The functions of cells and tissues in all organisms require:

(1) Energy which is obtained from digestion and degradation of ingested foods
(carbohydrates, lipids and proteins).
(2) Synthesis of complex molecules for building new structures.
Humans have the machinery needed to liberate and store energy from food, to
synthesize complex molecules from simpler one and to degrade and get rid of waste
and toxic molecules. This process is collectively called metabolism.

Metabolism consists of enzymatic reactions organized into metabolic pathways.

These pathways proceed in a stepwise fashion, transforming substrates into end
products through many specific chemical intermediates or metabolites.
Metabolism is sometimes referred to as intermediary metabolism.
Substrate Enzyme -1
1
Product
=
Substrate Enzyme -2
2
2

Click to view animation

Product
=
Substrate
3 Enzyme -3
Product
=
Substrate
4
Enzyme -4

A Metabolic Pathway: The enzymatically catalyzed reactions occur in

consecutive steps including removal, transfer and / or addition of a specific
atom, group or molecule to produce a product which inturn serves as a
substrate for the next reaction.
Metabolism occurs intracellularly either in the cytosol or in the intracellular
compatments (mitocondria, lysosomes, peroxisomes). Each cell membrane acts
as a barrier to hold its cellular components and to regulate the transport of ions
and metabolites moving into and out of the cell.
An important aspect of metabolism is the transport across cell membrane
and subcellular membranes. Cells are systems that process food, release waste
and carry out complex degradative and biosynthetic reactions essential to
survival. They operate under conditions of essential constant temperature to
maintain a constant internal environment (homeostasis).
Chapter 1 Introduction to Metabolism

Biomedical Importance of Metabolism:

Health depends on a harmonious balance of biochemical reactions occurring
in the body. Diseases reflect abnormalities in biomolecules at the structural
levels, in biochemical reactions and / or in biochemical processes.
Normal metabolism achieves cellular homoestasis and includes the
variations and adaptation in metabolism to periods of starvation, exercise,
pregnancy and lactation
A knowledge of metabolism is a prerequisite to a sound understanding of
abnormal metabolism underlying many disease. Abnormal metabolism results;
for example; from nutritional deficiency, enzyme deficiency, abnormal
hormone secretion or genetic disease.
Approximately 10% of death in childhood are due to genetic disorders
resulting in inborn errors of metabolism. The primary defect in an inborn error
of metabolism is probably a change in the base sequence of a gene. This gene
mutation may affect a protein which may be either an enzyme, structural or
transport protein. The consequences of the inborn error depend on the function
of the defective protein.
Chapter 1 Introduction to Metabolism

Metabolic Pathways:
Metabolism serves 2 different purposes: the generation of energy to drive
vital functions and the synthesis of biological molecules. To achieve these
goals, metabolism consists of 2 contrasting processes: catabolism and
anabolism. Catabolic pathways are energy-yielding whereas anabolic pathways
are energy requiring .

I-Catabolic Pathways:

Catabolism involves the oxidative degradation of complex nutrient molecules

(carbohydrates, lipids and proteins) obtained either from dietary sources or
from cellular reserves. The breakdown of these molecules by catabolism leads
to formation of simpler molecules (as lactic acid, ammonia, urea, CO2).
Catabolic reactions are usually exergonic and often the chemical energy
released is captured as ATP.

Catabolism occurs in 3 stages :

Stage I: nutrient macromolecules (starch, proteins and triacyglycerols) are

degraded to their respective building blocks (monosaccharides, amino acids,
glycerol and fatty acids). No useful energy is generated in this phase.
Stage II: degradation of products obtained from stage I converge to a common
end product acetyl CoA. Some ATP is generated in this phase but the amount is
small compared to complete oxidation of acetyl Co A.
Stage III: consists of the citric acid cycle and oxidative phosphorylation which
are the final common pathways in the oxidation of fuel molecules. Oxidation of
acetyl Co A produces CO2 and H2 O (which represents the waste products of
areobic catabolism) and generates energy (mainly by oxidative
phosphorylation). More than 90 % of the ATP generated by degradation of
food is formed in this third stage.

Proteins Carbohydrate lipids

A i acids
Amino id Gl
Glucose Gl
Glycerol
l + FA

Glyceraldehyde
3 phosphate

H2O

Click to view animation

Pyruvate
ATP

Acetyl CoA
ADP

Oxidative
Citric Acid Phosphorylation
cycle

CO2
NH3
Chapter 1 Introduction to Metabolism

Catabolism is oxidative for the most parts, part of the chemical energy is
conserved as energy- rich electrons transferred to the coenzymes NAD+ and
NADP+.
NAD+ reduction is part of catabolism. The energy released by oxidation of
NADH is coupled to synthesis of ATP (oxidative phosphorylation).
NADPH oxidation is an important aspect of anabolism. NADPH is the
source of reducing power needed to drive biosynthetic reactions.
Energy
Energy containing
containing Energy
Energy depleted
depleted
Nutrients
Nutrients endproducts
endproducts
Carbohydrates
Carbohydrates CO
CO22
Fat H
H22O
O
Fat
Catabolism
C NH
NH33
Proteins
Proteins C b b li
Catabolism
li

ADP
ADP ATP
ATP
NAD
NAD NADH +H
NADH +H Chemical
Chemical
FAD
FAD FADH2 Energy
FADH2 Energy
NADP
NADP NADPH
NADPH

Cell
Cell Macromolecules
Macromolecules Precursor
Precursor molecules
molecules
Protein
Protein Amino acids
Amino acids
Anabolism
Anabolism
Polysaccharides
Polysaccharides Simple Sugars
Simple Sugars
Lipids
p
Lipids
p FA
FA

Click to view animation

Nucleic
Nucleic acids
acids Nitrogenous
Nitrogenous bases
bases
Dr.
Dr. Amal
Amal Mansour
Mansour

II- Anabolic Pathways:

Anabolism is a synthetic process in which complex biomolecules (proteins,
nucleic acids, polysaccharides and lipids) are assembled from simpler
precursors. Biosynthesis involves the formation of new bonds and an input of
energy to drive these endergonic reactions. The ATP generated by catabolism
provides this energy. Furthermore, NADPH is an excellent donor of high
energy- electrons for reductive reactions of anabolism.
Maior anabolic pathways of body:

Citric
CitricAcid
AcidCycle
CycleIntermediates
Intermediates Acetyl
AcetylCoA
CoA

Amino
AminoAcid
Acid Gluconeogenesis
Gluconeogenesis F.A
F.ASynthesis
Synthesis

Catichol
Catichol
Catichol
Catichol Nucleotides
Nucleotides TAG
TAG Lipids
Lipids
Amino
Amino
Heme
Heme

Protein
Protein

DNA
DNA&&RNA
RNA
Glycogen
Glycogen
Click to view animation

Under normal metabolic conditions in adulthood, there is a balance

between anabolism and catabolism. In a growing child, anabolic
reactions exceed those of tissue breakdown. The reverse occurs in
senelity aging, starvation and cancer
Chapter 1 Introduction to Metabolism

Corresponding pathways of catabolism and anabolism differ in important

aspects:
The anabolic pathway used for synthesis of a particular end product usually
does not precisely match the pathway used for catabolism of the same
substance i.e. it does not operate simply by reversal of the pathway. Some of
the intermediates may be common to steps in both pathways, but different
enzymatic reactions regulated by distinst specific mechanisms and unique
metabolites characterize each pathway.
For example, fatty acids are synthesized from acetyl Co A but they are also
converted to acetyl Co A by -oxidation. Another example is the catabolism of
glucose to pyruvate by glycolysis and the biosynthesis of glucose from pyruvate
by gluconeogenesis. Similarly, degradation of proteins to amino acids differ
from protein synthesis.
Why is the distinction between corresponding anabolic and catabolic
pathways ?
Using separate pathways for biosynthetic and degradative processes is
crucial for control. Independent regulation of anabolism and catabolism is
only possible if these contrasting processes move along different routes.
Conditions which activate one pathway tend to inhibit the reverse pathway and
vice versa. In case of shared pthaways, the rate limiting steps serving as points
of regulation are catalyzed by unique enzymes to each pathway .
Think what happens for example if fatty acid synthesis and oxidation took
place in the same cell compartment and in an uncontrolled fashion. Two
carbons released by oxidation (acetyl Co A) would be immedialy used for
resynthesis. Biochemists call this situation a futile cycle. No useful work is
done and the net result is consumption of ATP used in the endergonic reactions
of fatty acids synthesis.

Anabolism and catabolism are interrelated in spite of their different roles:

Anabolism and catabolism are complementary to each other. Many
metabolic intermediates are shared between the 2 processes and the precursors
needed for anabolic pathways may be provided by products of catabolism:

- Hexose monophosphate pathway, a process for catabolism of glucose,

provides pentoses for nucleic acid synthesis.
- In case of an adequate carbohydrate diet, glucose degradation produces acetyl
Co A whicn can be either oxidized in the mitochondria to produce energy
(catabolic pathway) or used in cytosolic fatty acid synthesis (anabolic
pathway).
Chapter 1 Introduction to Metabolism

Enzymes organization in metabolic pathways:

The individual metabolic pathways consists of a sequence of enzymatic
steps. A fundamental aspect of biochemical organization is that the enzymes
that catalyze a sequence of reactions are often clustered together in the cell. As
a result, an intermediate produced in the first reaction is passed directly to the
second enzyme in the pathway, and so on. Such an arrangement minimize the
loss of intermediates by diffusion and facilitate regulation of the pathway.
Three types of ezymes clustering are present :

1- All the catalytic activities for a particular pathway exists as independent

soluble proteins in the same cellular compartment (eg, glycolytic enzymes in
the cytosol).
2- A multienzyme complex: The enzymes common to a pathway are collected
to form a multienzyme complex. The substrate is modified as it passes from
enzyme to enzyme.(eg. fatty acid synthase complex in the cytosol consists of
7 enzymes, each having a specific activity).
3- A membrane bound multienzyme system: enzymes of electron transport and
oxidative phosphorylation are linked to the inner mitochondrial membrane.

Amphibolic Pathways: Certain pathways of metabolism, such as the

citric acid cycle have dual functions: they serve both catabolism and
anabolism. This dual nature is reflected in the designation of such
pathways as amphibolic rather than solely as catabolic or anabolic
Chapter 1 Introduction to Metabolism

Regulation of Metabolis

Humans are in metabolic homeostasis: all their intracellular and extracellular

reactions and processes are proceeding to maintain a healthy state. Cellular
metabolism is a tightly regulated process designed to operate at maximum
economy and to maintain a finally balanced homeostatic state.

Fuel molecules are degraded in catabolic pathways only at a rate to satisfy

cellular needs of energy (usually as ATP or as reducing equivalents e.g.
NADH).
In a similar fashion, biosynthetic activity is matched to cellular demand for
essential biomolecules (neurotransmitters, hormones, enzymes, receptors,
immunoglobulins etc) required to maintain vital activities and growth.
Any excess intermediates are stored as triacylglycerols (adipose tissue) or
glycogen (liver and muscles).

Metabolism is regulated by different methods:

1. Regulation of catalytic activity of enzymes.
2. Regulation of enzyme synthesis and degradation.
3. The flux of substrates.
4. Compartmentation.
5. Energy state of the cell.

1) Regulation of catalytic activity of enzymes:

a- Reversible allosteric control:
Control of a metabolic pathway is accomplished through modulation of the
catalytic activity of one or a few key enzymes. These regulatory enzymes
catalyze the first or an early reaction in a metabolic sequence which is the rate
limiting step that controls the overall pathway. Usually the enzyme catalyzing
this rate limiting step is the first enzyme unique to the pathway and the reaction
it catalyze is the committed step. Regulatory enzymes are subject to allosteric
regulation.
Allosteric regulation involves the non-covalent binding of an allosteric
regulator to an allosteric site of enzyme which results either in allosteric
activation or allosteric inhibition (feed back inhibition) of the enzyme.
Chapter 1 Introduction to Metabolism

Feed back inhibition is a rapid process responding to cellular needs and

represents an important auto-regulatory mechanism. The first reaction in
many biosynthetic pathways is allosterically inhibited by the end product of
the pathway.

Allosteric enzymes are also present at branch points in metabolism, so the

flux of metabolites toward various fates can be regulated by allosteric
activators and inhibitors. In branched - anabolic pathways, end product
inhibition regulates the enzyme after the branch point. This leads to control
of either pathway after the branch.

Sometimes, the first step in the overall pathway is inhibited by the end
products of both branches.

b) Covalent modification hormonal regulation

Hormonal regulation of metabolism is achieved through covalent
modification of enzymes.
The most important forms of covalent modification is phosphorylation -
dephosphorylation. Phosphorylation invloves covalent binding of inorganic
phosphate (to OH group of serine, threonine or tyrosine residue of the
enzyme) catalyzed by protein kinases and requiring ATP. Phosphorylation of
the target enzyme may result in its activation or inhibition. Dephosphorylation
is the reverse process catalyzed by phosphatases. A classic example of covalent
modification is glycogen phosphorylase which catalyze breakdown of glycogen.
Phosphorylation activates the enzyme. Dephosphorylation has the reverse
action.

Role of hormones in covalent modification reactions will be presented in detail

in "biosignaling".
Chapter 1 Introduction to Metabolism

2) Enzyme regulation through synthesis and degradation:

This metabolic regulation control the absolute quantity of enzymes in the
cell. The amount of a paticular enzyme is the result of a balance between its
rate of synthesis and its rate of degradation, changing either rate alters enzyme
concentration. Usually (but not always), this level of regulation controls
enzyme synthesis at the level of gene expression by induction and repression.
In induction, enzyme synthesis is increased by activating transcription of the
gene encoding the enzyme. Translation of its mRNA transcript leads to
synthesis of the enzyme protein.
Repression is the opposite of induction. The presence of a substance signals
that an enzyme is no longer needed and its synthesis can be inhibited. For
example, accumulation of an end product of an anabolic pathway blocks gene
transcription and inhibits enzyme synthesis.
Cholesterol regulates its de novo synthesis by repressing HMG CoA reductase
gene the key enzyme of cholesterol synthesis.
Induction and repression are not a rapid change and occur often in response to
change in nutritional state. Hormones affect the synthesis of rate- controlling
enzymes. They can act as inducers or repressors of mRNA transcription in the
nucleus or stimulators of the translation stage of protein synthesis at the
ribosomal level.

3) The flux of substrates:

Substrate concentration is of primary importance in regulating the rate of
a metabolic pathway. Insulin for example, promotes the entry of glucose into
many kinds of cells (adipose tissue, skeletal muscles). The transfer of substrates
from one compartment to the other (eg. from cytosol to the mitochondria) can
also serve as a control point.

Click to view animation

Chapter 1 Introduction to Metabolism

4) Compartmentation:
The enzymes of certain metabolic pathways are present in the cytosol
(glycolysis), others are confined to the mitochondria (as TCA cycle), a third
group operates partly in the cytosol and partly in the mitochondria. Metabolic
regulation and flexibility are enhanced by compartmentation which allows tight
and independent regulation of both anabolic and catabolic pathways.

5) Energy State of the cell

The energy state of the cell determines its net metabolic character: either
anabolic or catabolic. Since ATP is the chemical driving force of most
metabolic processes that require energy, its concentration in the cell relative to
ADP and AMP is an index of the energy state (energy charge). Energy charge
of the cell. describes the proportion of adenine ribonucleotides pool that
contains high energy phosphate. It is calculated as the molar ratio of adenine
nucleotides shown in the equation :

[ATP } + {ADP ]
Energy charge =
[AMP] +[ADP] + [ATP]

Energy charge ranges from zero, in a cell with no ATP or ADP to 1.0 in a cell
where all adenenine ribonucleotides are present as ATP. In most cells energy
charge ranges from 0.8- 0.9.

ATP-generating (catabolic) pathways are inhibited by high energy charge

whereas ATP- utilizing (anabolic) pathways are stimulated by high energy
charge

Energy is the milestone of all cellular activities the cell is a machine

drived by energy. Metabolism is regulated according to the energy
stateofthecell.Enzymeshavenoinfluenceonenergychangesintheir
reactions.Theyonlyinfluencereactions rate.
Chapter 1 Introduction to Metabolism

In this book ; Metabolism of carbohydrates, lipids, proteins, purines and

pyrimidine nucleotides, heme, minerals and xenobiotic will be discussed
individually. Regulation of metabolic pathways as well as metabolic defects
and inborn errors of metabolism will be illuminated. However, you must
alawys remember that the metabolism is an interrelated, highly regulated
process to achieve the dynamic steady state of life. integration of metablism.