Virtually
everyone knows that the genes, located in the nuclei of all cells of the body,
control heredity from parents to children, but most people do not realize that
these same genes also control day-today function of all the body’s cells. The
genes control cell function by determining which substances are synthesized
within the cell—which structures, which enzymes, which chemicals. Diagram shows
the general schema of genetic control. Each gene, which is a nucleic acid
called deoxyribonucleic acid (DNA), automatically controls the formation of another
nucleic acid, ribonucleic acid (RNA); this RNA then spreads throughout the cell
to control the formation of a specific protein. Because there are more than
30,000 different genes in each cell, it is theoretically possible to form a
very large number of different cellular proteins. Some of the cellular proteins
are structural proteins, which, in association with various lipids and
carbohydrates, form the structures of the various intracellular organelles.
However, by far the majority of the proteins are enzymes that catalyze the
different chemical reactions in the cells. For instance, enzymes promote all
the oxidative reactions that supply energy to the cell, and they promote
synthesis of all the cell chemicals, such as lipids, glycogen, and adenosine triphosphate
(ATP).
Genes in the Cell Nucleus
In the cell
nucleus, large numbers of genes are attached end on end in extremely long
double-stranded helical molecules of DNA having molecular weights measured in
the billions. A very short segment of such a molecule is shown in diagram. This
molecule is composed of several simple chemical compounds bound together in a
regular pattern, details of which are explained in the next few paragraphs.
Basic
Building Blocks of DNA.
Diagram
shows the basic chemical compounds involved in the formation of DNA. These
include
(1)
Phosphoric acid,
(2) A sugar
called deoxyribose and
(3) Four
nitrogenous bases (two purines, adenine and guanine, and two pyrimidines,
thymine and cytosine).
The
phosphoric acid and deoxyribose form the two helical strands that are the
backbone of the DNA molecule, and the nitrogenous bases lie between the two
strands and connect them, as illustrated in diagram.
Nucleotides
The first
stage in the formation of DNA is to combine one molecule of phosphoric acid,
one molecule of deoxyribose and one of the four bases to form an acidic
nucleotide. Four separate nucleotides are thus formed, one for each of the four
bases: deoxyadenylic, deoxythymidylic, deoxyguanylic, and deoxycytidylic acids.
Diagram shows the chemical structure of deoxyadenylic acid and diagram shows
simple symbols for the four nucleotides that form DNA.
Organization
of the Nucleotides to Form Two Strands of DNA Loosely Bound to Each Other.
Diagram shows the manner in which multiple numbers of nucleotides are bound
together to form two strands of DNA. The two strands are, in turn, loosely
bonded with each other by weak cross-linkages, illustrated in diagram by the
central dashed lines. Note that the backbone of each DNA strand is comprised of
alternating phosphoric acid and deoxyribose molecules. In turn, purine and
pyrimidine bases are attached to the sides of the deoxyribose molecules. Then,
by means of loose hydrogen bonds (dashed lines) between the purine and
pyrimidine bases, the two respective DNA strands are held together. But note
the following:
1. Each
purine base adenine of one strand always bonds with a pyrimidine base thymine
of the other strand and
2. Each
purine base guanine always bonds with a pyrimidine base cytosine.
Thus, in diagram,
the sequence of complementary pairs of bases is CG, CG, GC, TA, CG, TA, GC, AT and
AT.
Because of
the looseness of the hydrogen bonds, the two strands can pull apart with ease,
and they do so many times during the course of their function in the cell. To
put the DNA of diagram into its proper physical perspective, one could merely
pick up the two ends and twist them into a helix. Ten pairs of nucleotides are
present in each full turn of the helix in the DNA molecule, as shown in
diagram.
Genetic Code
The
importance of DNA lies in its ability to control the formation of proteins in
the cell. It does this by means of the so-called genetic code. That is, when
the two strands of a DNA molecule are split apart, this exposes the purine and
pyrimidine bases projecting to the side of each DNA strand, as shown by the top
strand in diagram. It is these projecting bases that form the genetic code. The
genetic code consists of successive “triplets” of bases—that is, each three
successive bases is a code word. The successive triplets eventually control the
sequence of amino acids in a protein molecule that is to be synthesized in the
cell. Note in diagram that the top strand of DNA, reading from left to right,
has the genetic code GGC, AGA, CTT, the triplets being separated from one
another by the arrows. As we follow this genetic code through the given
pictures, we see that these three respective triplets are responsible for
successive placement of the three amino acids, proline, serine, and glutamic
acid, in a newly formed molecule of protein.
The DNA Code in the Cell Nucleus Is
Transferred to an RNA Code in the Cell Cytoplasm—The Process of Transcription
Because the
DNA is located in the nucleus of the cell, yet most of the functions of the
cell are carried out in the cytoplasm, there must be some means for the DNA
genes of the nucleus to control the chemical reactions of the cytoplasm. This
is achieved through the intermediary of another type of nucleic acid, RNA, the
formation of which is controlled by the DNA of the nucleus. Thus, as shown in diagram,
the code is transferred to the RNA; this process is called transcription.
The RNA, in
turn, diffuses from the nucleus through nuclear pores into the cytoplasmic
compartment, where it controls protein synthesis.
Synthesis of RNA
During
synthesis of RNA, the two strands of the DNA molecule separate temporarily; one
of these strands is used as a template for synthesis of an RNA molecule. The
code triplets in the DNA cause formation of complementary code triplets (called
codons) in the RNA; these codons, in turn, will control the sequence of amino
acids in a protein to be synthesized in the cell cytoplasm.
Basic
Building Blocks of RNA
The basic
building blocks of RNA are almost the same as those of DNA, except for two
differences. First, the sugar deoxyribose is not used in the formation of RNA. In
its place is another sugar of slightly different composition, ribose,
containing an extra hydroxyl ion appended to the ribose ring structure. Second,
thymine is replaced by another pyrimidine, uracil.
Formation of RNA Nucleotides
The basic
building blocks of RNA form RNA nucleotides, exactly as previously described
for DNA synthesis. Here again, four separate nucleotides are used in the
formation of RNA. These nucleotides contain the bases adenine, guanine,
cytosine and uracil. Note that these are the same bases as in DNA, except that
uracil in RNA replaces thymine in DNA.
“Activation”
of the RNA Nucleotides. The next step in the synthesis of RNA is “activation”
of the RNA nucleotides by an enzyme, RNA polymerase. This occurs by adding to
each nucleotide two extra phosphate radicals to form triphosphates (shown in diagram by the two RNA nucleotides to the far right during RNA chain
formation).These last two phosphates are combined with the nucleotide by
high-energy phosphate bonds derived from ATP in the cell. The result of this
activation process is that large quantities of ATP energy are made available to
each of the nucleotides, and this energy is used to promote the chemical
reactions that add each new RNA nucleotide at the end of the developing RNA
chain.
Assembly of
the RNA Chain from Activated Nucleotides Using the DNA Strand as a Template—The
Process of “Transcription”
Assembly of
the RNA molecule is accomplished in the manner shown in diagram under the
influence of an enzyme, RNA polymerase. This is a large protein enzyme that has
many functional properties necessary for formation of the RNA molecule.
They are as
follows:
1. In the
DNA strand immediately ahead of the initial gene is a sequence of nucleotides
called the promoter. The RNA polymerase has an appropriate complementary
structure that recognizes this promoter and becomes attached to it. This is the
essential step for initiating formation of the RNA molecule.
2. After the
RNA polymerase attaches to the promoter, the polymerase causes unwinding of
about two turns of the DNA helix and separation of the unwound portions of the
two strands.
3. Then the
polymerase moves along the DNA strand, temporarily unwinding and separating the
two DNA strands at each stage of its movement.
As it moves
along, it adds at each stage a new activated RNA nucleotide to the end of the
newly forming RNA chain by the following steps:
a. First, it
causes a hydrogen bond to form between the end base of the DNA strand and the
base of an RNA nucleotide in the nucleoplasm.
b. Then, one
at a time, the RNA polymerase breaks two of the three phosphate radicals away
from each of these RNA nucleotides, liberating large amounts of energy from the
broken high-energy phosphate bonds; this energy is used to cause covalent
linkage of the remaining phosphate on the nucleotide with the ribose on the end
of the growing RNA chain.
c. When the
RNA polymerase reaches the end of the DNA gene, it encounters a new sequence of
DNA nucleotides called the chain-terminating sequence; this causes the
polymerase and the newly formed RNA chain to break away from the DNA strand. Then
the polymerase can be used again and again to form still more new RNA chains.
d. As the
new RNA strand is formed, its weak hydrogen bonds with the DNA template break
away, because the DNA has a high affinity for rebonding with its own
complementary DNA strand. Thus, the RNA chain is forced away from the DNA and
is released into the nucleoplasm. Thus, the code that is present in the DNA
strand is eventually transmitted in complementary form to the RNA chain. The
ribose nucleotide bases always combine with the deoxyribose bases in the
following combinations:
DNA Base RNA
Base
Guanine . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cytosine
Cytosine . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . Guanine
Adenine . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . Uracil
Thymine . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . Adenine
Three Different Types of RNA
There are
three different types of RNA, each of which plays an independent and entirely
different role in protein formation:
1. Messenger
RNA, which carries the genetic code to the cytoplasm for controlling the type
of protein formed.
2. Transfer
RNA, which transports activated amino acids to the ribosomes to be used in
assembling the protein molecule.
3. Ribosomal
RNA, which, along with about 75 different proteins, forms ribosomes, the
physical and chemical structures on which protein molecules are actually
assembled.
Messenger
RNA—the Codons
Messenger
RNA molecules are long, single RNA strands that are suspended in the cytoplasm.
These molecules are composed of several hundred to several thousand RNA
nucleotides in unpaired strands, and they contain codons that are exactly
complementary to the code triplets of the DNA genes. diagram shows a small
segment of a molecule of messenger RNA. Its codons are CCG, UCU and GAA. These
are the codons for the amino acids proline, serine and glutamic acid. The
transcription of these codons from the DNA molecule to the RNA molecule is
shown in Figure.
RNA Codons for the Different Amino Acids
Table gives
the RNA codons for the 20 common amino acids found in protein molecules. Note
that most of the amino acids are represented by more than one codon; also, one
codon represents the signal “start manufacturing the protein molecule,” and
three codons represent “stop manufacturing the protein molecule.” In Table, these
two types of codons are designated CI for “chain-initiating” and CT for
“chain-terminating.”
Transfer
RNA—The Anticodons
Another type
of RNA that plays an essential role in protein synthesis is called transfer
RNA, because it transfers amino acid molecules to protein molecules as the
protein is being synthesized. Each type of transfer RNA combines specifically
with 1 of the 20 amino acids that are to be incorporated into proteins. The
transfer RNA then acts as a carrier to transport its specific type of amino acid
to the ribosomes, where protein molecules are forming. In the ribosomes, each
specific type of transfer RNA recognizes a particular codon on the messenger RNA
(described later) and thereby delivers the appropriate amino acid to the
appropriate place in the chain of the newly forming protein molecule. Transfer
RNA, which contains only about 80 nucleotides, is a relatively small molecule
in comparison with messenger RNA. It is a folded chain of nucleotides with a
cloverleaf appearance similar to that shown in diagram. At one end of the
molecule is always an adenylic acid; it is to this that the transported amino
acid attaches at a hydroxyl group of the ribose in the adenylic acid. Because
the function of transfer RNA is to cause attachment of a specific amino acid to
a forming protein chain, it is essential that each type of transfer RNA also
have specificity for a particular codon in the
Messenger RNA
The specific
code in the transfer RNA that allows it to recognize a specific codon is again a
triplet of nucleotide bases and is called an anticodon. This is located
approximately in the middle of the transfer RNA molecule (at the bottom of the
cloverleaf configuration shown in Figure). During formation of the protein
molecule, the anticodon bases combine loosely by hydrogen bonding with the
codon Ribosomal RNA
The third
type of RNA in the cell is ribosomal RNA; it constitutes about 60 per cent of
the ribosome. The remainder of the ribosome is protein, containing about 75
types of proteins that are both structural proteins and enzymes needed in the
manufacture of protein molecules. The ribosome is the physical structure in the
cytoplasm on which protein molecules are actually synthesized. However, it
always functions in association with the other two types of RNA as well: transfer
RNA transports amino acids to the ribosome for incorporation into the
developing protein molecule, whereas messenger RNA provides the information
necessary for sequencing the amino acids in proper order for each specific type
of protein to be manufactured. Thus, the ribosome acts as a manufacturing plant
in which the protein molecules are formed.
Formation of
Ribosomes in the Nucleolus
The DNA
genes for formation of ribosomal RNA are located in five pairs of chromosomes in
the nucleus and each of these chromosomes contains many duplicates of these
particular genes because of the large amounts of ribosomal RNA required for
cellular function. As the ribosomal RNA forms, it collects in the nucleolus, a
specialized structure lying adjacent to the chromosomes. When large amounts of
ribosomal RNA are being synthesized, as occurs in cells that manufacture large
amounts of protein, the nucleolus is a large structure, whereas in cells that
synthesize little protein, the nucleolus may not even be seen. Ribosomal RNA is
specially processed in the nucleolus, where it binds with “ribosomal proteins” to
form granular condensation products that are primordial subunits of ribosomes.
These subunits are then released from the nucleolus and transported through the
large pores of the nuclear envelope to almost all parts of the cytoplasm. After
the subunits enter the cytoplasm, they are assembled to form mature, functional
ribosomes. Therefore, proteins are formed in the cytoplasm of the cell, but not
in the cell nucleus, because the nucleus does not contain mature ribosomes.
Formation of
Proteins on the Ribosomes—The Process of “Translation”
When a
molecule of messenger RNA comes in contact with a ribosome, it travels through
the ribosome, beginning at a predetermined end of the RNA molecule specified by
an appropriate sequence of RNA bases called the “chain-initiating” codon. Then,
as shown in diagram, while the messenger RNA travels through the ribosome, a
protein molecule is formed— a process called translation. Thus, the ribosome
reads the codons of the messenger RNA in much the same way that a tape is
“read” as it passes through the playback head of a tape recorder. Then, when a “stop”
(or “chain-terminating”) codon slips past the ribosome, the end of a protein
molecule is signaled and the protein molecule is freed into the cytoplasm.
Polyribosomes
A single
messenger RNA molecule can form protein molecules in several ribosomes at the
same time because the initial end of the RNA strand can pass to a successive
ribosome as it leaves the first, as shown in Figure. The
protein molecules are in different stages of development in each ribosome. As a
result, clusters of ribosomes frequently occur, 3 to 10 ribosomes being
attached to a single messenger RNA at the same time. These clusters are called
polyribosomes. It is especially important to note that a messenger RNA can
cause the formation of a protein molecule in any ribosome; that is, there is no
specificity of ribosomes for given types of protein. The ribosome is simply the
physical manufacturing plant in which the chemical reactions take place.
Many
Ribosomes Attach to the Endoplasmic Reticulum. It was noted that many ribosomes
become attached to the endoplasmic reticulum. This occurs because the initial
ends of many forming protein molecules have amino acid sequences that
immediately attach to specific receptor sites on the endoplasmic reticulum; this
causes these molecules to penetrate the reticulum wall and enter the
endoplasmic reticulum matrix. This gives a granular appearance to those
portions of the reticulum where proteins are being formed and entering the
matrix of the reticulum. Figure shows the functional relation of messenger RNA
to the ribosomes and the manner in which the ribosomes attach to the membrane
of the endoplasmic reticulum. Note the process of translation occurring in
several ribosomes at the same time in response to the same strand of messenger
RNA. Note also the newly forming polypeptide (protein) chains passing through
the endoplasmic reticulum membrane into the endoplasmic matrix. Yet it should
be noted that except in glandular cells in which large amounts of
protein-containing secretory vesicles are formed, most proteins synthesized by
the ribosomes are released directly into the cytosol instead of into the
endoplasmic reticulum. These proteins are enzymes and internal structural
proteins of the cell.
Chemical
Steps in Protein Synthesis. Some of the chemical events that occur in synthesis
of a protein molecule are shown in Figure. This figure shows representative
reactions for three separate amino acids, AA1, AA 2, and AA20.The stages of the
reactions are the following:
(1) Each
amino acid is activated by a chemical process in which ATP combines with the
amino acid to form an adenosine monophosphate complex with the amino acid,
giving up two high-energy phosphate bonds in the process.
(2) The
activated amino acid, having an excess of energy, then combines with its
specific transfer RNA to form an amino acid tRNA complex and, at the same time, releases
the adenosine monophosphate.
(3) The
transfer RNA carrying the amino acid complex then comes in contact with the
messenger RNA molecule in the ribosome, where the anticodon of the transfer RNA
attaches temporarily to its specific codon of the messenger RNA, thus lining up
the amino acid in appropriate sequence to form a protein molecule. Then, under
the influence of the enzyme peptidyl transferase (one of the proteins in the
ribosome), peptide bonds are formed between the successive amino acids, thus
adding progressively to the protein chain. These chemical events require energy
from two additional high-energy phosphate bonds, making a total of four high-energy
bonds used for each amino acid added to the protein chain. Thus, the synthesis
of proteins is one of the most energy-consuming processes of the cell.
Peptide Linkage
The
successive amino acids in the protein chain combine with one another according to
the typical reaction:
In this
chemical reaction, a hydroxyl radical (OH–) is removed from the COOH portion of
the first amino acid, and hydrogen (H+) of the NH2 portion of the other amino acid is
removed. These combine to form water, and the two reactive sites left on the
two successive amino acids bond with each other, resulting in a single
molecule. This process is called peptide linkage. As each additional amino acid
is added, an additional peptide linkage is formed.
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