into
disaccharide – maltose
1
CARBOHYDRATE METABOLISM
BioChemistry
By: Mrs. Teresa Maralle
Step 1: Formation of glucose-6-phosphate:
★ Phosphorylation of glucose phosphate group from ATP is
transferred to the hydroxyl group on
carbon 6 of glucose
★ Reactions catalyzed by Hexokinase
★ Endothermic reaction
★ Energy needed is derived from ATP
A section of the small intestine, showing its
folds and the villi that cover the inner
surface of the folds. Villi greatly increases
the inner intestinal surface area.
hydrolysis
Step 2: Formation of
Fructose-6-phosphate:
★ Glucose 6 phosphate is isomerized to
Fructose -6-Phosphate.
★ Enzyme: Phosphoglucoisomerase
Step 3: Formation of Fructose
1,6-bisphosphate:
★ Further phosphorylation of
Fructose-6-bisphosphate
★ Endothermic reaction
★ Energy derived from ATP hydrolysis
Glycolysis
Six-Carbon Stage of Glycolysis
Glycolysis: The metabolic pathway in which
glucose is converted to two molecules of
pyruvate (a C3 carboxylate), and ATP and
NADH are produced.
★ Occurs in two stages: 6 carbon and 3
Carbon stages
★ Steps 1-3: Six carbon stage
○
The six-carbon stage of glycolysis
is an energy-consuming stage
○
Phosphate derivatives glucose
and fructose are formed via ATP
coupling reactions.
★ Enzyme: phosphofructokinase
Three-Carbon Stage of Glycolysis (Steps
4-10)
★ Reaction intermediates are
derivatives of glycerol and acetone
★ All reaction intermediates are
phosphorylated derivatives of
dihydroxyacetone, glyceraldehyde,
glycerate, or pyruvate
Step 4: Formation of Triose Phosphates:
★ C6 species is split into two C3 species
★ Two C3 species formed are
dihydroxyacetone phosphate and
glyceraldehyde 3-phosphate
★ Enzyme : Aldolase
2
CARBOHYDRATE METABOLISM
BioChemistry
By: Mrs. Teresa Maralle
★ Two ATP molecules are produced for
Step 5: Isomerization of Triose Phosphates:
★ Dihydroxyacetone phosphate is
isomerized to glyceraldehyde
each original glucose molecule
★ Note: Steps 1,3 and 10 are control
points for glycolysis
3-phosphate
★ Enzyme: Triosephosphate isomerase
Step 7: Formation of 3-Phosphoglycerate:
★ Diphosphate from step 6 is converted
back to monophosphate species
★ It is an ATP producing step
○
C1 high energy phosphate group
of 1,3-bisphosphoglycerate is
transferred to an ADP molecule to
form an ATP
★ Enzyme: phosphoglycerokinase
★ Two ATP molecules are produced for
each original glucose molecule
Step 8: Formation of 2-phosphoglycerate:
★ Isomerization of 3-phosphoglycerate
to 2-phosphoglycerate
★ Phosphate group moved from C-3 to
C-2
★ Enzyme: Phosphoglyceromutase
Step 9: Formation of Phosphoenolpyruvate:
★ This is an alcohol dehydration
reaction, results in another high
energy phosphate group containing
compound
★ Enzyme: Enolase
Step 10: Formation of Pyruvate:
★ High energy phosphate is transferred
from phosphoenolpyruvate to ADP
molecule to produce ATP and
ATP Production and Consumption
★ There is a net gain of two ATP
molecules in glycolysis for every
glucose molecule processed
pyruvate
★ Enzyme: Pyruvate kinase
3
CARBOHYDRATE METABOLISM
BioChemistry
By: Mrs. Teresa Maralle
★ The entry of galactose into glycolysis
also needs phosphorylation by ATP to
produce glucose 1-phosphate and is
isomerized to glucose 6-phosphate
★ Overall equation for glycolysis
Indicate at what step in the glycolysis
pathway each of the following events occur:
a. Second formation of ATP occurs
(Step 10)
b. Second “energy-rich” compound is
produced (Step 9)
c. Second time ATP is converted to ADP
(Step 3)
d. A hydration reaction occurs (Step 9)
Entry of Galactose and Fructose into
Glycolysis
★ Both fructose and galactose are
converted in the liver to
intermediates that enter into the
Regulation of Glycolysis
★ Control points of glycolysis: Steps 1, 3,
and 10
★ Step 1- Conversion of glucose to
glucose 6-phosphate by hexokinase:
○
6-phosphate (feedback
glycolysis pathway.
★ Entry of fructose into the glycolytic
pathway involves:
○
Phosphorylation by ATP to
produce fructose 1-phosphate
○
Fructose 1-phosphate is
converted to two trioses:
■
glycolysis
■
inhibition)
★ Step 3: Fructose 6-phosphate
converted to fructose
1,6-bisphosphate by
phosphofructokinase:
○
Dihydroxyacetone phosphate enters into glycolysis directly
High concentrations of ATP and
citrate inhibit
Glyceraldehyde:
phosphorylated to enter into
Hexokinase inhibited by glucose
phosphofructokinase
★ Step 10: Conversion of
phosphoenolpyruvate to pyruvate by
Pyruvate kinase:
○
Enzymes are inhibited by high ATP
concentrations.
4
CARBOHYDRATE METABOLISM
BioChemistry
○
Both pyruvate kinase (Step 10)
and phosphofructokinase (Step 3)
By: Mrs. Teresa Maralle
★ Strenuous muscular activity can
result in lactate accumulation.
are allosteric enzymes.
Fates of Pyruvate
Oxidation to Acetyl CoA
★ Under aerobic (oxygen-rich)
conditions, pyruvate is oxidized to
acetyl CoA by pyruvate
dehydrogenase complex
★ Acetyl CoA thus formed enters the
mitochondrial matrix for further
processing through the citric acid
cycle
★ Most pyruvate formed during
glycolysis is converted to Acetyl CoA.
Lactate Fermentation
★ An enzymatic anaerobic reduction of
pyruvate to lactate occurs mainly in
Anaerobic lactate formation allows for
muscles
“recycling” of NAD1, providing the NAD1
★ Purpose: Conversion of NADH to NAD+
for increased rate of glycolysis
★ Lactate is converted back to pyruvate
needed for Step 6 of glycolysis.
Ethanol Fermentation
★ Enzymatic anaerobic conversion of
when aerobic conditions are
pyruvate to ethanol and carbon
reestablished in the cell
dioxide
★ Muscle fatigue associated with
★ Simple organisms, e.g., yeast and
strenuous physical activity is
bacteria, regenerate NAD+ through
attributed to increased build-up of
ethanol fermentation reactions
lactate
★ Involves two reactions:
5
CARBOHYDRATE METABOLISM
BioChemistry
○
○
By: Mrs. Teresa Maralle
Pyruvate decarboxylation by
a. Ethanol fermentation: Acetaldehyde is an
pyruvate decarboxylase
intermediate in this pathway
Acetaldehyde reduction to
b. Ethanol fermentation: An anaerobic
ethanol by alcohol
pathway that does not function in humans
dehydrogenase
c. Lactate fermentation: An anaerobic
pathway that does function in humans
d. Acetyl CoA formation: A C2 molecule is a
product under aerobic reaction conditions
★ Ethanol fermentation involving yeast
for this pathway
causes bread and related products
to rise as a result of CO2 bubbles
being released during baking.
★ Beer, wine, and other alcoholic drinks
are produced by ethanol
fermentation of the sugars in grain
and fruit products.
★ Overall ethanol fermentation
reaction:
ATP Production for the Complete
Oxidation of Glucose
★ NADH produced during Step 6 of
Glycolysis cannot directly participate
in the electron transport chain
because mitochondria are
impermeable to NADH and NAD+
★ Glycerol
3-phosphate-dihydroxyacetone
phosphate transport system shuttles
electrons from NADH, but not NADH
itself, across the membrane:
○ Dihydroxyacetone phosphate
and glycerol phosphate freely
cross the mitochondrial
membrane
○ The interconversion shuttles the
electrons from NADH to FADH2
Which of the three common metabolic
pathways for pyruvate is compatible with
each of the following characterizations
concerning the reactions that pyruvate
undergoes?
6
CARBOHYDRATE METABOLISM
BioChemistry
★ Total of 30 ATP molecules are
produced in muscle and nerve cells:
○ 26 from oxidative
phosphorylation of electron
transport chain
○ 2 from oxidation of glucose to
pyruvate
○ 2 from conversion of GTP
(guanosine triphosphate) to ATP
★ Aerobic oxidation of glucose is 15
times more efficient in the ATP
production as compared to
anaerobic lactate and ethanol
processes
★ In other cells such as heart and liver
cells a more complex shuttle system
is used and 32 molecules are
produced instead of 30 per glucose
molecule
Glycogen Synthesis and Degradation
Glycogen:
★ A branched polymer form of glucose
is the storage form of carbohydrates
in humans and animals (animal
starch):
○ In muscle: source of glucose for
glycolysis
○ In liver tissue: source of glucose to
maintain normal blood glucose
levels
By: Mrs. Teresa Maralle
Produced by the process of
glycogenesis
Glycogenesis
★ Metabolic pathway by which
glycogen is synthesized from glucose
★ Involves three steps:
○ Formation of Glucose 1-phosphate
○ Formation of UDP Glucose (uridine
diphosphate glucose)
○ Glucose transfer to a Glycogen
Chain
Step 1: Formation of glucose 1-phosphate:
★ Starting material is glucose
6-phosphate -- from first step of
glycolysis
★ Enzyme phosphoglucomutase
catalyzes conversion of glucose
6-phosphate to glucose 1-phosphate
Step 2: Formation of UDP Glucose:
★ High energy compound UTP (uridine
triphosphate) activates glucose
1-phosphate to uridine diphosphate
glucose (UDP-glucose)
Step 3: Glucose transfer to a Glycogen
Chain:
★ The glucose unit of UDP-glucose is
attached to the end of a glycogen
chain and UDP is produced
★ UDP reacts with ATP to form UTP and
ADP
★ Adding one glucose unit to a
glycogen chain requires the
investment of two ATP molecules
★ One in the formation of glucose
6-phosphate and one in the
regeneration of UTP
Glycogenolysis
★ Breakdown of glycogen to
glucose-6-phosphate:
○
7
CARBOHYDRATE METABOLISM
BioChemistry
It is not just reverse of
glycogenesis because it does not
require UTP or UDP molecules
○ Glycogenolysis is a two-step
process
Step 1: Phosphorylation of a glucose
residue:
★ Glycogen phosphorylase catalyzes
the removal of an end glucose
residue from a glycogen molecule as
glucose 1-phosphate.
Step 2: Glucose 1-phosphate Isomerization:
★ Phosphoglucomutase isomerizes
glucose 1-phosphate is to glucose
6-phosphate (reverse of the first step
of glycogenesis)
○
★ The locally produced glucose
6-phosphate directly enters the
glycolysis pathway:
★ Low glucose levels stimulates
glycogenolysis in liver cells
★ Glucose 6-phosphate is ionic and
cannot cross the membrane:
○ Enzyme glucose 6-phosphatase
found in liver, kidneys and
intestine convert glucose
6-phosphate to glucose
○ This enzyme is not present in
muscle and brain tissues
○ The free glucose is then
transported to muscle and brain
via blood
By: Mrs. Teresa Maralle
Gluconeogenesis
★ Metabolic pathway by which
glucose is synthesized from
non-carbohydrate sources:
○ The process is not exact opposite
of glycolysis
★ Glycogen stores in muscle and liver
tissue are depleted with in 12-18 hours
from fasting or in even less time from
heavy work or strenuous physical
activity
★ Without gluconeogenesis, the brain,
which is dependent on glucose as a
fuel would have problems functioning
if food intake were restricted for even
one day
★ Gluconeogenesis helps to maintain
normal blood-glucose levels in times
of inadequate dietary carbohydrate
intake
★ About 90% of gluconeogenesis takes
place in the liver
★ Non-carbohydrate starting materials
for gluconeogenesis:
○ Pyruvate
○ Lactate (from muscles and from
red blood cells)
○ Glycerol (from triacylglycerol
hydrolysis)
○ Certain amino acids (from dietary
protein hydrolysis or from muscle
protein during starvation)
Overall Reaction
★ 2 Pyruvate + 4ATP + 2GTP + 2NADH +
2H2O Glucose + 4ADP + 2GDP + 6Pi +
2NAD+
★ Pyruvate to glucose conversion
requires the expenditures of 4 ATP
and 2 GTP
8
CARBOHYDRATE METABOLISM
BioChemistry
By: Mrs. Teresa Maralle
★ Gluconeogenesis occurs at the
expense of other ATP-producing
metabolic processes
Nucleotide triphosphate change (gain or
loss) associated with the two parts of the
Cori cycle.
Terminology for Glucose Metabolic
Pathways
Cori Cycle
★ Gluconeogenesis using lactate as a
source of pyruvate is particularly
important because of lactate
formation during strenuous exercise
★ Lactate produced diffuses from
muscle cells into the bloodstream
and transported to liver
★ Enzyme lactate dehydrogenase
converts lactate to pyruvate in the
liver
★ Pyruvate is then converted to glucose
via gluconeogenesis
★ The glucose thus produced enters
the bloodstream and transported to
the muscles
★ Glycogenesis: 2-Step process in
which glycogen is synthesized from
glucose 6-phosphate
★ Gluconeogenesis: 11-step process in
which pyruvate is converted to
glucose
★ Glycolysis: 10 step process in which
glucose is converted to pyruvate
★ Glycogenolysis: The process in which
glycogen is converted to glucose
6-phosphate
○ Names ending with “lysis” Breakdown
○ Names ending with “genesis” Synthesis
9
CARBOHYDRATE METABOLISM
BioChemistry
Identify each of the following as a
characteristic of one or more of the
following processes: glycolysis,
glycogenesis, glycogenolysis, and
gluconeogenesis.
a. Glycogenesis: Glycogen is the final
product.
b. Glycolysis: Glucose is the initial reactant.
c. Glycogenesis: Glucose 1-phosphate is
produced in the first step.
d. Glycolysis: ADP is converted to ATP in this
process.
The Pentose Phosphate Pathway
Structure of NADPH
★ The pentose phosphate pathway: A
metabolic pathway in which glucose
is used to produce NADPH, ribose
5-phosphate (a pentose phosphate)
By: Mrs. Teresa Maralle
and numerous other sugar
phosphates
○ NADPH: reduced form of NADP+
(nicotinamide adenine
dinucleotide phosphate)
○ NADP+/NADPH is a
phosphorylated version of
NAD+/NADH
○ NADPH, like ATP, is essential for
biosynthetic reactions/pathways.
Two Stages
★ Oxidative stage:
○ Involves three steps through
which glucose 6-phosphate is
converted to ribulose
5-phosphate and CO2
★ Non-oxidative stage:
○ In the first step of the
non-oxidative stage of the
pentose phosphate pathway,
ribulose 5-phosphate (ketose) is
isomerized to ribose
5-phosphate (aldose)
★ The pentose phosphate pathway
helps meet cellular needs in
numerous ways:
○ When ATP demand is high, the
pathway continues to its end
products which enter glycolysis
10
CARBOHYDRATE METABOLISM
BioChemistry
○
○
By: Mrs. Teresa Maralle
When NADPH demand high,
intermediates are recycled to
glucose 6-phosphate (the start
of the pathway), and further
NADPH is produced
Helps generate ribose
5-phosphate for nucleic acid and
coenzyme production
Hormonal Control of Carbohydrate
Metabolism
★ The second major method for
controlling carbohydrate
metabolism, besides enzyme
inhibition by metabolism is hormonal
control
★ Three major hormones control
carbohydrate metabolism:
○ Insulin
○ Glucagon
○ Epinephrine
Insulin Hormone Produced by Beta Cells of
Pancreas
★ 51 amino acid polypeptide
★ Promotes utilization of glucose by
cells
★ Its function is to lower blood glucose
levels
★ Also involved in lipid metabolism
★ The release of insulin is triggered by
high blood-glucose levels
★ The mechanism for insulin action
involves insulin binding to proteins
receptors on the outer surfaces of
cells which facilitates entry of the
glucose into the cells
★ Insulin also produces an increase in
the rate of glycogen synthesis
Glucagon
★ 29 amino acid peptide hormone
★ Produced in the pancreas by alpha
cells
★ Released when blood glucose levels
are low
★ Principal function is to increase
blood-glucose concentration by
speeding up the conversion of
glycogen to glucose (glycogenolysis)
in the liver
★ Glucagon elicits the opposite effects
of insulin
Epinephrine
★ Also called adrenaline
★ Released by the adrenal glands in
response to anger, fear, or
excitement
★ Function is similar to glucagon, i.e.,
stimulates glycogenolysis
★ Primary target of epinephrine is
muscle cells
★ Promotes energy generation for quick
action
★ It also functions in lipid metabolism
11
CARBOHYDRATE METABOLISM
BioChemistry
By: Mrs. Teresa Maralle
B-Vitamins and Carbohydrate
Metabolism
★ Structurally modified B-vitamins
function as coenzymes in
carbohydrate metabolism
★ 6 B-Vitamins participate in various
reactions of carbohydrate
metabolism:
○ Niacin – NAD+ and NADH
○ Riboflavin – as FAD, FADH2 and
FMN
○ Thiamin – as TPP
○ Pantothenic acid - as CoA
○ Biotin
○ Vitamin B6 in the form of
PLP(pyridoxal 5-phosphate)
★ Without these B-vitamins the body
would be unable to utilize
carbohydrates as energy sources.
CHEMICAL CONNECTIONS
Lactate Accumulation
During strenuous exercise, conditions
in muscle cells change from aerobic to
anaerobic as the oxygen supply becomes
inadequate to meet demand. Such
conditions cause pyruvate to be converted
to lactate rather than acetyl COA. (Lactate
production can also be high at the start of
strenuous exercise before the delivery of
oxygen is stepped up via an increased
respiration rate.)
The resulting lactate begins to
accumulate in the cytosol of cells where it is
produced. Some lactate diffuses out of the
cells into the blood, where it contributes to a
slight decrease in blood pH. This lower pH
triggers fast breathing. which helps supply
more oxygen to the cells
Lactate
accumulation
and
pH
change are the cause of muscle pain and
cramping during prolonged, strenuous
exercise. As a result of such cramping,
muscles may be stiff and sore the next day.
Regular, hard exercise increases the
12
CARBOHYDRATE METABOLISM
BioChemistry
efficiency with which oxygen is delivered to
the body. Thus athletes can function longer
than nonathletes under aerobic conditions
without lactate production.
Recent research indicates that pH
change in muscle cells (H accumulation)
may
be
as important as lactate
accumulation as a cause of muscle pain.
Hydrogen ions are produced when NAD is
reduced to NADH when glucose (as well as
fats) is used by the body as a source of
energy.
Lactate
production
consumes
hydrogen ions as the reverse of the
preceding
reaction
occurs.
During
strenuous exercise, lactate production (H"
ion consumption) may not be fast enough
to keep up with H ion production
Lactate accumulation can also occur
in heart muscle if it experiences decreased
oxygen supply (from artery blockage). The
heart muscle experiences cramps and
stops beating (cardiac arrest). Massage of
heart muscle often reduces such cramps,
just as it does for skeletal muscle, and it is
sometimes possible to start the heart
beating again by using such a technique.
The pain associated with a heart attack is
related to lactate and H accumulation.
Hunters are usually aware that meat
from game animals that have been run to
exhaustion usually tastes sour, lactate
accumulation is the reason for this problem.
Lactate formation is also relevant to
a practice that short distance sprinters
often use just prior to a race, the practice of
hyperventilation.
Rapid
breathing
(hyperventilation). raises slightly the pH of
blood. The CO: loss associated with the
rapid breathing causes carbonic acid
By: Mrs. Teresa Maralle
(H,CO) present in the blood to dissociate in
CO; and H₂O to replace the lost CO2.
A decreased amount of carbonic
acid causes blood pH to rise, which makes
the blood slightly more basic. A few seconds
before the start of the race, sprinters
decrease the amount of CO in their lungs
through hyperventilation, making their
blood a little bit more basic. This slight
increase in basicity means the runner can
absorb slightly more lactic acid before the
blood pH drops to the point where
cramping becomes a problem. Having such
an advantage for only a few seconds in a
short race can be helpful.
In diagnostic medicine, lactate levels
in blood can often be used to determine the
severity of a patient's condition. Higher than
normal lactate levels are a sign of impaired
oxygen delivery to tissue. Conditions that
can cause higher lactate levels include lung
disease and congestive heart failure.
Premature
infants
with
underdeveloped lungs are often given
increased amounts of oxygen to minimize
lactate accumulation. They are also often
given bicarbonate (HCO,) solution to
counteract the acidity change in the blood
that accompanies lactate buildup.
Diabetes Mellitus
Diabetes mellitus, which is usually
simply referred to as diabetes is a
metabolic
disorder
characterized
by
elevated levels of glucose in the blood.
Classic symptoms associated with an
uncontrolled diabetic condition are frequent
urination, increased thirst, and increased
hunger. These symptoms are the basis for
13
CARBOHYDRATE METABOLISM
BioChemistry
the
name
diabetes mellitus, which
originates from the Greek words "diabetes,"
meaning "siphon," and "mellitus," meaning
"sweet." In the second century A.D. The Greek
physician Aretaeus the Cappado cian
named this condition; he observed that
some people had a condition in which the
body acts like a siphon-taking water in at
one end and discharging it at the other-and
that the urine produced was sweet to the
taste. The name diabetes mellitus can
roughly be translated as "sweet urine."
As of 2010, it is estimated that 26
million Americans (about 1 in 12) are
diabetic. Diagnosis of diabetes is based on
measurement of fasting blood-glucose
levels. A fasting blood glucose level greater
than 126 mg/dL is considered a positive test,
and a level less than 100 mg/dL is
considered a negative test. Readings
between 100 mg/dL and 126 mg/dL indicate
a prediabetic condition; the blood-glucose
level is higher than it should be but not high
enough to be classified as diabetic.
Prediabetic conditions are found in 15% of
Americans.
There are two major forms of
diabetes
mellitus:
type
1
(insulin-dependent)
and
type
2
(non-insulin-dependent).
Type 1 diabetes is the result of
inadequate insulin production by the beta
cells of the pancreas. Control of this
condition involves insulin injections and
special dietary programs. A risk associated
with the insulin injections is that too much
insulin can produce severe hypoglycemia
(insulin shock); blackout or a coma can
result. Treatment involves a quick infusion of
By: Mrs. Teresa Maralle
glucose. Diabetics often carry candy bars
(quick glucose sources) for use if they feel
any of the symptoms that signal the onset
of insulin shock.
Type 2 diabetes results from insulin
resistance, a condition in which cells fail to
use
insulin
properly.
Bodily
insulin
production may be normal, but the cells do
not respond to it normally. Treatment
involves use of medications that decrease
glucose production and/or increase insulin
levels, as well as a carefully regulated diet
to decrease obesity if the latter is a
problem. More efficient use of undamaged
insulin receptors occurs at increased insulin
levels.
About 10% of all cases of diabetes are
type
1.
The
more
common
non-insulin-dependent type 2 diabetes
occurs in the other 90% of cases. The effects
of both types of diabetes are the
same-inadequate glucose uptake by cells.
The result is blood-glucose levels much
higher than normal (hyperglycemia). With
an inadequate glucose intake, cells must
resort to other procedures for energy
production, procedures that involve the
breakdown of fats and protein.
The
above
graph
contrasts
blood-glucose levels for diabetic and
nondiabetic individuals in the context of a
two hour oral glucose-tolerance test. A
person must fast for eight hours prior to
testing. A blood sample is taken at the
beginning of the test, a 50-g glucose
beverage is consumed, and a second blood
sample is taken two hours later.
Most people with diabetes take oral
medication rather than insulin, and the
proportion who do so is increasing. Oral
14
CARBOHYDRATE METABOLISM
BioChemistry
By: Mrs. Teresa Maralle
medication use rose from 60% in 1997 to 77%
in 2007. One of the most used oral
anti-diabetic drugs is the compound
metformin. Structurally, metformin is a
noncyclic organic compound that contains
more nitrogen atoms (five) than carbon
atoms (four).
Metformin does not increase how
much insulin the pancreas makes; instead it
acts on the liver, decreasing the amount of
glucose it produces. An average person
with type 2 diabetes has a gluconeogenesis
rate that is three times the normal rate.
Metformin slows down the production of
glucose via gluconeogenesis.
15
LIPID METABOLISM
BioChemistry
Digestion and Absorption of Lipids
Dietary Lipids:
★ 98% triacylglycerols (TAGs):
○ Fats and oils
★ Salivary enzymes (water soluble) in
the mouth have no effect on lipids
(TAGs) which are water insoluble
★ In Stomach: Most, not all, of TAGs
change physically to small globules
or droplets -- called chyme which
floats above other material:
○ It is a physical not chemical
process
★ Lipid digestion starts in the stomach:
○ Gastric lipase hydrolyzes ester
bonds -- 2 fatty acids and one
monoacylglycerol --About 10% of
TAGS are hydrolyzed
■ High fat foods stay in stomach
for longer time -- high fat
meal gives you a feeling of
being full for longer time
By: Mrs. Teresa Maralle
★ Fatty acids, monoacyglycerols and
bile salts make small droplets: called
micelles -- hydrophobic chain in the
interior
★ Micelles consist of monoacyglycerols
and free fatty acids:
○
Small enough to absorb through
intestinal cells
★ In the intestinal cells onoacylglycerols
and free fatty acids are repackaged
to from TAGs
★ These new TAGs combine with
membrane lipids (phospholipids and
cholesterol) and lipoproteins to form
chylomicrons
★ Chylomicrons transport TAGs from
intestinal cells to the bloodstream
○
This is accomplished through the
lymphatic system
★ In the bloodstream TAGs are
completely hydrolyzed by lipase
enzymes
★ Fatty acids and glycerol are
absorbed by the cell and are either
broken down to the acetyl Co-A for
★ Chyme enters into small intestine
energy or repacked to store as lipids
and is emulsified (stabilization of
colloidal suspension) with bile salts
★ Pancreatic lipase hydrolyzes ester
bonds to form fatty acids and
glycerol
○
Normally 2 out of 3 fatty acids are
hydrolyzed
1
LIPID METABOLISM
BioChemistry
By: Mrs. Teresa Maralle
★ Several hormones trigger the
hydrolysis of TAGs via activation of
cAMP (activate hormone sensitive
lipase; HSL) and release of glycerol
and fatty acids into the bloodstream
-- called triacylglycerol mobilization
A summary of the events that must occur
before triacylglycerols (TAGs) can reach the
bloodstream through the digestive process.
Triacylglycerol Storage and Mobilization
★ ~10% of TAGs replaced everyday
★ Triacylglycerol energy reserves (fat
reserves) are the human body’s
major source of stored energy:
○
Energy reserves associated with
protein, glycogen, and glucose
★ Most cells have limited capability of
are small to very small when
TAGs storage
★ TAGs stored in specialized cells called
compared to fat reserves
adipocytes found in adipose tissue:
Glycerol Metabolism
○
Largest cells in the body -cytoplasm converted to TAG’ s
droplet
○
Located primarily beneath the
skin especially in abdominal
region and vital organs
○
Adipose tissue also serves as a
protection against the heat loss
★ Taken to liver or kidney by blood -converted to dihydroxyacetone
phosphate in two steps:
○
Phosphorylation of primary
hydroxyl group of the glycerol
○
Secondary alcohol group of
glycerol is oxidized to ketone
and mechanical shock
Oxidation of Fatty Acids
★ There are three parts to the process
by which fatty acids are broken down
to obtain energy.
★ Activated by binding to Coenzyme-A
- product called acyl Co-A.
★ Transported to mitochondrial matrix
2
LIPID METABOLISM
BioChemistry
★ Repeatedly (fatty acid spiral)
oxidized to produce acetyl Co-A,
FADH2 and NADH
○ Note acyl has longer R group but
acetyl has CH3 attached to C=O
Fatty Acid Activation
★ Takes place in outer mitochondrial
membrane
★ FA reacts with coenzyme A in the
By: Mrs. Teresa Maralle
carbon from carboxyl end of the
chain oxidized
★ This process removes two carbon
units and converts to acetyl CoA with
FADH2 and NADH being produced
Four Steps of the Beta-Oxidation Pathway
★ Step 1: Oxidation (dehydrogenation):
○
Hydrogen atoms are removed
from the alpha and beta carbons,
presence of ATP to produce high
creating a double bond between
energy acyl CoA
these two carbon atoms.
★ ATP is converted to AMP
○
FAD is the oxidizing agent, and a
FADH2 molecule is a product.
★ Step 2: Hydration:
Fatty Acid Transport
○
A molecule of water is added
across the trans double bond,
★ A shuttle mechanism is involved in
the transport of acyl CoA from
producing a secondary alcohol at
mitochondrial membrane to
the beta carbon position
mitochondrial matrix
★ Step 3: Oxidation (dehydrogenation):
○
The beta-hydroxyl group is
oxidized to a keto functional group
with NAD+ serving as the oxidizing
agent.
★ Step 4: Chain Cleavage:
○
The fatty acid chain is broken
between the alpha and beta
carbons by reaction with a
coenzyme A molecule.
○
Reactions of the Beta-Oxidation Pathway
★ Four reactions repeatedly cleave
The result is an acetyl CoA
molecule and a new acyl CoA
molecule that is shorter by two
two-carbon units from the carboxyl
carbon atoms than its
end of saturated fatty acids
predecessor.
○
Also called beta-oxidation spiral
because the second or beta
3
LIPID METABOLISM
BioChemistry
Beta-Oxidation Pathway
By: Mrs. Teresa Maralle
ATP Production From Fatty Acid
Oxidation
Fatty Acid vs. Glucose Oxidation: A
Comparison
★ Spiral fatty acid oxidation produces a
net of 120 ATP molecules by oxidation
of 18 carbon atom fatty acid (stearic
acid)
★ Note that 2 ATP molecules are
needed for activation of fatty acids
so net ATP production is 120
molecules
★ 1 Glucose molecule (6 carbon atoms)
produces 30 ATP molecules
★ Three molecules of glucose (18
Carbon atoms) produce 90 ATP
★ 1 Stearic acid molecule (18 carbon
atoms) produces 122 molecules of
ATP
Reactions of the b-oxidation pathway for
an 18:0 fatty acid (stearic acid).
Unsaturated Fatty Acids
★ Oxidation of unsaturated fatty acids
require two additional steps
compared to saturated fatty acids
★ Epimerase: changes D-configuration
to an L configuration
★ Cis-trans isomerase: trans-(2,3)
double bond is formed from cis-(3,4)
★ Stoichiometric Comparison:
○ 1.00 g Stearic acid produces =
0.423 mole ATP
○ 1.00 g glucose produces 0.167
mole ATP
■ Stearic acid produces 2.5 time
more energy than glucose
double bond
○
The interconversion shuttles the
4
LIPID METABOLISM
BioChemistry
Ketone Bodies
★ Acetyl CoA formed from fatty acid
spiral further processed by Citric Acid
Cycle (Krebs Cycle)
○ Therefore an adequate balance in
carbohydrate and lipid
metabolism required
★ Lipid-Carbohydrate Metabolism
disturbed by:
○ Dietary intakes high in fat and low
in carbohydrates
○ Diabetic conditions -- glucose not
used properly
○ Prolonged fasting conditions
★ Under low supply of oxaloacetate the
acetyl CoA will be in excess
(increased concentration)
★ As a consequence the excess acetyl
CoA is converted to ketone bodies
Ketogenesis
★ Ketogenesis involves the production
of ketone bodies from acetyl CoA
★ Synthesis of ketone bodies from
acetyl CoA primarily in liver
mitochondria -- diffused into
bloodstream and transported to
peripheral tissues
★ The 3 ketone bodies produced are:
○ Acetone
○ Acetoacetate
○ Beta-hydroxybutyrate
★ Step 1: First Condensation of two
acetyl CoA molecules to produce
acetoacetyl CoA, a reversal of the
last step of the Beta-oxidation
pathway
★ Step 2: Second Condensation:
Acetoacetyl CoA then reacts with a
third acetyl CoA and water to
By: Mrs. Teresa Maralle
produce 3- hydroxy-3-methylglutaryl
CoA (HMG-CoA) and CoA-SH.
★ Step 3: Chain cleavage: HMG-CoA is
cleaved to acetyl CoA and
acetoacetate.
★ Step 4: Reduction: Acetoacetate is
reduced to Betahydroxybutyrate
The initial stages of exercise are fueled
primarily by glucose; in later stages,
triacylglycerols become the primary fuel.
Biosynthesis of Fatty Acids: Lipogenesis
Lipogenesis vs. Fatty Acid Degradation
★ Lipogenesis
○ Takes place in cell cytosol
○ A multi-enzyme complex called
fatty acid synthase catalyzes
reactions
○ Intermediates bonded to acyl
carrier protein (ACP)
○ Depends upon reducing agent
NADPH
5
LIPID METABOLISM
BioChemistry
★ Degradation of a fatty acids
○ Takes place in mitochondrial
matrix
○ Enzymes are not complexed and
the steps are independent
○ The carrier for fatty acid spiral is
CoA
○ Dependent upon FAD and NAD+
The Citrate–Malate Shuttle System
★ Acetyl CoA is the starting material for
lipogenesis.
★ Acetyl CoA needed for lipogenesis is
generated in mitochondria, therefore
it must first be transported to the
cytosol.
★ Citrate-malate transport system
helps transport acetyl CoA to cytosol
indirectly
By: Mrs. Teresa Maralle
ACP-SH can be regarded as a
“giant CoA-SH molecule”
Chain Elongation
★ Four reactions constitute first step of
chain elongation process
○ Condensation: Acetyl-ACP and
malonyl-ACP condense together
to form acetoacetyl-ACP
○ Hydrogenation: The keto group of
the acetoacetyl complex is
reduced to alcohol by NADPH
○ Dehydration: Water is removed
from alcohol to form an alkene
○ Hydrogenation: Hydrogen is added
to alkene 3 to form saturated
butyryl ACP from NADPH
Unsaturated Fatty Acid Biosynthesis
★ To produce a double bond oxygen is
needed and water is removed
★ In humans and animals, enzymes
can only introduce double bond
between C-4 and C-5 and between
C-9 and C-10
★ Consequence: Important essential
unsaturated fatty acids linoleic (18
carbons with C-9 and C-12 double
bond and linolenic acid (18 carbon
with C-9, C-12 and C15 double bonds
can’t be synthesized - should come
from diet - plants have enzymes to
synthesize them
○
Relationships Between Lipogenesis and
Citric Acid Cycle Intermediates
ACP Complex Formation
★ ACP (Acyl Carrier Protein) Complex
Formation:
○ All intermediates in fatty acid
synthesis are linked to carrier
proteins (ACP-SH)
★ The last four intermediates of the
citric acid cycle bear the following
relationship to each other.
★ Saturated C4 diacid Unsaturated C4
diacid hydroxy C4 diacid keto C4
diacid.
6
LIPID METABOLISM
BioChemistry
★ The intermediate C4 carbon chains
of lipogenesis bear the following
relationship to each other.
★ Keto C4 monoacid hydroxy C4
monoacid unsaturated C4
monoacid saturated C4 monoacid.
★ Two important contrasts between
citric acid cycle intermediates and
Lipogenesis intermediates:
○ The citric acid intermediates
involve C4 diacids and the
lipogenesis intermediates involve
C4 monoacids
○ The order in which the various
acid derivative types are
encountered in lipogenesis is the
reverse of the order in which they
are encountered in the citric acid
cycle.
By: Mrs. Teresa Maralle
between carbohydrate and lipid
metabolism
○ Fatty acid biosynthesis: the
buildup of excess acetyl CoA
when dietary intake exceeds
energy needs energy needs
leads to accelerated fatty acid
biosynthesis
○ Cholesterol biosynthesis: It
occurs when the body is in an
acetyl CoA- rich state
Cholesterol
★ Secondary component of cell
membrane
★ Precursor for bile salts, sex hormones
and adrenal hormone
★ Body synthesizes 1.5 - 2.0 g of
cholesterol everyday from acetyl
CoA units
○ Average daily dietary intake is ~
0.3 g
★ Synthesis of cholesterol occur in liver
★ Synthesis requires at least 15 acetyl
CoAs and involves ~27 separate
enzymatic steps
Relationships Between Lipid and
Carbohydrate Metabolism
Fate of Fatty-Acid Generated Acetyl CoA
★ Acetyl-CoA formed from fatty acids is
further channeled in various different
routes:
○ Oxidation in the citric acid cycle:
both lipids and carbohydrates
supply acetyl CoA
○ Ketone body formation: Very
important when imbalance
★ Acetyl Co-A is the primary link
between these two metabolic
pathways
○ Acetyl Co-A is the starting
material for the biosynthesis of
fatty acids, cholesterol and ketone
bodies
○ Acetyl CoA is the product for
glucose, glycerol and fatty acids
7
LIPID METABOLISM
BioChemistry
B-Vitamins and Lipid Metabolism
★ Structurally modified B-vitamins
function as coenzymes in lipid
metabolism
★ Four B-Vitamins participate in various
pathways of lipid metabolism:
○ Niacin – NAD+ and NADH
○ Riboflavin – as FAD, FADH2 and
FMN
○ Pantothenic acid - as CoA
○ Biotin
★ Without these B-vitamins body would
be unable to utilize lipids as energy
sources
B vitamin participation, as coenzymes, in
chemical reactions associated with lipid
metabolism
CHEMICAL CONNECTIONS
Statins: Drugs That Lower Plasma Levels of
Cholesterol
More than half of all deaths in the
United States are directly or indirectly
related to heart disease, in particular to
athero- sclerosis. Atherosclerosis results
from the buildup of plaque (fatty deposits)
on the inner walls of arteries. Cholesterol,
obtained from low-density lipoproteins
(LDLs) that circu- late in blood plasma, is
also a major component of plaque.
By: Mrs. Teresa Maralle
Because most of the cholesterol in the
human body is synthesized in the liver, from
acetyl CoA, much research has focused on
finding ways to inhibit its biosynthesis. The
rate-determining
step
in
cholesterol
biosynthesis involves the conversion of
3-hydroxy-3-methylglutaryl
CoA
(HMG-CoA) to mevalonate, a process
catalyzed by the enzyme HMG-CoA
reductase. H,C
In 1976, as the result of screening
more than 8000 strains of microorganisms,
a compound now called mevastatin, a
potent inhibitor of HMG-CoA reductase was
isolated from culture broths of a fungus.
Soon thereafter, a second, more active
compound called lovastatin was isolated,
These ‘statins’ are very effective in
lowering plasma concentrations of LDL by
functioning as competitive inhibitors of
HMG-CoA reductase.
After years of testing, the statins are
now available as prescription drugs for
lowering blood cholesterol levels. Clinical
studies indicate that use of these drugs
lowers the incidence of heart disease in
individuals with mildly elevated blood
cholesterol levels. A later-generation statin
with a ring structure distinctly different from
that of earlier statins atorvastatin (Lipitor)
became the most prescribed medication in
the United States starting in the year 2000.
Note the structural resemblance between
part of the structure of Lipitor and that of
mevalonate.
Recent
research
studies
have
unexpectedly
shown
that
cholesterol-lowering statins have two
added benefits.
8
LIPID METABOLISM
BioChemistry
By: Mrs. Teresa Maralle
Laboratory studies with animals
indicate that statins prompt growth of cells
to build new bone, replacing bone that has
been leached away by osteoporosis
("brittle-bone disease"). A retrospective
study of osteoporosis patients who also
took statins shows evidence that their
bones became more dense than did bones
of osteoporosis patients who did not take
the drugs.
Statins have also been shown to
function as anti-inflammatory agents that
counteract the effects of a common virus,
cytomegalovirus, which is now believed to
contribute to the development of coronary
heart disease. Researchers believe that by
age 65, more than 70% of all people have
been exposed to this virus. The virus, along
with other infecting agents in blood, may
actually
trigger
the
inflammation
mechanism for heart disease.
9
PROTEIN METABOLISM
BioChemistry
Protein Digestion and Absorption
Protein digestion:
★ (denaturation and hydrolysis) starts
in the stomach
★ Dietary protein in stomach promotes
release of Gastrin hormone
○ Gastrin promotes secretion of
pepsinogen and HCl
★ HCl in stomach has 3 functions:
○ Gastric acidity denatures protein
exposing peptide bonds
○ Gastric acidity (pH of 1.5-2.0) kills
most bacteria
○ Activates pepsinogen (inactive)
to pepsin (active)
★ Enzyme pepsin hydrolyzes about 10%
peptide bonds
★ Large polypeptide chains pass from
stomach into small intestine:
○ Passage of acidified protein
promotes secretion of “Secretin”
★ Secretin hormone stimulates:
○
Bicarbonate (HCO3 - ) production
By: Mrs. Teresa Maralle
○
Trypsin, chymotrypsin and
carboxypeptidase in pancreatic
juice released into the small
intestine help hydrolyze proteins
to smaller peptides
○
Aminopeptidase secreted by
intestinal mucosal membrane
further hydrolyze the small
peptides to amino acids
★ Amino acids liberated are
transported into blood stream via
active transport process
★ The passage of polypeptides and
small proteins across the intestinal
wall is uncommon in adults.
★ In infants the transport of
polypeptides allows the passage of
proteins such as antibodies in
colostrum milk from a mother to a
nursing infant to build up
immunologic protection in the infant.
which in turn helps neutralize the
acidified gastric content
○
Promotes secretion of pancreatic
digestive enzymes Trypsin,
chymotrypsin and
carboxypeptidase in their in
active forms
★ Protein digestive enzymes in Intestine:
○
Enzymes (Trypsin, chymotrypsin
carboxypeptidase , and
aminopeptidase) are produced
Amino Acid Utilization
Amino acid pool
★ Amino acids formed through
in inactive forms called zymogens
digestion process enters the amino
and are activated at their site of
acid pool in the body:
action.
1
PROTEIN METABOLISM
BioChemistry
○
Amino acid pool: the total supply
of free amino acids available for
By: Mrs. Teresa Maralle
Amino Acids
★ Amino acids from the body's amino
use in the human body.
acid pool are used in four different
★ The amino acid pool is derived from 3
sources:
ways:
1.
Protein synthesis:
○
Dietary protein
•About 75% of amino acids go into
○
Protein turnover: A repetitive
synthesis of proteins that is needed
process in which the body
continuous replacement of old
proteins are degraded and
tissues (protein turnover) and to
resynthesized
build new tissues (growth).
○
Biosynthesis of amino acids in
2. Synthesis of non-protein
the liver – only non-essential
nitrogen-containing compounds:
amino acids are synthesized
•Synthesis of purines and pyrimidines
Nitrogen Balance
★ The state that results when the
amount of nitrogen taken into the
human body as protein equals the
for nucleic acid synthesis
•Synthesis of heme for hemoglobin,
neurotransmitters and hormones
3. Synthesis of nonessential amino
amount of nitrogen excreted from the
acids:
body in waste materials.
•Essential amino acids can’t be
★ Two types of nitrogen imbalance can
occur in human body.
○
Negative nitrogen imbalance:
appropriate carbon chain
4. Production of energy
Protein degradation exceeds
•Amino acids are not stored in the
protein synthesis
body, so the excess is degraded
■
■
○
synthesized because of the lack of
Amount of nitrogen in urine
•Each amino acid has a different
exceeds nitrogen consumed
degradation pathway
Results in tissue wasting
Positive nitrogen imbalance: Rate
of protein synthesis (anabolism)
is more than protein degradation
(catabolism)
■
Results in large amounts of
tissue synthesis
■
During growth, pregnancy, etc.
2
PROTEIN METABOLISM
BioChemistry
Degradation Pathways
By: Mrs. Teresa Maralle
Transamination
★ The amino nitrogen atom is removed
★ Transamination: Biochemical
and converted to ammonium ion,
reaction that involves the
which ultimately is excreted from the
interchange of amino group of an
body as urea.
alpha-amino acid to an alpha-keto
★ The remaining carbon skeleton is
acid:
then converted to pyruvate, acetyl
CoA, or a citric acid cycle
intermediate, depending on its
makeup, with the resulting energy
production or energy storage.
Transamination and Oxidative
Deamination
★ • Degradation of an amino acid takes
place in two stages: ̶
○
The removal of the -amino group
○
The degradation of the remaining
carbon skeleton
★ Removal of amino group is a two
step process
★ Transamination - Biochemical
process in which the amino group of
an alpha-amino acid is transferred to
an alpha-keto acid.
★ Oxidative deamination- an amino
acid is converted into the
corresponding keto acid by the
removal of the amine functional
group as ammonia and the
★ Transamination is an enzyme
catalyzed reaction
★ There are at least 50 transaminase
enzymes associated with
transamination reactions
Glutamate Production via Transamination
★ Effect of transamination: Collect the
amino groups from a variety of
amino acids into just two amino
acids — glutamate (most cells) and
alanine (muscle cells)
○
In most cells: Collection of the
amino groups from a variety of
amino acids into a single
compound — the amino acid
glutamate
ammonia eventually goes into the
urea cycle.
3
PROTEIN METABOLISM
BioChemistry
By: Mrs. Teresa Maralle
Aspartate Production via Transamination
dehydration-hydration process
★ Further processing of glutamate is in
rather than oxidative deamination
two different ways
★ Conversion to aspartate by
transamination – used in urea cycle
for urea production
★ Oxidative deamination
Practice Exercise
Indicate whether each of the following
reaction characteristics is associated with
the process of transamination or with the
process of oxidative deamination:
a. Transamination: One of the reactants is a
keto acid and one of the products is a keto
acid.
Oxidative Deamination
★ Ammonium ion (NH4 + ) group is
b. Transamination: Enzymes with a
specificity toward a-ketoglutarate are often
liberated from the glutamate amino
active.
acid formed from transamination
c. Oxidative deamination: NAD is used as an
★ Oxidative deamination reaction is a
oxidizing agent.
biochemical reaction catalyzed by
d. Transamination: An aminotransferase
glutamate dehydrogenase in which
enzyme is active.
glutamate is converted into
alpha-ketoglutarate with the release
of an ammonium ion
★ Occurs in liver and kidney
★ The ammonium ion produced by
oxidative deamination is a toxic
substance, so it is quickly converted
carbomyl phosphate and then to
urea via the urea cycle in mammals
★ Two amino acids, serine and
threonine, undergo direct
The Urea Cycle
★ The net effect of transamination and
deamination reactions is the
production of ammonium ions
(relatively toxic) and aspartate
(nitrogen source for urea production)
★ Urea cycle: A series of biochemical
reactions in which urea is produced
from ammonium ions and aspartate
as nitrogen source and carbon
dioxide.
★ Urea is produced in the liver,
transported via the blood to the
kidneys and eliminated from the
body via urine.
deamination by
4
PROTEIN METABOLISM
BioChemistry
★ Urea: Odorless white solid with a salty
taste, has a melting point of 133oC
and it is soluble in water
Carbamoyl Phosphate
★ The fuel for the urea cycle
By: Mrs. Teresa Maralle
★ Stage 4: Hydrolysis of urea from
arginine:
○
urea and regenerates ornithine one of the cycle’s starting
★ Two ATP molecules are expended in
the formation of one carbamoyl
phosphate molecule
★ A high energy phosphate bond is
present in carbamoyl phosphate
materials
○
Steps of the Urea Cycle
★ Stage 1: Carbomyl group transfer
○
The carbamoyl group of
carbamoyl phosphate is
transferred to ornithine to form
citrulline
★ Stage 2: Citrulline-aspartate
condensation
○
Citrulline is transported into the
cytosol, citrulline reacts with
The oxygen atom present in the
urea comes from water
○
Ornithine is transported back to
mitochondria to be used in the
★ Reaction occurs in mitochondrial
matrix
Hydrolysis of arginine produces
urea cycle
Urea Cycle Net Reaction
★ Total of four ATP molecules are
expended in the production of one
urea molecule
○
Two molecules are consumed in
the production of carbamoyl
phosphate and the equivalent of
two ATP molecule is consumed in
step 2 of the urea cycle to give
AMP and two Pi
aspartate to produce
argininosuccinate utilizing ATP
○
In this reaction the second of two
nitrogen atoms of urea is
introduced into the cycle (One
nitrogen comes from carbamoyl
phosphate and the other from
aspartate -- original source of
both is glutamate)
★ Stage 3: Argininosuccinate cleavage
○
Argininosuccinate is cleaved to
arginine and fumarate by the
enzyme argininosuccinate lyase
5
PROTEIN METABOLISM
BioChemistry
Linkage Between the Urea and Citric Acid
Cycles
★ Fumarate produced is used in citric
acid cycle
★ Aspartate produced through
transamination is used in the urea
cycle at step 2
By: Mrs. Teresa Maralle
containing degradation product
that can be used to produce
glucose via gluconeogenesis.
★ The amino acids converted to acetyl
CoA or acetoacetyl CoA can serve as
precursors for fatty acids and/or
ketone body synthesis (ketogenic
amino acids)
○ Ketogenic amino acid: An amino
acid that has a carbon
containing degradation product
that can be used to produce
ketone bodies
Fates of Carbon Skeletons of Amino Acids
Amino Acid Carbon Skeletons
★ Transamination and oxidative
deamination reactions produce an
alpha-keto acids that contain the
carbon skeleton from the amino
acids
★ Each of 20 amino acids carbon
skeletons undergo a different
degradation process
★ Degraded products are pyruvate,
acetyl CoA, acetoacetyl CoA,
alpha-ketoglutarate, succinyl CoA,
fumarate, and oxaloacetate
○ Last four are intermediates in the
citric acid cycle
★ The amino acids converted to citric
acid cycle intermediates can serve
as glucose precursors (glucogenic
amino acids).
○ Glucogenic amino acid: An
amino acid that has a carbon
Amino Acid Biosynthesis
★ Non essential amino acids are
synthesized in 1-3 steps
★ Essential amino acids are
synthesized in 7-10 steps
★ Excess amino acids are converted to
fat and stored
★ Diet with lack of high quality proteins
results in breakage of body proteins
6
PROTEIN METABOLISM
BioChemistry
Summary of the Starting Materials for the
Biosynthesis of the 11 Nonessential Amino
Acids
Hemoglobin Catabolism
★ Red blood cells (RBCs) are highly
specialized cells whose primary
function is to deliver oxygen to cells
and remove carbon dioxide from
body tissues
★ Mature red blood cells have no
nucleus or DNA -- filled with red
pigment hemoglobin
★ Red blood cells are formed in the
bone marrow – ~ 200 billion new red
blood cells are formed daily
★ The lifespan of a red blood cell is
about 4 months
★ Hemoglobin is a conjugated protein
with two parts:
○ Protein portion is globin
○ Prosthetic group is heme
★ Iron atom interacts with oxygen
forming a reversible complex
(oxygen can come on and out) with it
★ Old RBCs are broken down in the
spleen (primary site) and liver
(secondary site):
★ Degradation of hemoglobin
By: Mrs. Teresa Maralle
Globin protein part is converted to
amino acids and are put in amino
acid pool
○ Fe atom becomes part of ferritin -an iron storage protein -- saves
the iron for use in biosynthesis of
new hemoglobin molecules
○ The heme (tetrapyrrole) is
degraded to bile pigments and
eliminated in feces or urine.
Bile Pigments
★ The tetrapyrrole degradation
products secreted via the bile.
★ There are four bile pigments:
○ Biliverdin - green in color
○ Bilirubin - reddish orange in color.
○ Stercobilin – brownish in color
(gives feces their characteristic
brown color).
○ Urobilin - yellow in color and
present in urine (gives
characteristic yellow color to
urine).
★ Daily normal excretion of bile
pigments: 1–2 mg in urine and
250–350 mg in feces.
★ Jaundice: Results from liver, spleen
and gallbladder malfunction.
○ Results in higher than normal
bilirubin levels in the blood and
gives the skin and white of the eye
yellow tint
○
Interrelationships Among Metabolic
Pathways
★ The metabolic pathways of
carbohydrates, lipids, and proteins
are integrally linked to one another.
○ A change in one pathway can
affect many other pathways
7
PROTEIN METABOLISM
BioChemistry
By: Mrs. Teresa Maralle
★ Examples:
○ Feasting (over eating): Causes
the body to store a limited
amount as glycogen and the rest
as fat.
○ Fasting (no food ingestion): The
body uses its stored glycogen and
fat for energy.
○ Starvation (not eating for a
prolonged period):
■ Glycogen stores are depleted,
■ Body protein is broken down to
amino acids to synthesize
glucose.
■ Fats are converted to ketone
bodies.
B-Vitamins and Protein Metabolism
★ Structurally modified B-vitamins
function as coenzymes in protein
metabolism as well
★ All 8 B-Vitamins participate in various
pathways of protein metabolism:
○ Niacin – NAD+ and NADH
■ oxidative deamination
reactions
○ PLP – transamination reactions
○ All 8 B-vitamins – Degradation
and biosynthesis of amino acids
■ B1 (thiamin)
■
B2 (riboflavin)
■
B3 (niacin)
■
B5 (pantothenic acid)
■
B6 (pyridoxine)
■
B7 (biotin)
■
B9 (folate [folic acid])
■
B12 (cobalamin)
8