Notes on Nucleic Acids

NOTES ON NUCLEIC ACIDS

CHROMOSOMES, located in the nuclei of cells, contain the genetic or hereditary information needed for
directing and controlling the growth and reproduction of an organism. Each chromosome contains many GENES,
the fundamental unit of heredity. The differences between species, e.g. between humans and horses, and the
differences between members of the same species, lies in the differences in their genes. Similarities between
offspring of the same parents lie in the similarities in their genes. Genes are responsible for the characteristics of
the species and the individual member of a species.

Two types of NUCLEIC ACIDS are involved in carrying out the hereditary process – RIBONUCLEIC
ACID (RNA) and DEOXYRIBONUCLEIC ACID (DNA). Chromosomes contain DNA molecules and each gene
is a portion of a DNA molecule. DNA contains the hereditary information and directs reproduction of itself and the
synthesis of RNA. RNA molecules diffuse out of the cell nucleus and carry out the critical task of protein synthesis
in ribosomes located in the cytoplasm.

NUCLEIC ACIDS, like carbohydrates and proteins, are polymers. Controlled hydrolysis of nucleic acids
shows that NUCLEOTIDES are the building blocks of nucleic acids.

NUCLEOSIDES AND NUCLEOTIDES

NUCLEOTIDES are derived from three types of molecules – PHOSPHORIC ACID, PENTOSE SUGAR,
and HETEROCYCLIC NITROGEN BASE.

Two different pentoses are

used, RIBOSE for RNA and
DEOXYRIBOSE for DNA.

Five different heterocyclic

bases are used, three pyrimidine bases
and two purine bases. Adenine,
Guanine and Cytosine are used to
synthesize both DNA and RNA.
Thymine is used only for DNA while
Uracil is used only for RNA.

In Figure 1, the hydrogens

enclosed in boxes are lost when the
bases are bonded to C-1 of the sugars.
A NUCLEOSIDE is formed when either
a purine or pyrimidine base is linked to
the sugar molecules ribose and
deoxyribose. Typical structures of
nucleosides are shown in Figure 2.

Figure 1. Components of Nucleotides

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 Notes on Nucleic Acids

Figure 2. Structures of typical ribonucleosides and deoxyribonucleosides.

Table 1. Composition of Ribonucleosides and Deoxyribonucleosides

Name Composition Abbreviation
Adenosine Adenine – ribose A
Deoxyadenosine Adenine – deoxyribose dA
Guanosine Guanine – ribose G
Deoxyguanosine Guanine – deoxyribose dG
Cytidine Cytosine – ribose C
Deoxycytidine Cytosine – deoxyribose dC
Uridine Uracil – ribose U
Deoxythymidine Thymine - deoxyribose dT

Synthesis of a NUCLEOTIDE from phosphoric acid, sugar and base can be describes as proceeding by two
dehydration processes. The synthesis of the ribonucleotide from phosphoric acid, ribose and cytosine proceeds as
follows:

Dehydration between phosphoric acid and the sugar takes place at C-5 of the sugar and an –OH of the
phosphoric acid. Dehydration between the sugar and the heterocyclic nitrogen base takes place at C-1
of the sugar and an N-H bond of the nitrogen base (Figure 3).

Figure 3. Formation of the ribonucleotide from phosphoric acid, ribose and cytosine (CMP)

NOMENCLATURE OF NUCLEOTIDES

Nucleotides are named by the following set of rules:

1. The prefix DEOXY- is used to indicate deoxyribose as the sugar. No prefix means the sugar is ribose.
2. The purine base combines with sugar is named by replacing the ending –INE of the base by
-OSINE;. adenosine and guanosine. The pyrimidine bases are named cytidine, thymidine and uridine.
3. MONOPHOSPHATE is the second part of the name.
An alternative nomenclature system for nucleotides emphasizes their acidic properties (a result of the
phosphate group). The name of the base unit from the above nomenclature system forms the basis of the name.
The ending – OSINE MONOPHOSPHATE or – INE MONOPHOSPHATE is replaced by
–YLIC ACID. The prefix DEOXY- is used as before to distinguish deoxyribose from ribose as the sugar used.

Abbreviations are also used. The prefix d- is used instead of deoxy- . This is followed by the one letter
symbol for the base and MP for monophosphate.

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 Notes on Nucleic Acids

FORMATION OF NUCLEIC ACIDS

Nucleic acids are polynucleotides. They are formed by the polymerization of nucleotides. The reaction
involves dehydration between nucleotide molecules, specifically dehydration between the –OH group at C-3 of one
nucleotide molecule and the phosphate group at C-5 of another nucleotide molecule. The linkage joining one
nucleotide residue to another is the PHOSPHODIESTER LINKAGE.

Figure 4. Formation of a dinucleotide UMP-CMP

Drawing structures of nucleic acids becomes very difficult when more than a few nucleotide residues are
involved. Various abbreviated schematic representations are used. Figure 5 shows some of these representations
for the nucleotide sequence UMP-GMP-CMP-AMP.

U
G
C
A

Figure 5. A segment of RNA consisting of the four nucleotides adenosine monophosphate, cytidine monophosphate,
guanosine monophosphate, and uridine monophosphate

PRIMARY STRUCTURES OF NUCLEIC ACIDS

The primary structure of nucleic acids is its nucleotide sequence. All polynucleotides show two important
features: sense or directionality and individuality. A nucleotide chain has a sense or directionality. The
phosphodiester linkage between monomer units is between the C-3 of one monomer and the C-5 of the next. A
polynucleotide chain has individuality that is determined by the sequence of its bases.

The GENETIC INFORMATION is stored in the PRIMARY STRUCTURE of DNA.

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 Notes on Nucleic Acids

SECONDARY STRUCTURE OF DNA

DNA molecules do not exist as

individual molecules. Two paired DNA
molecules (often referred to as
STRANDS) fold around each other to
form a right-handed DOUBLE HELIX
(Figure 6).

Figure 6. DNA Double Helix

Bases from opposite sides

of the double helix are paired.
This BASE PAIRING occurs in
a COMPLEMENTARY
MANNER – adenine pairs only
with thymine and cytosine pairs
only with guanine (Figure 7).
This is maintained by hydrogen
bonding, a noncovalent
attraction, between the nitrogen
bases in the center of the helix.

In RNA, adenine pairs

with uracil.

Figure 7. Complementary base-pairing in DNA

One important feature of the DNA double helix is that the two strands are antiparallel strands, as the
example below shows. The two strands run in opposite directions and only when the two strands are antiparallel
can the base pairs form the hydrogen bonds that hold the two strands together.

5’ P – S – P – S – P –S – P – S - P – S – P – S – OH 3’
│ │ │ │ │ │
A T G C G A
‫׃‬ ‫׃‬ ‫׃‬ ‫׃‬ ‫׃‬ ‫׃‬
T A C G C T
│ │ │ │ │ │
3’ OH – S – P – S – P – S – P – S - P – S – P – S – P 5’

FLOW OF GENETIC INFORMATION

CENTRAL DOGMA OF BIOCHEMISTRY

“Information and thereby chemical product formation flow from DNA to RNA to Protein.”

Transcription Translation
Replication DNA RNA Protein

Figure 8. Basic features of the central dogma of biochemistry

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 Notes on Nucleic Acids

DNA REPLICATION

DNA must be replicated before a cell divides so that each daughter cell inherits a copy of each gene. A cell
that is missing a critical gene will die, just as an individual with a genetic disease, a defect in an important gene,
may die early in life. It is essential that the DNA replication process produces an absolutely accurate copy of the
original genetic information since any mistake made in critical genes could result to lethal mutations.

The two chains of DNA double helix come apart (unwind) and the hydrogen bonds “unzip”. Each chain
serves as a TEMPLATE or PATTERN for the synthesis of a new, complementary chain (Figure 9). Over 20
enzymes are involved in directing and controlling replication. Helicase and topoisomerase catalyze the unwinding
process, single-strand DNA-binding proteins stabilize the unwound DNA, and DNA polymerase catalyzes the
addition of nucleotide to growing DNA chains.

Assembly of daughter strands is directed by the principle of complementary base pairing. Two identical
double helices result from the process, each containing chains of the original double helix. This mode of DNA
replication is called semiconservative replication

In REPLICATION, DNA directs the synthesis of itself. The process controls the appearance and
physiological processes that establish similarities among the members of a particular species and make each species
distinct from other species.

Figure 9. Replication of DNA double helix

SECONDARY, TERTIARY AND QUATERNARY STRUCTURES OF RNA

Ribonucleic acids exist as single-strand molecules, not double helices as do deoxynucleic acids. RNA
molecules, however, possess a wide variety of secondary, tertiary and quaternary structures. Figure 10 shows one
type of RNA molecule called transfer RNA or tRNA. The overall shape of tRNA resembles a cloverleaf, especially
in the two-dimensional representation.

Figure 10.
Representation of
tRNA.

There is a considerable intramolecular base pairing of nucleotide residues in tRNA. The base pairing scheme is the
same as for DNA except that URACIL is used in RNA instead of THYMINE. Adenine pairs with uracil and
cytosine pairs with guanine.
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 Notes on Nucleic Acids

Classes of RNA Molecules

1. Messenger RNA (mRNA) carries the genetic information for a protein from the DNA in the nucleus to the
ribosomes. It is a complementary RNA copy of a gene on the DNA. The message is in the form of
TRIPLETS OF BASES specifying AMINO ACIDS or PUNCTUATIONS called CODONS. The mRNA
exists long enough to carry the message and have its corresponding protein synthesized then the mRNA is
degraded. A new mRNA of the same type will be produced when more of its protein is needed.
2. Transfer RNA (tRNA) translates the genetic code of the mRNA into the primary sequence of amino acids
in the protein. It brings amino acids to the site of protein synthesis for assembly into a protein. Each of the
20 amino acid is transported by a different tRNA. The clover leaf structure of the tRNA has an
ACCEPTOR SITE for the amino acid and an opposite loop with an AFFINITY SITE called the
ANTICODON. The anticodon can base pair to a group of complementary bases, the codon on mRNA.
3. Ribosomal RNA (rRNA) is a structural and functional component of the ribosomes, which are “platforms”
on which protein synthesis occurs. Complexed with proteins, the rRNA forms the cellular structures called
ribosomes that provide the physical site for protein synthesis.

TRANSCRIPTION

Transcription, the
synthesis of rRNA,
tRNA, and mRNA using
the information from
DNA, proceeds in the
manner shown in Figure
11. The process is similar
to replication. A portion
of the DNA unwinds to
form a transcription
bubble. One of the two
DNA strands will act as
the template strand for
RNA synthesis.
Figure 11. Transcription

The initially formed RNA, often referred to as a primary transcripts RNA (ptRNA), is altered by chemical
reactions to achieve biological activity before it is exported out of the nucleus.

Post-Transcriptional Modifications for Eukaryotic ptRNA

1. Capping the ends of an RNA molecule with certain nucleotide sequences.
2. Modification of certain nucleotides in the RNA chain to protect it from enzymatic degradation.
3. Splicing operations to remove portions of the ptRNA that are not protein coding.

Eukaryotic genes are discontinuous; not all of the DNA sequence codes for protein. Some segments are
between coding sequences. The sequences that do not encode any amino acid sequences for the protein are called
intervening sequences or INTRONS. The protein coding sequences are called the EXONS. The ptRNA, the first
DNA-directed mRNA product contains both the INTRONS and the EXONS. But the presence of introns in the
mRNA would make it impossible for the process of translation to synthesize the correct protein. RNA splicing is
done to remove these portions.

Figure 12. Splicing of RNA by excision of introns and linking of introns

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 Notes on Nucleic Acids

THE GENETIC CODE

The mRNA carries the genetic code for a protein. It is the language required in the conversion of the
hereditary information carried by the bases of DNA. The GENETIC CODE, the complete description of the amino
acids specified by various base triplets, is tabulated in terms of the codons on mRNA (Table 2). The base sequence
in mRNA is identical with the base sequence in the information strand of DNA except that U replaces T. The
information strand contains many messages (base sequences), each message corresponding to a particular
polypeptide to be synthesized. The individual messages are separately sent out of the nucleus in the form of
different mRNAs.

The genetic code is degenerate, i.e., most of the amino acids are coded by more than one codon. One of the
64 codons (AUG) code simultaneously for methionine, Met, as well as for the initiation of synthesis. Three of the
codons (UAA, UAG, UGA) code for the termination of polypeptide synthesis. A codon sequence is always written
in the 5’ → 3’ direction. The genetic code is universal; it applies to all organisms, plant and animal alike. The
codon UUU specifies phenylalanine in a yeast, mushroom or human cell.

Example:
DNA strand: DEOXYRIBOSE – PHOSPHATE BACKBONE
│││ │││ │││ │││ │││ │││
AGA CGT TGA CAA CGG AGT
: : : : : : : : : : : : : : : : : :
UCU GCA A CU GUU GCC UCA
│││ │││ │ ││ │││ │ ││ │││
RNA strand: RIBOSE – PHOSPHATE BACKBONE

Amino Acid Sequence: Ser ▬ Ala ▬ Thr ▬ Val ▬ Ala ▬ Ser

Table 2. Genetic Code: Codon Assignments

His
His
Gln
Gln

TRANSLATION

The process of protein synthesis is called TRANSLATION. It involves translating the genetic information
from the sequence of nucleotides into the sequence of amino acids in the primary structure of a protein.

Four Steps in the Translation of the Genetic Message Encoded in mRNA into a Protein Molecule

1. MESSAGE POSITIONING
mRNA lines up on the ribosome so that it can accept the incoming amino acid for orderly
assembly.
2. AMINO ACID TRANSPORT BY tRNA
tRNA brings an amino acid to its proper position along the mRNA message. This assures the
proper placement of amino acids in the protein chain.
3. PROTEIN CHAIN GROWTH
The protein chain grows as amino acids take their positions and are linked together.
4. PROTEIN CHAIN TERMINATION
The protein chain is terminated and released from RNA and “finishing touches” to the
construction are applied.

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 Notes on Nucleic Acids

Figure 13. (a) – (e) Synthesis of polypeptide

MESSAGE POSITIONING

The biosynthesis of proteins begins when mRNA leaves the cellular nucleus and travels to the cytoplasm.
Each mRNA is then bound to five or more ribosomes. The first codon to line up in the ribosome is AUG, the
INITIATOR or the START SIGNAL. The tRNA recognizes the codon and carries the amino acid methionine
(Figure 13-a).

The ribosome has two sites for binding tRNA molecules. The first site, the peptidyl or P-site, holds the
peptidyl tRNA, the growing peptide bound to tRNA molecule. The second site, the aminoacyl or A-site, holds the
aminoacyl tRNA carrying the next amino acid to be added to the peptide chain.

AMINO ACID TRANSPORT BY tRNA

Specific tRNAs bind to specific amino acids. Pickup of amino acids by tRNAs is controlled by enzymes
referred to as aminoacyl-tRNA synthetases. Cells contain at least 32 different tRNAs. Each tRNA recognizes and
bonds to only one amino acid due to these synthetases. There must be a match between the amino acid attached
and the ANTICODON in the tRNA. For example, phenylalanine could only be attached to a tRNA with an
anticodon AAA or AAG.

All amino acids are brought into position by the principle of BASE PAIRING between CODONS on
mRNA and ANTIODONS on tRNA.

PROTEIN CHAIN GROWTH

After the first codon at the P-site is base paired to Met-tRNA, the second codon is aligned on the A-site; if
the codon shown at the A-site is GGG, glycine-tRNA bearing the anticodon CCC lines up at the A-site (Figure 13-
a). The enzyme peptidyl transferase then catalyzes the transfer and bonding of Met to Gly (Figure 13-b). The
reaction is an acyl transfer reaction that results to an empty tRNA at the P-site and a dinucleotide at the A-site.

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 Notes on Nucleic Acids

An empty tRNA is released from the ribosome and can move back into the cytoplasm, where it can regain
an amino acid and be available for further use. The ribosome moves in the 5’ → 3’ direction, and the dipeptide is
now in the P-site (Figure 13-c). The tRNA with the Ile base-pairs at the empty A-site (Figure 13-d) and the Met-
Gly dipeptide is transferred and bonded to Ile to form the Met-Gly-Ile tripeptide at the A-site and an empty tRNA at
the P-site (Figure 13-e).

Synthesis proceeds in this manner over and over again with the ribosome moving to the end of the mRNA.

PROTEIN CHAIN TERMINATION

Termination of the polypeptide chain is signaled by the appearance at the A-site of one of the three STOP
codons, UAA, UAG or UGA. These codons are recognized by release factors, proteins that aid in the hydrolytic
cleavage of the polypeptide chain from its tRNA on the P-site.

MODIFICATIONS ON THE PROTEIN CHAINS

The peptide that is released following translation is not necessarily in its final functional form. In some
cases the peptide is proteolytically cleaved before it becomes functional. Synthesis of digestive enzymes uses this
strategy.

1. Cleavage of the initial methionine (Met) group

2. Oxidation of cysteine –SH group s to disulfide linkage
3. Attachment of prosthetic groups (ex. HEME in hemoglobin)
4. Coiling and folding to yield the three-dimensional shape of the protein

MUTATION

Mutation is the alteration in base sequences in DNA that produce permanent changes in the synthesized
proteins. These changes can arise from mistakes made by DNA polymerase during DNA replication. When a base
alteration in DNA is not repaired and replication continues, the error is therefore propagated. Mutations can also
result from the action of chemicals, called mutagens that damage the DNA.

Mutations are classified by the kind of change that occurs in the DNA.

1. SUBSTITUTION of one base for another

2. INSERTION of a new base
3. DELETION of a base

Normal Gene DNA template strand AAA TAG CGG TCC

mRNA UUU AUC GCC AGG
normal protein chain Phe – Ile – Ala – Arg

Substitution of G by A template AAA TAG CAG TCC

on DNA mRNA UUU AUC GUC AGG
mutant protein Phe – Ile – Val – Arg

Insertion of C base template AAA TAG CCG GTCC

on DNA mRNA UUU AUC GGC CAGG
mutant protein Phe – Ile – Gly – Gln

Deletion of an A base template AAT AGC GGT CCG

on DNA mRNA UUA UCG CCA GGC
mutant protein Leu – Ser – Pro – Gly

Substitution alters only one codon therefore no more than one amino acid is changed in the finished
polypeptide or protein. This may not necessarily have an effect on the biological activity of a protein. If the
change is at the active site of an enzyme, or if the change affects the hydrophilic characteristic of the exterior of
a globular protein, then there may be a dramatic change in its biological functioning. In the human genetic disease
sickle-cell anemia, hydrophobic valine replaces a hydrophilic glutamic acid in the hemoglobin molecule.

Insertion or deletion of DNA bases lead to more extensive genetic damage because all codons and thus all
amino acids beginning with and continuing past the point of insertion or deletion are affected.

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 Notes on Nucleic Acids

MUTAGENS AND CARCINOGENS

Mutagens are substances that cause mutations. Carcinogens are chemicals that cause a cancerous
condition. Often, mutagens are also carcinogens. DNA bases can be altered by chemical agents, especially
substances reacting with amine groups.
 NITROUS ACID can convert cytosine to uracil
 NITROGEN MUSTARDS are amine alkylating agents
 DIMETHYL SULFATE converts –OH groups of guanine into –OCH3 groups

OTHER AGENTS OF MUTATION

1. Chemical modifications in DNA base can occur from the impact of high energy radiation. The radiation
may raise an electron in the molecule to a high-energy level or completely remove the electron and produce
an unstable intermediate which proceeds to react further.
2. Ultraviolet radiation from sunlight can lead to base changes in the DNA of skin cells.
3. X-rays, radioactivity, and cosmic rays are all forms of ionizing radiations.

REPAIR ENZYMES

Repair enzymes are developed by nature and can remove and replace altered bases. However, an
accumulation of mutations combined with a simultaneous decrease in the efficiency of DNA repair mechanisms
leads to an increased incidence of cancer.

The genetic skin disorder XERODERMA PIGMENTOSUM for example, is a rare skin disease in
individuals, who lack the ultraviolet radiation repair enzyme UV-endonuclease. The individual is extremely
sensitive to sunlight and skin cancer often develops because bases altered by the sun’s ultraviolet rays are not
removed and repaired.

MOLECULAR DISEASES

Mutations that have negative biological consequences fall into two categories. When the damage occurs in
a SOMATIC CELL (a body cell) uncontrolled growth (cancer) of that cell may result. The individual may become
ill and even die, depending on the level of the mutation and the particular biological functions which are affected.
If damage to DNA bases occurs in a GERM CELL (sperm or egg cell) the offspring of the damaged organism will
inherit the defect. Such mutations are referred to as GENETIC DEFECTS or HEREDITARY DISEASES when
biological functions are severely affected (Table 3). This type of mutation leads to medical conditions called
MOLECULAR DISEASES where defects in DNA lead to the production of malformed and malfunctioning
proteins.

Table 3. Hereditary Diseases

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 Notes on Nucleic Acids

ANTIBIOTICS

Most antibiotics fight bacterial infections by interfering with some aspect of protein synthesis in the
bacteria. Antibiotics are designed to be specific for bacteria with minimal effect on animal protein synthesis. Table
4 lists some of the common antibiotics used in medicine. Large scale use of antibiotics has been highly successful
but some bacteria have “fought back” by spontaneous mutation and propagation of antibiotic-resistant strains. This
requires that we keep ahead of the bacteria by synthesizing new antibiotics to kill the mutant strains.

Table 4. Antibiotic Inhibition of Protein in Bacteria

VIRUSES

Viruses are infectious, parasitic small particles containing either DNA or RNA (but not both) encapsulated
by a protein overcoat. They are unable to reproduce because they lack some or most of the apparatus (amino acids,
nucleotides, and enzymes) for replication, transcription, and translation. They are responsible for a wide range of
diseases – INFLUENZA, POLIOMYELITIS, LEUKEMIA, HEPATITIS, SMALLPOX, CHICKEN POX,
TUMORS (including cancer), and AIDS (acquired immune deficiency syndrome)
Infection of a host cell by virus particle occurs when the virus sticks to a host cell and then a portion of the
cell membrane is dissolved by an enzyme present in the protein overcoat of the virus. This is followed by the entry
of the nucleic acid of the virus or the complete virus into the host cell. There is high specificity in this process as
only certain types of hosts and host cells are involved by any particular virus.

The HIV virus which is responsible for AIDS, for instance, infects only the T (lymphocyte) cells of the
human immune system but the result is devastating. The immune system is inactivated and the person becomes
easy prey to pneumonia and a variety of diseases.

The virus uses the apparatus of the host cell to reproduce itself, i.e., the host cell is fooled into replicating
the virus. A portion of the viral RNA contains information for making an enzyme, RNA replicase, which directs
RNA synthesis from RNA. RNA replicase, synthesized in the host cell directs the subsequent replication and
transcription of viral RNA.

RETROVIRUSES are RNA viruses that reproduce through the intermediate formation of DNA. The
retroviruses contain genetic information for the synthesis of the enzyme reverse transcriptase, which directs the
synthesis of viral DNA from viral RNA. The host reproduces the viral RNA using this DNA as a template. HIV
and cancer-causing viruses (oncogenic viruses) are of this type.

HOW A VIRUS HARM THE HOST CELL

Uncontrolled reproduction of the virus results in the breakage of the cell membrane. Spillage of the cell
contents lead to the invasion of other host cells.

HOW A BACTERIUM HARM A HOST CELL

Bacteria do not enter a host cell. They cause harm through the toxicity of their metabolic products.

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 Notes on Nucleic Acids

APPLICATIONS OF GENETIC ENGINEERING

Recombinant DNA technology (also referred to as genetic engineering or cloning) involves the alteration of
the DNA of some organism with the objective of having that organism produce a desired polypeptide.

 Gene cloning to produce a desired protein

 INSULIN for glucose metabolism

 INTERFERON a protein which appears to have antiviral activity used in the treatment of certain types
of cancer
 HUMAN GROWTH HORMONE
 FISH GROWTH HORMONE to produce more protein for the world’s population, BOVINE GROWTH
HORMONE for an increase in milk production
 Plants that are more resistant to insect pests, diseases and other hazards; potato with a bacterial gene that
codes for a toxin that kills potato beetle, slow ripening tomatoes

 Gene therapy to cure molecular diseases through the insertion of a missing gene into a mammalian cell

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