You are on page 1of 6

2.

1 [BIOCHEMISTRY] Introduction to Metabolism


[BIOCHEMISTRY] 2.1 Introduction to Metabolism Dr. Balcueva
Dr. Balcueva

July 24, 2013

Go K, Golingan, Gomez, Gonzales A., Gonzales S, Gorospe, Hamtig, Hechanova


OUTLINE
I. Metabolism
A. Categories of Metabolism
II. Intermediary Metabolism
A. Energy Metabolism
III. Metabolic Pathways
IV. Metabolic Fuels
A. Fates of Glucose
B. Fates of Lipids
C. Fates of Amino Acids
V. Intracellular Location of Basic Pathways
VI. Metabolic Regulation
A. Patterns of Metabolic Regulation
VII. Clinical Correlation
VIII. Appendix
IX. Competencies

Catabolic Processes
Aerobic: Glucose pyruvate acetyl CoA
Glycolysis
Anaerobic: Glucose Lactate
oxidation

Citric Acid Cycle


Electron
Transport
System

Fatty acids Acetyl CoA


NADH-H+ and FADH2
(For chemiosmotic production of ATP)
Acetyl CoA oxidation NADH-H+ and FADH2
(For chemiosmotic production of ATP)
All 3 food groups converge here
Electrons passed down to O2
Chemiosmotic coupling

Nitrogen:
-Redistributed if reduced
-Eliminated by urea cycle if excess
Table 1. Catabolic Processes and their Products

AA Catabolism

OBJECTIVES
General Objective:
To explain thoroughly how cells carry out and regulate
complex reaction sequences
Specific Objectives:
1. To be able to differentiate between anabolic and
catabolic pathways
2. To be able to explain briefly how carbohydrates. Lipids,
and proteins are metabolized
3. To be able to correlate relationships between each
pathway

2. Anabolism
- Synthesis of complex organic molecules needed for
cell maintenance, growth and reproduction, i.e.:
Glycogenesis
Gluconeogenesis
Anabolic Processes
Glycogenesis
Glucose Glycogen
Gluconeogenesis
Pyruvate Glucose
Palmitate Biosynthesis
Acetyl CoA Fatty Acids
Non-essential AA
ketoacids
biosynthesis
aminotransferase rxn
Purine & pyrimidine
Nitrogen donors Ring
nucleotide biosynthesis
structures
Protein biosynthesis
Translation
Nucleic Acid biosynthesis
Replication, Transcription
Table 2. Anabolic Processes and their Products

Reference: Murray RK, Bender DA. Botham KM, Kennelly PJ,


Rodwell VW, Weil PA. 2009. Harpers Illustrated Biochemistry,
th
28 Edition. McGraw-Hill Companies; UERM Class 2016A
Trans; and lecture slides.
Special Notes: Bold emphasis
I. METABOLISM
- Entire network of chemical reactions carried out by living
cells
- Thousands of reactions simultaneously occuring
- Controlled so that unwanted accumulations or deficiencies of
intermediate products do not occur
- Causes of accumulation/deficiencies:
Nutritional, coenzyme, cofactor deficiency
Hormonal imbalance
Presence of drugs and toxins

Review:
Catabolic

3. Amphibolic
- Act as links between anabolism and catabolism
- At the crossroad between the 2 pathways, i.e.:
Citric Acid Cycle usually catabolic but
intermediates can be used as precursors of
other rxns

Metabolism includes:
1. Interconversion of chemical compounds within the body
2. Pathways taken by molecules
3. Interrelationships between the pathways
4. Regulating mechanisms
Categories:
1. Catabolism
- Degradation of complex substances to liberate
smaller molecules and energy, i.e.:
Degradation of CHON (protein) to AA (amino
acids)
Triglycerides to FA (fatty acids)
Glucose to Pyruvate

Anabolic

Complex Simple
Simple Complex
(Break down)
(Biosynthesis)
Exergonic
Endergonic
Energy releasing
Energy requiring
Table 3. Catabolic vs. Anabolic Processes

II. INTERMEDIARY METABOLISM


- Applied to reactions involving the low molecular weight
molecules that are metabolites in the degradation or
biosynthesis of biopolymers
Energy Metabolism:
- Part of intermediary metabolism consisting of pathways that
store or generate metabolic energy

- [1 of 6] -

[BIOCHEMISTRY] 21- Go K, Golingan, Gomez, Gonzales A, Gonzales S, Gorospe, Hamtig, Hechanova

[BIOCHEMISTRY] 2.1 Introduction to Metabolism Dr. Balcueva


- Most organisms derive both the raw materials and the
energy for biosynthesis from organic fuel molecules such as
glucose
III. METABOLIC PATHWAYS
- Sequences of reactions that include the reactants,
intermediates, products and the enzymes involved
- 3 molecules catabolized to produce energy:
Carbohydrates
Protein
Fats
- Products of digestion:
Glucose
Amino acids
Fatty acids and glycerol
- All the products of digestion are metabolized to a common
product: acetyl-CoA
Acetyl-CoA is oxidized by the citric acid cycle (CAC)
CAC substrate
- Carbohydrates simple sugars (glucose) Acetyl-CoA
- Protein Amino acids (composed of carbon skeleton and
amino group) Acetyl-CoA
- Fat Fatty acids + glycerol Acetyl-CoA

- Requirement for metabolic fuel is relatively constant


throughout the day (physical activity increases metabolic rate
only by 40-50% over metabolic rate)
- Need to form reserves of glycogen and triacylglycerol for use
during intervening time when there is no intake of food
- Obesity: Intake of metabolic fuels is consistently greater
than energy expenditure; surplus is stored largely as
triacylglycerol in the adipose tissue
- Emaciation: Intake of metabolic fuels is consistently lower
than energy expenditure, there are negligible reserves of fat
and carbohydrate; amino acids from protein turnover are
used for energy-yielding metabolism rather than replacement
protein synthesis
IV. METABOLIC FUELS
- In different phases/ levels of glucose in the body:
Fed state metabolic fuel is glucose
Fasting state glycogen, fatty acids, amino acids,
ketone bodies
- Major hormones that control utilization of fuel: Insulin and
Glucagon
Insulin
o In both liver and skeletal muscle, insulin acts to
stimulate glycogen synthetase and inhibit glycogen
phosphorylase
o In adipose tissue, insulin stimulates glucose uptake,
its conversion to fatty acids, and esterification to
TAG. Extracellular lipoprotein lipase is synthesized
and activated in response to insulin.
Glucagon
o Inhibits glycogen synthetase and activates glycogen
phosphorylase in the liver.
o In adipose tissue, increased glucagon results in
inhibition of lipogenesis.
Fates of Glucose
1. Converted to pyruvate acetyl CoA + CO2 + H2O
2. Glycogen storage for glucose in the liver and skeletal
muscle
3. Pentose phosphate pathway - provides NADPH and
ribose sugar for nucleic acid synthesis
4. Triose phosphates glycerol moeity provides for synthesis
of triacylglycerides
5. Pyruvate, -ketoglutarate and oxaloacetate precursors
of amino acids

Figure 1. Overview of the metabolic pathways

- Amino acids are not stored in the body


Excess/not needed amino group is degraded and
excreted as urea; carbon skeleton catabolized to acetylCoA and converted to fats or glucose
- Glucose stored as glycogen in the liver and muscles
- Triacylglycerol stored in the adipose tissue
- Citric Acid Cycle: Acetyl CoA is oxidized so energy is
released as reducing equivalent (2H) which is captured by
acceptors (ex. NADP, NAD, ADP, FMN, etc.)
Energy released: not wasted, but stored; can be brought
to mitochondria to be converted to ATP (in electron
transport chain)
Releases CO2 as well
Metabolic process:
- Nature of diet sets the basic pattern of metabolism

Glycolysis
- Can occur anaerobically (oxygen absent) but instead of
pyruvate, the product will be lactate
- Linked to oxidative phosphorylation and thus, also
producing ATP
Pentose Phosphate Pathway
- A source of reducing equivalents but instead NADPH is
used for biosynthesis
- Source of ribose for nucleotide and nucleic acid synthesis
- In liver and skeletal muscles: reduction of glutathione
Acyl glycerol (fat) Pathway
- Triose phosphate glycerol moiety of triacylglycerols
Amino Acid Synthesis
- Via pyruvate and/or via intermediates of TCA
Steroid Synthesis
- Acetyl-CoA is a precursor of fatty acids and cholesterol
Glycogenesis
- Formation of glycogen when glucose in in excess
Gluconeogenesis
- Synthesis of glucose from non-carbohydrate sources such
as lactate, amino acids, glycerol

- [2 of 6] -

[BIOCHEMISTRY] 21- Go K, Golingan, Gomez, Gonzales A, Gonzales S, Gorospe, Hamtig, Hechanova

[BIOCHEMISTRY] 2.1 Introduction to Metabolism Dr. Balcueva

Figure 4. Overview of the major pathways and end products in amino


acid metabolism

Figure 2. Interrelationships of Carbohydrate Metabolic Pathways

Fates of Lipids
1. Oxidizes to CO2 and H2O with reducing equivalents
2. Precursor for cholesterol and other steroids
3. Forms ketone bodies (acetoacetate and 3-hydroxybutyrate
[fuels in prolonged fasting])

- Integration of metabolism at the tissue and organ level:


Glucose and amino acids are absorbed by the liver via
hepatic portal vein
Liver maintains blood level by:
o Glycogenolysis
o Gluconeogenesis

Figure 5. Transport and Fate of carbohydrates and amino acid


substrates and metabolites

Dietary Lipids:
Hydrolyzed to monoacylglycerols and fatty acids

Re-esterified in intestinal mucosa and packaged with protein

Lymphatic system as chylomicrons


Figure 3. Overview of major lipid metabolism pathways

Fates of Amino Acids


1. Oxidized to CO2 and H2O (only the carbon skeleton of the
AA side-chains are left alone)
2. Gluconeogenesis AAs can be deaminated and
precursors can be formed ie. alanine to pyruvate
3. Form ketone bodies (again, only carbon skeleton used)

Metabolized by muscle and adipose tissue via lipoprotein lipase

- Very low density lipoproteins (VLDL)


o Triacylglycerol (TAG) from lipogenesis, fatty acids, and
chylomicron remnants and secreted into the circulation
- Ketone Bodies
o Partial oxidation of fatty acids in the liver
o Used as fuel by extrahepatic tissues including the brain
but not the erythrocytes

- [3 of 6] -

[BIOCHEMISTRY] 21- Go K, Golingan, Gomez, Gonzales A, Gonzales S, Gorospe, Hamtig, Hechanova

[BIOCHEMISTRY] 2.1 Introduction to Metabolism Dr. Balcueva


- Products of lipid digestion enter the circulation as

chylomicrons

Figure 6. Transport and Fate of major lipid substrates and metabolites.


[FFA, free fatty acids; LPL, lipoprotein lipase; MG, monoacylglycerol;
TG, triacylglycerol; VLDL, very low density lipoprotein]

- Many metabolic fuels are inconvertible


Fatty acids, and ketone bodies formed from them
cannot be used for the synthesis of glucose
The reaction of pyruvate dehydrogenase, forming acetyl
CoA, is irreversible
o For every 2 carbon unit from acetyl CoA that enters
the citric acid cycle, there is a loss of 2 carbon
atoms as CO2 before oxaloacetate is formed.
Lysine and leucine yield only acetyl CoA on oxidation.
o Cannot be used for gluconeogenesis
Phenylalanine, tyrosine, tryptophan, and isoleucine give
rise to both acetyl CoA and intermediates that can be
used for gluconeogenesis
Ketogenic used to refer to amino acids that give rise
to acetyl CoA
Glucose is always required by the CNS and RBCs.

Figure 7. Intracellular location and overview of major metabolic


pathways in a liver perenchymal cell
(AA metabolism ofone or more essntial amino acids;
AAmetabolism of more nonessential amino acids)

V. INTRACELLULAR LOCATIONS OF BASIC PATHWAYS


- Pathways in the cytoplasm:
Glycolysis
Pentose Phosphate Ppathway
Lipid Synthesis
Protein Synthesis
Gluconeogenesis
Glycogenesis and Glycogenolysis
- Pathways in the mitochondria:
Citric Acid Cycle
Electron Transport Chain
ATP Synthesis
Synthesis of Ketone Bodies
Beta Oxidation of Fatty Acids

Figure 8. Relative changes in metabolic parameters during onset of


starvation
- During the onset of starvation, blood glucose levels are

maintained through the production of glucose from glycogen,


proteins, and fats. At first glycogen is broken down into
glucose with the aid of glucagon. However, only enough
glycogen is stored in the liver to last a few hours. Increasing
demands for glucose continuously increases glycogen
breakdown, which eventually depletes its amount in the liver.
Thereafter, blood glucose levels are maintained by the
breakdown of fats that will become the primary energy
source. The liver metabolizes fatty acids into ketone bodies
that can be used as a source of energy. (McGraw-Hill
Education)
-

- [4 of 6] -

[BIOCHEMISTRY] 21- Go K, Golingan, Gomez, Gonzales A, Gonzales S, Gorospe, Hamtig, Hechanova

[BIOCHEMISTRY] 2.1 Introduction to Metabolism Dr. Balcueva


Fed

40 Hours
Fasting
3.6
1.15

Skeletal muscles: It utilizes glucose as its energy


source, resulting to lactate and CO2 formation. It stores
glycogen for muscle contraction and represents a
considerable amount ofprotein, reserved for use during
starvation.
Adipose tissue: It is considered the main fuel reserve
of the body, used during starvation. Glucagon activates
a
hormone-sensitive
lipase,
which
hydrolyzes
triacylglycerols yielding glycerol and fatty acids. These
are then released into the bloodstream as lipoproteins.
These are taken up by tissues, except the brain and
RBC, and oxidized as fuel.
Brain: Usually neurons use only glucose as energy
source. Since the brain stores only a very small amount
of glycogen, it needs a steady supply of glucose. During
long fasts, it oxidizes ketone bodies.
Kidney: It can perform gluconeogenesis and release
glucose into the bloodstream. It is also responsible for
the excretion of urea, electrolytes, etc.
Heart: Myocardium (cardiac muscle cells) is able to
produce energy from several substrates: fatty acids,
glucose, lactate, pyruvate, ketone bodies and even
aminoacids. Preference of individual substrates
representing the particular sources of energy depends
on their current concentration in both blood and cardiac
muscle cells. The selection of substrates is also
determined by natural capacity of particular enzymatic
systems of the cardiac muscle cell, which limitates
predominantly the utilization of atypical sources of
energy also in case of their high concentration in blood.
Erythrocytes: The RBC has no nucleus or mitochondria
to metabolize fatty and amino acids for the provision of
energy substrates. Energy metabolism in the RBC is
almost exclusively through the breakdown of glucose.

7 Days
starvation
3.5
1.19

Glucose
5.5
Free fatty
0.30
acids
Ketone
Negligible
2.9
4.5
bodies
Table 4. Plasma Concentrations of Metabolic Fuels (mmol/L) in the Fed
and Fasting States (The amount of Ketone bodies (negligible in Fed
State) and Free fatty acids increase as one approaches the starvation
state. The opposite is true for Glucose)
Energy
yield
(kJ/g)

O2
consumed
(L/g)

CO2
produced
(L/g)

RQ (CO2
prod/O2
consumed)

Energy
(kJ/L
O2)

Carbohydrates
Protein
Fat
Alcohol

16
0.829
0.829
1.00
20
17
0.966
0.782
0.81
20
37
2.016
1.427
0.71
20
29
1.429
0.966
0.66
20
Table 5. Energy Yields, Oxygen Consumption, and Carbon Dioxide
Production in the Oxidation of Metabolic Fuels

STARVE-FEED CYCLE
Feed: refers to the intake of meals (the variable fuel input)
after which the fuel is stored (as glycogen and
triacylglycerol) to meet metabolic needs of fasting.
Fed State: glucose as its major fuel; its respiratory
quotient is the ratio of CO2 produced to O2 consumed
o Insulin: controls uptake of glucose in muscle cells
and adipose tissues
o GLUT4: glucose transporter in muscles and
adipose tissues
Fasting State: the metabolic status of a person who has
not eaten overnight; the metabolic state achieved after
complete digestion and absorption of a meal; stimulates
mobilization of the metabolic fuel reserves; raises
circulating glucose
(Source:
http://www.biochem.ucl.ac.uk/~dab/MSc%20clinbioc/MSc%20gluc
ose%20homeostasis.pdf)

VI. METABOLIC REGULATION


- Most pathways are irreversible under physiologic conditions
- When a metabolite enters the pathway, each step occurs in
sequence without backing up or wasting cellular material or
energy
- Reactions are regulated so as to proceed in only one
direction

Reasons for multistep pathway:


1. Limited reaction- specificity of enzymes; each active site
catalyzes only a single step of the pathway
2. To control energy input and output energy flow is
mediated by energy donors and acceptors
3. Catabolism of metabolic fuels yield 3 types of compounds
that mediate the release of energy:
a) acetyl CoA
b) nucleoside triphosphate (ATP)
c) reduced coenzymes (NADH,FADH)
4. Some compounds can be substrates or products of more
than 1 enzyme so they can have 2 or more metabolic
functions.
5. To establish control points:
- Balance of energy supply and demand in living cells
- Ability to respond to internal signals or change in the
environment

- Patterns of Metabolic Regulation


1. Allosteric Modification
a. Feedback inhibition when the end product of a
pathway controls its own rate of synthesis
b. Feedforward activation when a metabolite
produced early in the pathway activates an enzyme
that catalyzes a reaction further down the pathway.
ABCDEP
|_______________

Major metabolic features of principal organs


For the summary of the major metabolic features of the principal
organs, see appendix

Liver: Digestion of carbohydrates and proteins to


glucose and amino acids are directed to the liver
through the hepatic portal vein. The liver also
deaminates excess amino acids, forming urea, which is
delivered to the kidneys for excretion.

2. Covalent modification alters catalytic rate by


attachment to some group by a covalent bond (usually a
phosphate group)
Phosphorylation:
o activates enzymes regulating catabolic
pathways
o inhibits enzymes regulating anabolic pathways
o catalyzed by protein kinases
Dephosphorylation:
o inhibits enzymes regulating catabolic pathways
o activates enzymes regulating anabolic
pathways
o catalyzed by protein phosphatase

- [5 of 6] -

[BIOCHEMISTRY] 21- Go K, Golingan, Gomez, Gonzales A, Gonzales S, Gorospe, Hamtig, Hechanova

[BIOCHEMISTRY] 2.1 Introduction to Metabolism Dr. Balcueva


o rate of protein synthesis in response to availability of
amino acids and metabolic acids is a response also to
insulin action

3. Supply of Substrate
ATP or ADP
4. Hormones
Insulin and Glucagon
VII. CLINICAL CORRELATION
Cachexia
- Release of cytokines in response to tumors and other
pathologic conditions
- Happens in prolonged starvation (Harpers)
o Depletion of adipose tissue reserves (increased
metabolic rate)
o Catabolism of muscle tissue and used as fuel (increased
protein catabolism)
Death results when essential tissue proteins are
catabolized and not replaced.

Diabetes Mellitus
- Inability to utilize glucose can either be:
o Receptor resistance to insulin (Type II)
o insulin due to destruction of -cells of pancreas (Type
I)
Hyperglycemic patients
No insulin = gluconeogenesis and lipolysis =
ketogenesis in liver
o In uncontrolled diabetes, ketoacidosis may occur and
lead to coma
o For the fetus, demand for glucose by the fetus +
lactose synthesis in lactation = ketosis
Mild ketosis with hypoglycemia (Harpers)

- Associated with cancer


APPENDIX
Summary of the Major Metabolic Features of Principal Organs

COMPETENCIES
- Given a normal person, identify biochemical pathways or processes of carbohydrates that are involved to achieve normal growth and
development.
- Apply the biochemical concepts and principles that will help explain the growth and development of the normal person
- Correlate the biochemical or molecular basis with the growth and development of the normal person

- [6 of 6] -

[BIOCHEMISTRY] 21- Go K, Golingan, Gomez, Gonzales A, Gonzales S, Gorospe, Hamtig, Hechanova