BIOCHEMISTRY

2.5.3 Overview of Metabolism

Gabriel Molina
II. What do Metabolic Pathways Accomplish?

OUTLINE  They accomplish a few things, among of which are:

I. Introduction 1. Generation of Energy
II. What do Metabolic Pathways Accomplish? 2. Degradation or Catabolism of Organic
III. General Principles Common to Metabolic Molecules
Pathways 3. Synthesis of Cellular Building Blocks and
IV. What is the best way to comprehend and retain Precursors of Molecules
a working knowledge of intermediary 4. Storage of Energy
metabolism?
5. Excretion of Potentially Harmful Substances
REFERENCES 6. Generation of Regulatory Substances
• Rodwell VW, Bender DA, Botham KM, Kennelly PJ, Weil PA.
Generation of Energy
Harper’s Illustrated Biochemistry, 30/e. McGraw Hill Education
• Rosenthal MD. Glew RH. 2009. Medical Biochemistry –  The primary dietary fuels for human beings are
Human Metabolism in Health and Disease. John Wiley & Sons carbohydrates and fats.
Inc.
 The human body also obtains energy from dietary
I. Introduction proteins and – for some people – ethanol.
 Intermediary metabolism is the name given to the  Metabolism of these fuels generates energy, much
sequence of biochemical reactions that degrade, of which is captured as high-energy molecule
synthesize, or interconvert small molecules inside adenosine triphosphate (ATP).
the living cells.  Uses of ATP include:
 Knowledge of the core metabolic pathways and • Biosynthetic processes
their interrelations is critical to understanding both • Muscle contraction
normal function and the metabolic basis of most • Active transport of ions and other solutes
human diseases. across a membrane
Metabolic Pathways
 Metabolism occurs in small discrete steps, each of
which is catalyzed by an enzyme.
 The term metabolic pathway refer to a particular
set of reactions that carries out a certain function or
functions.

Metabolic Intermediates
 Biochemical pathways are comprised of organic
compounds called metabolic intermediates, all of
which contain carbon, hydrogen, and oxygen. Figure 1: Structure of ATP
 Some metabolic intermediates also contain
As a review:
nitrogen or sulfur.
Which of the following is high in energy?
Homeostasis
A. The phosphates
 Homeostasis refers to an organism’s tendency or B. The phosphate bonds
drive to maintain the normalcy of its internal
environment, including maintaining the C. The ester bonds
concentration of nutrients and metabolites within D. None of the above
relatively strict limits.
Why does FADH2 generate less ATP than NADH during
• Blood glucose metabolism oxidative phosphorylation?
• Calcium homeostasis
A. FADH2 skips complex I
B. FADH2 enters complex II which does not pump any protons
C. NADH enters complex I, which pumps 4 H+
D. All of the above

Lecture Title: Overview of Metabolism

Module: 2.5.3
Transcribed by: Mahiwagang Tokwa 😊 1
Imagine a condition in which the inner mitochondrial membrane
is more permeable to H+ allowing H+ from the intermembrane
space to diffuse into the mitochondrial matrix, what is the effect
of this condition?
A. Decreased ATP because less H+ passes through complex V
B. Increased Pi because there is decreased ATP synthesis
C. Increased ADP/ATP ratio
D. All of the above
Degradation or Catabolism of Organic Molecules
 Catabolic pathways (Figure 2) are involved in the
• breakdown of larger molecules;
• commonly involving oxidative reactions;
• they are exothermic and usually exergonic;
• they produce reducing equivalents
(hydrogen atoms or NAD+ or FAD), and;
• mainly via the respiratory chain
 Catabolic pathways usually involve cleavage of
• C-O
• C-N
• C-C
Figure 2: Outline of the pathways for the catabolism of
carbohydrates, proteins and fats.
Digestion
 Before dietary fuels can be absorbed into the body,
they must be broken down into simpler molecules.
Thus, starch is hydrolyzed to yield glucose, and
proteins are hydrolyzed to their constituent amino
acids.
Glycolysis
 Glycolysis is the oxidation of 6-carbon glucose
into 3-carbon pyruvate
Lecture Title: Overview of Metabolism
Module: 2.5.3
Transcribed by: MOLINA GASE
Amino Acid Catabolism
 Breakdown of most of the 20 common amino acids
is initiated by removal of the α-amino group of the
amino acid via transamination.
• The resulting carbon skeletons are further
catabolized to generate energy or are used in
the synthesis of other molecules (e.g.,
glucose, ketones).
• The nitrogen atoms of amino acids can be
utilized for the synthesis of other nitrogenous
compounds, such as heme, purines and
pyrimidines. Excess nitrogen is excreted as
urea.
Fatty Acid Oxidation
 The major route of fatty acid degradation is β-
oxidation, which accomplishes stepwise two-
carbon cleavage of fatty acids into acetyl-CoA.
Review:
A reaction is said to be catabolic, what do you expect of its ∆G
value?
A. ∆G < 0
B. ∆G > 0
C. ∆G = 0
D. ∆G is infinite
Anabolism – Synthesis of Cellular Building Blocks and
Precursors of Macromolecules
 Anabolic pathways are involved in the synthesis
of larger and more complex molecules
• Synthesis of larger molecules;
• Involves reductive reactions;
• They are usually endothermic and are also
endergonic;
Gluconeogenesis: Synthesis of Glucose
 Produces glucose from glycerol, pyruvate, lactate,
and the carbon skeletons of glucogenic amino
acids.
 Gluconeogenesis is crucial in maintaining an
adequate supply of glucose to the brain during
fasting and starvation.
Blast from the past… all amino acids are glucogenic except for
LY = Leucine and Lysine
What are your ketogenic amino acids?
WIFY L = Tryptophan, Isoleucine, Phenylalanine, Tyrosine,
Leucine
Lipogenesis: Synthesis of Fatty Acids
 Excess dietary carbohydrates and the carbon
skeletons of ketogenic amino acids are catabolized
to acetyl-CoA
2
  Acetyl-CoA is then utilized to synthesize long-chain
fatty acids.
 Storage of these fatty acids as adipocyte
triacylglycerols provides the major fuel source
during the fasted state.
Synthesis of Heme
 Heme is a component of hemoglobin and
myoglobin
 Also functions as part of cytochromes, both in the
mitochondrial ETC involved in oxidative
phosphorylation and in certain oxidation-reduction
enzymes.
 Although most heme synthesis occurs in
hemopoietic tissues, nearly all cells of the body
synthesize heme for their own cytochromes and
heme-containing enzymes.
Storage of Energy
Creatine Phosphate
 Most cells, especially muscle, can store a limited
amount of energy in the form of creatine
phosphate.
 This is accomplished by a reversible process
catalyzed by creatine kinase:
ATP + creatine ↔ creatine phosphate + ADP
 Energy need is low, reaction shifts toward the right
 Energy need is high, reaction shifts to the left,
thereby making ATP available
Glycogen
 Glycogen is the storage form of glucose.
 Glycogen serves two very different functions in the
muscle and liver:
• Liver glycogen is utilized to maintain a
constant supply of glucose in the blood.
• Muscle glycogen does not serve as a reservoir
for blood glucose. Instead, muscle glycogen is
broken down when that tissue requires energy,
releasing glucose, which is subsequently
oxidized to provide energy for muscle work.
Fat or Triacylglycerol
 After a meal, excess dietary carbohydrates are
metabolized to fatty acids in the liver.
• Some fatty acids are used directly as fuel by
peripheral tissues
• Most are stored as in adipocytes as
triacylglycerols (TAGs)
 When additional metabolic fuel is required during
periods of fasting or exercise, the TAGs stores in
adipose are mobilized and fatty acids are made
available to tissues such as muscle and liver
Lecture Title: Overview of Metabolism
Module: 2.5.3
Transcribed by: MOLINA GASE
Review:
Accumulation of which of the following metabolites of glycolysis
will directly result in the shift to the storage pathway?
A. G6P
B. Glucose
C. Pyruvate
D. Lactate
Excretion of Potentially Harmful Substances
Urea Cycle
 Takes place in the liver and synthesizes urea from
ammonia (ammonium ions) derived from the
catabolism of amino acids and pyrimidines.
 Urea synthesis is one of the body’s major
mechanisms for detoxifying and excreting
ammonia.
Bile Acid Synthesis
 Metabolism of cholesterol to bile acids in the liver
serves two purposes:
• Provides the intestine with bile salts, whose
emulsifying properties facilitate fat digestion
and absorption
• Mechanism for disposing excess cholesterol.
Cholesterol is excreted as cholesterol per se
and as bile salts.
Heme Catabolism
 When heme-containing proteins and enzymes are
turned over, the heme moiety is oxidized to
bilirubin, which after conjugation with glucuronic
acid is excreted via the hepatobiliary system.
Generation of Regulatory Substances
 Metabolic pathways generate molecules that play
key regulatory roles.
• Citric acid – modulates glycolysis and
gluconeogenesis
• 2,3-bisphosphoglycerate – modulates affinity
of hemoglobin for oxygen
III. General Principles Common to Metabolic
Pathways
ATP Provides Energy for Synthesis
 ATP is needed during anabolic pathways, which is
generated during catabolic reactions, substrate-
level phosphorylation or during oxidative
phosphorylation.
Paano mag-emote sa Biochem…
GAGs = glycosaminoglycans!
Nakakainis ka! = Kinase ka!!!
3
 Many Metabolic Reactions Involve Oxidation or
Reduction
 During catalysis, oxidative reactions transfer
equivalents (hydrogen atoms) to cofactors such
as NAD+ or FAD.
 Reduced NADH and FADH2 can be used to
generate ATP through oxidative phosphorylation in
the mitochondria.
• NADPH is the reduced molecule used in in
fatty acids and cholesterol oxidation
Only Certain Metabolic Reactions Occur in Human
Metabolism
 Although humans posses the machinery to
interconvert many dietary compounds, not all
interconversions are possible.
• Humans can convert glucose into LCFA, but
they cannot convert LCFA into glucose
Some Organic Molecules Are Essential to Human
Health
 Certain key cellular components cannot be
synthesized in the body and must therefore be
provided preformed in the diet and are therefore
designated essential.
• Linoleic and α-linoleic acid
• Some amino acids
 Some cellular components are synthesized by the
body, and are therefore not needed in the diet and
are named non-essential.
Review
Essential amino acids = IFLWHKMTV
“I Freaking Love (and) Want Hong Kong MTV”
Some Metabolic Pathways are Irreversible or Contain
Irreversible Steps
 Metabolic pathways contain a rate-limiting step that
is controlled for by physiologic factors such as
insulin/glucagon ratio; ATP/ADP ratio, etc.
 For example, although glycolysis and
gluconeogenesis share many enzymes, specific
gluconeogenic enzymes are required to bypass the
steps in glycolysis that are irreversible under
physiologic conditions.
Metabolic Pathways are Interconnected
 Good example here is glycolysis to PDH complex
to TCA cycle to ETC (refer to appendix figure).
Metabolic Pathways are not Neccesarily Linear
 TCA cycle and urea cycle are circular pathways.
 In each case the pathway is initiated by addition of
a small molecule to a key metabolic intermediate.
At the end of one cycle, the key intermediate is
regenerated and available to participate in another
turn of the cycle.
Lecture Title: Overview of Metabolism
Module: 2.5.3
Transcribed by: MOLINA GASE
Metabolic Pathways are Localized to Specific
Compartments Within the Cell
 Many metabolic pathways occur in the
mitochondria
• B-oxidation
• TCA cycle
• Oxidative phosphorylation
 Other pathways are cytosolic
• Glycolysis
• Pentose phosphate pathway
• Fatty acid synthesis
 Both mitochondrial and cytosolic
• Urea cycle
• Heme synthesis
Figure 3: Localization of metabolic pathways in a cell.
A Different Repertoire of Pathways Occur in Different
Organs
 All cells are capable of glycolysis but RBCs cannot
further oxidize pyruvate to CO2 and water via
pyruvate dehydrogenase and the TCA cycle.
 Most cells and organs can also utilize fatty acids as
fuels. Although neural cells do contain
mitochondria, they do not oxidize fatty acids. The
brain is therefore dependent on constant supply of
glucose to provide energy.
 Gluconeogenesis occurs in the liver.
Different Metabolic Processes Occur in the Fed State
Than During Fasting
 After a meal, glucose is plentiful and utilized both
for energy generation and to replenish glycogen
stores. Excess glucose is metabolized to fatty acids
in liver and fat cells and the resulting
triacylglycerols are stored in adipocytes.
 When a person is fasting, there is a need to
generate energy from stored fuel. During a fast,
most of the body’s energy needs are sustained by
oxidation of fatty acids.
4
 Metabolic Pathways are Regulated V. Appendix
 Several levels of regulation Table 2: Major organs involved in integration of fuel metabolism
Organ Major Fuel Fuel Exported When
• Gene transcription and translation, which Store Exported
determines which enzymes are actually Adipocytes TAG Free fatty acids and Fasting,
present within the cell glycerol moderate-
• Substrate-level regulation, whereby intensity
exercise
concentrations of key metabolites activate or Liver Glycogen Glucose Fasting,
inhibit enzymatic reactions exercise
• Hormones – act to coordinate processes Ketones Fasting
VLDL-TAG Fed state
between the organs of complex, multicellular
Skeletal Glycogen Lactate Intense
organisms Muscle exercise
Protein Alanine, glutamine Fasting
IV. What is the Best way to Comprehend and Retain a
Working Knowledge of Intermediary Metabolism?
 When encountering a metabolic pathway, ask Table 3: Preferred fuels in the well-fed and fasting states.
Organ Well-Fed Fasting
yourself the following questions: Liver Glucose and amino Fatty acids
• Why does the pathway exist? What are its acids
functions? Resting skeletal Glucose Fatty acids, ketones
muscle
• Where does the pathway take place (e.g., what Cardiac muscle Fatty acids Fatty acids, ketones
organ, tissue, cell, subcellular compartment, or Adipose tissue Glucose Fatty acids
Brain Glucose Glucose (ketones in
organelle)? prolonged fast)
• When is it up-regulated, when is it down- Red blood cells Glucose Glucose
regulated? During the fasted state? During the
fed state? During exercise? During a particular
stage of development (e.g., puberty, neonatal,
old age, etc.)?
• What are the actual steps of the pathway, and
what cofactors does it require?
• Whet regulates it? What are the enzymes?
Substrates? Hormones?
• What can go wrong?

Table 1: Summary of fed vs fasted state metabolism

Lecture Title: Overview of Metabolism 5

Module: 2.5.3
Transcribed by: MOLINA GASE
 Figure 4: Important reactions of intermediary metabolism. Curved reaction arrows indicate forward and reverse reactions that are catalyzed
by different enzymes. The straight arrows indicate forward and reverse reactions that are catalyzed by the same enzyme. BLUE text =
intermediates of carbohydrate metabolism; BROWN text = intermediates of lipid metabolism; GREEN text = intermediates of protein
metabolism.

Lecture Title: Overview of Metabolism 6

Module: 2.5.3
Transcribed by: MOLINA GASE
Lecture Title: Overview of Metabolism 7
Module: 2.5.3
Transcribed by: MOLINA GASE