BCH 202 I ntroduction to metabolism

Prelude1
Metabolism is the entire network of chemical reactions carried out by living cells. In
other words it’s defined as the sum total of all the chemical reactions that are taking place in
the body. Metabolites are the small molecules that are intermediates in the degradation or
biosynthesis of biopolymers (metabolism). It is convenient to consider separately reactions
that synthesize molecules (anabolic reactions) and reactions that degrade molecules (catabolic
reactions).

Anabolic reactions are those responsible for the synthesis of all the compounds needed for
cell maintenance, growth, and reproduction. These biosynthesis reactions make simple
metabolites such as amino acids, carbohydrates, coenzymes, nucleotides, and fatty acids.
They also produce larger molecules such as proteins, polysaccharides, nucleic acids, and
complex lipids. In some species all of the complex molecules that make up of a cell are
synthesized from inorganic precursors (carbon dioxide, ammonia, inorganic phosphates, etc.).
Some species derive energy from these inorganic molecules or from the creation of
membrane potential. Photosynthetic organisms use light energy to drive biosynthesis
reactions.

Catabolic reactions degrade large molecules to liberate smaller molecules and energy. These
reactions also degrade small molecules to inorganic products. All cells carry out degradation
reactions as part of their normal cell metabolism but some species rely on them as their only
source of energy. Animals, for example, require organic molecules as food. The ultimate
source of these organic molecules is a biosynthetic pathway in another species. Keep in mind
that all catabolic reactions involve the breakdown of compounds that were synthesized by a
living cell—either the same cell, a different cell in the same individual, or a cell in a different
organism. In addition to the energy required in biosynthesis, organisms need energy to
perform other kinds of cellular activity such as transport and movement. Whether we observe
bacteria or large multicellular organisms, we find a bewildering variety of biological
adaptations. More than 10 million species may be living on Earth, and several hundred
million species may have come and gone throughout the course of evolution. Multicellular
organisms have a striking specialization of cell types or tissues. Despite this extraordinary
diversity, the biochemistry of living cells is surprisingly similar not only in the chemical
composition and structure of cellular components but also in the metabolic routes by which
the components are modified.

1
A.Z Umar
Metabolism serves two important purposes:
1. To release energy from the ingested food material through catabolic degradation, and to
convert this energy into a form that can be used for cellular work.
2. To transform small organic compounds into macromolecules. This aspect of metabolism
also includes transformation of one group of organic compounds into another. During
catabolic degradation, the energy inherent in the organic molecules (particularly
carbohydrates and lipids) is released. It is then trapped and stored as adenosine triphosphate
(ATP). The stored energy can be released from ATP when needed and used to perform
cellular work. The major cellular works are:

i. Transport of organic molecules and inorganic ions across the cell membrane.
ii. Mechanical work, such as muscle contraction.
iii. Electrical work (e.g. nerve conduction) to ensure fidelity of information transfer.

The second major purpose of metabolism is to synthesize a vast array of macromolecules,

which include carbohydrates, proteins, lipids and nucleic acids. It is amazing that so many
diverse biomolecules are intracellularly synthesized from a limited number of organic
compounds. Evidently, thousands of reactions are involved in the processes which split, join
and rearrange the atoms of organic compounds, thus resulting in generation of complex
biomolecules. Each of these reactions is catalyzed by a specific enzyme.
Metabolic reactions are interconnected and interdependent
Metabolic reactions do not occur in isolation, or in a random or haphazard manner. Rather
they are organized into multi-step sequences called metabolic pathways. Each reaction forms
just one step in a metabolic pathway and is part of a larger scheme that involves several other
interrelated reactions. In metabolic pathways, the product of one reaction serves as a substrate
for the next one; the product of second reaction is substrate for the third reaction, and so on.
A B C D
Such series of consecutive reactions allows the cell to carry out highly complex molecular
conversions intracellularly. It is noteworthy that these conversions occur in mild conditions of
temperature and pH that prevail within the cell.
An important example that illustrates this design is the sequence of reactions that converts
glucose to pyruvate (i.e. glycolytic sequence). As soon as the glucose enters the cell, a
phosphate group from ATP is added to it to form glucose 6-phosphate. Glucose 6-phosphate
becomes the substrate for the next reaction, in which an Isomerase converts it into fructose 6-
phosphate. The latter then serves as substrate for another enzyme-catalyzed reaction, and the
sequence continues through six more reactions until glucose is converted to pyruvate. The
energy inherent in the substrate glucose is released in small packets in a stepwise fashion and
is effectively captured.
If the glucose to pyruvate conversion occurred in a single step, the energy inherent in the
glucose molecule could not have been trapped as ATP so effectively. A stepwise
transformation ensures efficient and effective trapping of the energy. Further, some of the
intermediates of this pathway are channeled into other pathways; for example, glucose 6-
phosphate can enter glycogenesis or the pentose phosphate pathway, and1,3-
bisphosphoglycerate can form 2,3-bisphosphoglycerate.
Metabolic pathway appears like an intricate and integrated web of chemical reactions wherein
the individual threads are interconnected at several points. In subsequent class, individual
metabolic pathways would be discussed separately with an aim to simplify and categorize.
This might give an erroneous impression that each pathway is self-contained and isolated.
Regulation of metabolism
How metabolic pathways are regulated and why is it necessary to regulate them? As noted
earlier, all cells are capable of carrying out the central metabolic pathways (such as
glycolysis, critic acid cycle, gluconeogenesis, beta-oxidation, lipogenesis, etc.). However, it
is not desirable to run them all at the same time. For example, when the cell is adequately
supplied with energy, the energy-yielding pathways like beta-oxidation and TCA must be
impeded; and at the same time, the available energy should be used to drive forward the
energy requiring pathways, such as lipogenesis and gluconeogenesis. Moreover, regulation of
the metabolic pathways ensures economical use of nutrients. Imagine a cell present in a
glucose rich medium. Glucose serves as its major carbon source in this environment. If this
cell is shifted to a medium containing alanine as well, it would be a wasteful expenditure if
the cell continued to produce alanine from glucose. An efficient cell would turn off its own
alanine producing machinery and instead obtain alanine from the medium.
Control of metabolic reactions is accomplished through regulation of enzyme activity. Within
a cell, the enzyme activity can be regulated in two ways.
1. By increasing or decreasing the catalytic activity of the enzyme molecule. This is
accomplished through (i) allosteric modulation, or by (ii) covalent modulation.
Both the mechanisms induce change in conformation of the enzyme protein, thereby altering
its activity.
2. By increasing or decreasing the total number of enzyme molecules. This is accomplished
by inducing changes in the enzyme synthesis (by alteration in either transcription or
translation), or the enzyme degradation. Hormones play an important role in regulating the
enzymes by this mechanism, termed induction-repression.

Fuel oxidation and ATP Generation

All physiologic processes in living cells require energy transformation. Cells convert the
chemical bond energy in foods into other forms, such as an electrochemical gradient across
the plasma membrane, or the movement of muscle fibers in an arm, or assembly of complex
molecules such as DNA. These energy transformations can be divided into three principal
phases: (1) oxidation of fuels (fat, carbohydrate, and protein), (2) conversion of energy from
fuel oxidation into the high energy phosphate bonds of ATP, and (3) utilization of ATP
phosphate bond energy to drive energy-requiring processes.
The first two phases of energy transformation are part of cellular respiration; the overall
process is using O2 and energy derived from oxidizing fuels to generate ATP. We need to
breathe principally because our cells require O2 to generate adequate amounts of ATP from
the oxidation of fuels to CO2. Cellular respiration uses over 90% of the O2 we inhale.
In phase 1 of respiration, energy is conserved from fuel oxidation by enzymes that transfer
electrons from the fuels to the electron-accepting coenzymes NAD + and FAD, which are
reduced to NADH and FAD(2H), respectively. The pathways for the oxidation of most fuels
(glucose, fatty acids, ketone bodies, and many amino acids) converge in the generation of the
activated 2-carbon acetyl group in acetyl CoA. The complete oxidation of the acetyl group to
CO2 occurs in the tricarboxylic acid (TCA) cycle, which collects the energy mostly as
NADH and FADH+H .

In phase 2 of cellular respiration, the energy derived from fuel oxidation is converted to the
high-energy phosphate e bonds of ATP by the process of oxidative phosphorylation. Electrons
are transferred from NADH and FADH+H to O2 by the electron transport chain, a series of
electron transfer proteins that are located in the inner mitochondrial membrane. Oxidation of
NADH and FADH+H by O2 generates an electrochemical potential across the inner
mitochondrial membrane in the form of a transmembrane proton gradient. This
electrochemical potential drives the synthesis of ATP from ADP and Pi by a transmembrane
enzyme called ATP synthase (or F0F1 ATPase).
In phase 3 of cellular respiration, the high-energy phosphate bonds of ATP are used for
processes such as muscle contraction (mechanical work), maintaining lowering intracellular
Na concentrations (transport work), synthesis of larger molecules such as DNA in anabolic
pathways (biosynthetic work), or detoxification (biochemical work). As a consequence of
these processes, ATP is either directly or indirectly hydrolyzed to ADP and inorganic
phosphate (Pi), or to AMP and pyrophosphate (PPi). Cellular respiration occurs in
mitochondria. The mitochondrial matrix, which is the compartment enclosed by the inner
mitochondrial membrane, contains almost all of the enzymes for the TCA cycle and oxidation
of fatty acids, ketone bodies, and most amino acids. The inner mitochondrial membrane
contains the protein complexes of the electron transport chain and ATP synthase, the enzyme
complex that generates ATP from ADP and Pi.

Oxidation of major biomolecule with concomitant generation of ATP

ATP serves as common link between the exergonic and the endergonic reactions
Composition of ATP
ATP (adenosine triphosphate) serves as the mediator of biological energy transfers. It acts as
an energy carrier in biological systems. It links the energy-yielding (i.e. exergonic) and the
energy-requiring (i.e. endergonic) processes.
Composition: ATP is a nucleotide consisting of the following three components
1. Purine base which is adenine.
2. Ribose sugar which is a 5-carbon sugar (i.e. a pentose).
The first carbon of ribose is linked to N-9 of adenine through N-glycosidic linkage.
3. Phosphate groups, three in number. The first phosphate is linked to C-5 of the ribose.

Structure of ATP
Summary
Metabolism comprises a highly integrated network of chemical reactions, which can be
subdivided into catabolism and anabolism. Catabolic reactions are used to extract energy
from fuels, and anabolism comprises reactions that use this energy for biosynthesis.

Introduction to thermodynamics
Define thermo

The First Law

The first law of thermodynamics, also referred to as the law of conservation of energy, states
that energy can neither be created nor destroyed. In course of any physical or chemical
reaction, one form of energy may change to some other form, but the total amount of energy
in the universe always remains constant. For example, electric energy changes to heat energy
in room heater, heat energy changes to mechanical energy in rail engine and mechanical
energy changes to electric energy in hydroelectric plants. These examples show that various
forms of energy are inter-convertible. However, none of these transformations brings about
any net generation or loss of energy.
The Second Law
All physical and chemical reactions tend to proceed in such a direction that useful energy of
the reacting system is irreversibly converted to a randomized and useless form, known as
entropy. The reactions proceed in this direction till entropy reaches maximum possible under
the prevailing circumstances. At this point, called the equilibrium point, no further progress
of the spontaneous reaction is possible. Thus in all reacting systems, disorder or randomness
is favoured at the cost of orderliness. To be more explicit, fall in useful energy content of the
system occurs with a concomitant rise in the randomized energy of the universe. The reacting
system implies collection of matter undergoing a reaction, and the universe includes both, the
system and its surroundings. This literally includes the whole of earth, or even the outer space
Free Energy, Entropy and Enthalpy
Useful energy is the form of energy that is capable of performing work. It is broadly
classified in two major types:
1. Heat energy, which is capable of performing work through change of temperature
2. Free energy which is capable of performing work at a constant temperature.
Since human body maintains a constant temperature (i.e. isothermic), it cannot utilize the heat
energy. Free energy is the useful form of energy in humans because of its ability to function
at constant temperature. It performs various functions and, in the process, gets converted to
the randomized form, i.e. entropy. These relations can be expressed in the equation form as
below:
.

BCH 202 Marking scheme

Q1.
a. Explain the term metabolism and state the 2 main purpose of metabolism
b. Metabolic reactions are interconnected and interdependent. Discuss?
Answer
Q1. Metabolism is the entire network of chemical reactions carried out by living cells.
In other words it’s defined as the sum total of all the chemical reactions that are taking place
in the body. Metabolites are the small molecules that are intermediates in the degradation or
biosynthesis of biopolymers (metabolism). It is convenient to consider separately reactions
that synthesize molecules (anabolic reactions) and reactions that degrade molecules (catabolic
reactions).
Anabolic reactions are those responsible for the synthesis of all the compounds needed for
cell maintenance, growth, and reproduction. These biosynthesis reactions make simple
metabolites such as amino acids, carbohydrates, coenzymes, nucleotides, and fatty acids.
They also produce larger molecules such as proteins, polysaccharides, nucleic acids, and
complex lipids. In some species all of the complex molecules that make up of a cell are
synthesized from inorganic precursors (carbon dioxide, ammonia, inorganic phosphates, etc.).
Catabolic reactions degrade large molecules to liberate smaller molecules and energy. These
reactions also degrade small molecules to inorganic products. All cells carry out degradation
reactions as part of their normal cell metabolism but some species rely on them as their only
source of energy. Animals, for example, require organic molecules as food. The ultimate
source of these organic molecules is a biosynthetic pathway in another species.

Metabolism serves two important purposes:

1. To release energy from the ingested food material through catabolic degradation, and to
convert this energy into a form that can be used for cellular work.
2. To transform small organic compounds into macromolecules. This aspect of metabolism
also includes transformation of one group of organic compounds into another. During
catabolic degradation, the energy inherent in the organic molecules (particularly
carbohydrates and lipids) is released. It is then trapped and stored as adenosine triphosphate
(ATP). The stored energy can be released from ATP when needed and used to perform
cellular work. The major cellular works are:

i. Transport of organic molecules and inorganic ions across the cell membrane.
ii. Mechanical work, such as muscle contraction.
iii. Electrical work (e.g. nerve conduction) to ensure fidelity of information transfer.
b. Metabolic reactions do not occur in isolation, or in a random or haphazard manner. Rather
they are organized into multi-step sequences called metabolic pathways. Each reaction forms
just one step in a metabolic pathway and is part of a larger scheme that involves several other
interrelated reactions. In metabolic pathways, the product of one reaction serves as a substrate
for the next one; the product of second reaction is substrate for the third reaction, and so on.
A B C D
Such series of consecutive reactions allows the cell to carry out highly complex molecular
conversions intracellularly. It is noteworthy that these conversions occur in mild conditions of
temperature and pH that prevail within the cell.
An important example that illustrates this design is the sequence of reactions that converts
glucose to pyruvate (i.e. glycolytic sequence). As soon as the glucose enters the cell, a
phosphate group from ATP is added to it to form glucose 6-phosphate. Glucose 6-phosphate
becomes the substrate for the next reaction, in which an Isomerase converts it into fructose 6-
phosphate. The latter then serves as substrate for another enzyme-catalyzed reaction, and the
sequence continues through six more reactions until glucose is converted to pyruvate. The
energy inherent in the substrate glucose is released in small packets in a stepwise fashion and
is effectively captured.
If the glucose to pyruvate conversion occurred in a single step, the energy inherent in the
glucose molecule could not have been trapped as ATP so effectively.