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NUCLEIC ACIDS

I. GENERAL DESCRIPTION

Polymeric molecules in which repeating unit is a nucleotide

Discovered by Swiss physiologist, Friedrich Miescher (1844-1895) in 1969 while studying the nuclei ofWBCs

The fact that they were initially found in the cell nuclei and were acidic accounts for the name nucleicacid

II. TYPES OF NUCLEIC ACIDS

Phosphate + Base + Sugar

Phosphate + Sugar = NUCLEOSIDE Nucleoside + Base = NUCLEOTIDE

FIGURE 1 Components of a Nucleic Acid (DNA)

Backbone of DNA/RNA always the same VARIABLE: A, U, C, G, T

FIGURE 1A Components of a Nucleic Acid

1. Deoxyribonucleic acid (DNA)

Primary function is the storage and transfer of genetic information (is widely used directly to control

many functions in the living cells)

2. Ribonucleic acid (RNA)

Primarily functions in protein synthesis, the molecules that carry out essential cellular functions

FIGURE 1B Ribonucleotide (RNA) and Deoxyribonucleotide (DNA)

Prepared by: Sunshine A. Tayaotao, RPh 2010 Page

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BASIS RNA DNA SugarBases (Pyrimidine)Strands# of nucleotides

TABLE 1 Major differences between RNA and DNA

III. NUCLEOTIDES: Building Blocks of Nucleic Acids Molecule composed of a pentose sugar bonded to both a phosphate group and a nitrogen-containing

heterocyclic base

FIGURE 2A Building Blocks of Nucleic Acids

(Fused ring) (Single hetero cyclic ring)FIGURE 2B General Structure of Nitrogen Bases

A. 3 PARTS OF NUCLEOTIDES:

1. Pentose Sugar

Sugar unit of nucleotide is either the pentose ribose (RNA) or 2-deoxyribose (DNA)

2. Nitrogen-containing bases/Heterocyclic basei. Purine

o Bi-cyclic base with fused five-and-six member rings

a. Adenine (A): 6-amino-purineb. Guanine (G): 2-amino-oxypurine

ii. Pyrimidineo Monocyclic base with a six-member ring

o RNA: Cytosine and Uracil

o DNA: Cytosine and Thymine

a. Thymine (T): 2,4-dioxy-5-methylpyrimidineb. Cytosine (C): 2-oxy-4-aminopyrimidine

c. Uracil (U): 2,4-dioxypyrimidine

3. Phosphate

Third component of nucleotide, derived from phosphoric acid (H3PO4)

An important nucleotide is adenosine monophosphate (AMP) formed from a reaction of adenosine (anucleotide) and one molecule of phosphoric acid


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B. NUCLEOTIDE FORMATION

FIGURE 4 Nucleotide Formation

Important characteristics of this combining of three molecules into one molecule (nucleotide) are:1. Dehydration (formation of water molecule) occurs at two locations: between the sugar and base, and

between the sugar and phosphate.2. The base is always attached at the C1 position of the sugar. For purine bases, attachment is through N9

for pyrimidine bases, N1 is involved. The C1 carbon atom of the ribose unit is always in configuration.3. The phosphate group is usually attached to the sugar at C5 position through the phosphate-ester-

linkage

C. NUCLEOTIDE NOMENCLATURE

1. All of the names end in 5-monophosphate, which signifies the presence of a phosphate group attachedto the 5-carbon/atom of ribose or deoxyribose2. Preceding the monophosphate ending is the name of the base present in the modified form. The suffix

osine is used for purine bases, the suffix idinewith the pyrimidine bases.3. The prefix deoxy at the start of the name signifies that the sugar present is deoxyribose, when no

prefix is used, the sugar is ribose.4. The abbreviations in the table for the nucleotides come from the one-letter symbol for the bases (A, C,

G, T and U); the use of MP for monophosphate and a lower case d at the start of the abbreviationwhenever deoxyribose is the sugar

BASE SUGAR NUCLEOTIDE NAME ABBREV.DNA Nucleotides

Adenine DeoxyriboseGuanine DeoxyriboseCytosine DeoxyriboseThymine DeoxyriboseRNA Nucleotides

Adenine RiboseGuanine RiboseCytosine RiboseUracil Ribose

TABLE 2 Names of Eight Nucleotides found in DNA and RNA

D. PRIMARY STRUCTURE OF NUCLEIC ACIDS

Nucleic Acid Backboneo The alternating sugar phosphate chain in nucleic acid structure.

o Constant all throughout the entire structure

DNA Backbone

RNA Backbone


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Deoxyribo

Deoxyribo

Deoxyribo

Phospha

Phospha

Ribose RiboseRibosePhospha Phospha


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FIGURE 3 Directionality of Nucleic Acid Backbone

PRIMARY STRUCTURE OF A NUCLEIC ACID: The Sequence of Nucleotides in the Molecule1. Each non-terminal phosphate group of the sugar-phosphate backbone is bonded to two sugar

molecules through a 35-phosphodiester linkage. There is a phosphoester bond to the 5 carbon ofone sugar unit and a phosphoester bond to the 3 carbon of the other sugar.

2. A nucleotide chain has directionality: one end of the nucleotide chain, the 5 end, normally carries afree phosphate group attached to the 5 carbon atom. The other end of the nucleotide chain, the 3end, normally has a free hydroxyl group attached to the 3 carbon atom. By convention, thesequence of bases of a nucleic acid strand is read from the 5 end to the 3 end.

3. Each non-terminal phosphate group in the backbone of a nucleic acid carries a -1 charge. The parentphosphoric acid molecule from which the phosphate was derived originally had three OH groups.

Two of these become involved in the 3,5-phosphodiester linkage. The remaining OH group is freeto exhibit acidic behavior that is, to produce a H+ ion.


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FIGURE 3A Nucleotide Sequence

E. THE DNA DOUBLE HELIX

The Watson-Crick Model of DNA

Proposed a double-coiled consisting of two strands intertwined around one another and heldtogether by hydrogen bonds, much like two entwined rails from spiral staircase

The solid lines

Dotted lines

All DNA molecules have the same sequence of deoxyribose and phosphates in the ladder part ofthe chain, the difference lies in the order of the adenine, thymine, cytosine and guanine parts of thechain makes up genetic code.

FIGURE 4A Watson-Crick Model of the DNA

FIGURE 4B Hydrogen Bonded Base Pairs

BASE PAIRING

Chargaffs Ruleo Number of Purine molecules = Number of Pyrimidine molecules

A = T

G C

Complementary Baseso Specific pairs of bases in nucleic acid structures that hydrogen-bond to each other

o Two strands of DNA in double helix are complementary.o DNA A C G T

o RNA A C G U

F. REPLICATION OF DNA MOLECULES:

CHROMOSOMES

Individual DNA molecule bound to a group of molecule


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These are nucleoproteins; they are combinations of nucleic acid (DNA) and various proteins.

15% by mass DNA and 85% by mass proteins

FIGURE 5A Chromosomes

DNA REPLICATION

Process by which DNA molecules produce exact duplicates of themselves.

Semi-conservative replication

o Produces two new DNAs (daughter strand DNAs) identical to each other and exact copies of the

original parent DNA

o Strands are identical to original due to complementary base pairing

Complementary base pairing ensures the correct placement of bases in the new DNA strands

Helicase

o Unwinds/uncoils DNA helix and splits double strand

Single-Strand Binding Proteins (SSB)

o A single-strand binding-protein stabilizes the separated strands, and prevents them from

recombining, so that the polymerization chemistry can function on the individual strands.

DNA polymerase

o Energy is provided to join each new nucleotide to the backbone of a growing DNA strand

o Catalyzes the replication process at each of these open DNA sections (replication forks)

o Catalyzes only phosphodiester bonds between the 5-phosphate of one of the nucleotide and the

3-hydroxyl of the next, which means that DNA polymerases have to move in opposite directions

along the separated strands of DNA

o Binds complementary bases

a. Leading strand(5 to 3 direction)

Replication is continuous

b. Lagging strand(3 to 5 direction)

Synthesized in the opposite direction

Formed in short segment of 100-200 nucleotides (Okazaki fragments)


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Grows in direction of 53 because DNA polymerase III only works in the 53

RNA Primaseo Places an RNA primer near fork

o Bonds the RNA nucleotides together

RNA primero Short sequence of RNA nucleotides, complementary to a small, initial section of the DNA strand

being prepared for replicationo Adds short RNA strand to DNA

o Made by adding complimentary RNA nucleotides to the lagging DNA strand by hydrogen

bonding of the bases

o Enzymatically removed and replaced with an appropriate sequence of DNA nucleotides

FIGURE 5A Initiation of Replication by RNA primerand RNA primase

DNA polymerase IIIo Initiates replication process; Bonds DNA nucleotides to the RNA primer

o Adds nucleotides in 5 3 direction (lagging strand)

FIGURE 5B Formation of Okazaki fragments

DNA polymerase Io Removes the RNA primers creating Okazaki fragments and replaces it with DNA

Okazakifragments

DNA ligaseo Adds DNA nucleotides to fill the gaps between Okazaki fragments and connect lagging strand

fragments by creating sugar-phosphate bond


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FIGURE 5C Replication fork, Leading and Lagging strand

FIGURE 5D Summary of DNA Replication

RIBONUCLEIC ACIDS (RNA)a. RIBOSOMAL RNA (rRNA)o Combines with a series of proteins to form complex structures called ribosomes, that serves as

the physical sites or platform for protein synthesis

b. MESSENGER RNA (mRNA)o Carries genetic information (instructions for protein synthesis) from DNA to ribosome

o Primary Transcript RNA (ptRNA)

Material from which messenger RNA (mRNA) is made

c. TRANSFER RNA (tRNA)o Delivers specific individual amino acids to the ribosomes, the sites of protein synthesis

c. OVERVIEW OF PROTEIN SYNTHESIS

FIGURE 6A Protein Synthesis


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1. TRANSCRIPTION

Process by which DNA directs the synthesis of RNA molecules that carry the coded information neededfor protein synthesis

Begins when the section of a DNA molecule that contains the gene to be copied unwinds, whichcontains a transcription bubble

Steps:a. A portion of the DNA double helix unwinds, exposing some bases. The unwinding process is

governed by the enzyme RNA polymerase rather than by DNA helicase (replication enzyme)b. Free ribonucleotides align along one of the exposed strands of DNA bases forming new base pairs.

In this process, U rather than T aligns with A in the base-pairing process. Because ribonucleotidesrather than deoxyribonucleotides are involved in the base-pairing, ribose rather than deoxyribose,

becomes incorporated into the new nucleic acid backbone.c. RNA polymerase links the aligned ribonucleic acids.d. Transcription ends when the RNA polymerase encounters a sequence of bases that is read as a

stop signal. The newly formed RNA molecules and the RNA polymerase enzyme are released, andthe RNA polymerase enzyme are released and the DNA then rewinds to reform the original double

bonds.

In DNA-RNA base pairing, the complementary base pairs are:o DNA

o RNA

RNA molecules contain the base U instead of To The primary function of mRNA molecules is to direct the synthesis of the many different

proteins needed for cellular function. Within a DNA strand are instructions for the synthesis ofnumerous mRNA molecules. During transcription, the DNA molecule unwinding is controlled

by RNA polymerase and occurs only at the particular spot where the appropriate base sequenceis found for the mRNA (and protein) of concern. Such short segments of DNA, containinginstructions for the formation of particular mRNAs are called genes

o Gene is a segment of DNA molecule that contains the base sequence for the production of singlespecific protein molecule.

It is now known that not all bases in a gene convey genetic information. Instead, a gene is segmented inportions called exons that contain genetic information and portions called introns that convey

genetic informationo EXON DNA segment that conveys (codes for) genetic information and helps express a genetic

message.o INTRON DNA segment that does not convey (code for) genetic information and interrupt a

genetic message.

Both exons and introns of a gene are transcribed during production of primary transcript RNA (ptRNA)or pre-mRNA. The ptRNA is then edited, under the direction of enzymes to remove introns. Theremaining exons are joined together to form a shortened RNA strand that carries the geneticinformation of the transcribed gene. This edited RNA is the messenger RNA (mRNA) that serves as a

blueprint for protein assembly.

2. TRANSLATION

Process by which the codes within the RNA molecules are decipheral and a particular molecule isformed.

Process whereby the nucleotide sequence in an mRNA molecule specifies the amino acid sequence ofprotein. Ribosome in the cytoplasm carries out translation.

CODON

ANTICODONa. ACTIVATION OF tRNA

o An amino acid interacts with an activator molecule (ATP) to form a highly energetic complex.This complex that reacts with an appropriate tRNA molecule to produce an activated tRNAmolecule that has an amino acid covalently bonded to it at its 3 end through an ester linkage

b. INITIATIONo Begins with mRNA which attaches itself to the surface of a small ribosomal subunit such that its

first codon, which is always the initiating codon AUG; occupies a site called the P site (peptidylsite)

c. ELONGATIONo The polypeptide continues to grow by way of translation until all necessary amino acids are in

place and bonded to each other.d. TERMINATION

o Appearance in the mRNA codon sequence of one of the three stop codons (UAA, UAG, or UGA)terminates the process

e. POST-TRANSLATION PROCESSING


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o Some modification of proteins usually occurs after translation

THE GENETIC CODE

1. The genetic code is highly degenerated that is many amino acids designated by more than onecodon. Codons that specify the same amino acids are called synonyms

2. There is a pattern to the arrangement of the genetic code table3. The genetic code is almost universal, the same codon specifies the same amino acid whether the cell

is a bacterial cell, a corn plant cell, or a human cell4. An initiation codon exists

o Stop codons

o Start codon

First Position (5end)

Second Position Third Position (3end)A C G U

A Lys Thr Arg Ile AAsn Thr Ser Ile CLys Thr Arg Met/Start G

Asn Thr Ser Ile UC Gln Pro Arg Leu A

His Pro Arg Leu CGln Pro Arg Leu GHis Pro Arg Leu U

G Glu Ala Gly Val AAsp Ala Gly Val CGlu Ala Gly Val G

Asp Ala Gly Val UU Stop Ser Stop Leu A

Typ Ser Cys Phe CStop Ser Trp Leu G

tyr Ser Cys Phe UTABLE 3 mRNA codons: The Genetic Code for Amino Acids

mRNA 5- GCC AUG GUA AAA UGC GAC CCA 3


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FIGURE 6B Steps in Transcription


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FIGURE 6B Steps in Transcription

GENETIC MUTATIONS:

Occurs if one of the code letters is omitted or if one is added or if the order of the code letters isrearranged. Such a change in the sequence of nucleotides may:

1. Give no detectable effect, particularly of the change is in the third letter of the code.

2. Cause a different amino acid to be incorporated into the chain (the results may be acceptable, ortotally unacceptable to the function of the protein)3. Cause the termination of the chain prematurely so that the protein cannot normal.

Causes:1. Exposure to radiation2. Because of naturally occurring radiation and cosmic rays3. Exposure to certain chemicals

Types:1. Frameshift Mutation


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Usually severe, producing a completely nonfunctional protein.

2. Point Mutation

Involves a single nucleotide, thus a single amino acid.

3. Silent, Missense, and Nonsense Mutationsa. Missense mutation b. Nonsense mutation c. Silent mutation

GENETIC DISEASES:

Mostly caused by defective gene resulting in a loss of activity of some enzyme

1. CYSTIC FIBROSIS

Thick mucus develops and results in bronchia. Obstruction early in childhood infection occurs andbecomes difficult to eradicate even with antibiotics. When such an infection develops in the lungs, thesubsequent inflammatory reaction results in the destruction of bacteria. Leukocytes and tissue, theprocess of cellular destruction releases DNA, which in turn substantially increases the viscosity of themucus.

Treatment DNAse, an enzyme that degrades extracellular DNA nut has no effect on the DNA withinintact cells

2. PHENYLKETANURIA (PKU)

Results when the enzyme phenylalanine hydroxylase is absent. A person with PKU cannot convertphenylalanine to tyrosine, and so the phenylalanine accumulates in the body, resulting in injury to thenervous system. In children up to 6, an accumulation of phenylalanine leads to retarded mentaldevelopment. It can be readily diagnosed from a sample of blood or urine.

Treatment Consists of giving the affected person a diet low in phenylalanine and adding tyrosine tothe diet.

3. SICKLE CELL ANEMIA

Sickle cells (containing hemoglobin) are fragile than normal red blood cells which leads to anemia. Theycan also occlude capillaries, leading to thrombosis. Sickle cells in the capillaries cause slowing andsludging of the red blood cells in the capillaries, with resulting hypoxia of the tissues which in turnproduces symptoms like fever, swelling, and pain in various parts of the body.

A defective Hgb from a mutation in a gene in chromosome 11 decreases the oxygen carrying ability ofRBC which takes on a sickle shape, causing anemia and plugged capillaries from RBC segregation.

4. GALACTOSEMIA

Results from the lack of enzyme uridyl transferase, which catalyzes the formation of glucose fromgalactose. This disease may result in an increased concentration of galactose in the blood. Galactose inthe blood is reduced in the eye to galacticol, which accumulates and causes a cataract, even liver failureand mental retardation will occur.

Transfer of enzyme requuired for the metabolism of glucose-1-phosphate is absent. Accumulation ofGal-1-P leads to cataracts and mental retardation.

Treatment Administration of galactose free diet

5. WILSONS DISEASE

Caused by the bodys failure to eliminate excess Cu2+ ions because of a lack of ceruplasmin or failure inthe bonding of copper ions to the copper-bonding globulin or both. In this disease, copper accumulatesin the liver, kidneys and brain. Increased copper in the kidneys may lead to damage of the renal tubules,leading to increased urinary output of amino acids and peptides.

6. ALBINISM

Caused by lack of enzyme tyrosinase, which is necessary for the formation of melanin, the pigment of

the hair, skin, and eyes. Although the disease is not serious, persons affected by it are very sensitive tosunburn.

7. HAEMOPHILIA

Caused by a missing protein, an antihemophilic globulin, which is important in the normal clottingprocess of the blood. Consequently, any cut may be life threatening to hemophiliacs, but the primarydamage is the crippling effect of repeated episodes of internal bleeding into body joints.

One or more defective blood clotting factors lead to poor coagulation, excessive bleeding, and internalhemmorhages.


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8. MUSCULAR DYSTROPHY (MD)

Duchennes muscular dystrophy, one of 10 forms of MD, is caused by the lack of protein calleddystrophin, as caused by a mutation in the X chromosome. This disease primarily affects boys at aboutage 5 with death by age 20. It causes progressive weakness and muscle wasting.

9. DOWN SYNDROME

The leading cause of mental retardation, occuring in about 1 in every 100 live births, although themothers age strongly influences its occurrence. Mental and physical problems including heart and eyedefects are the result of the formation of three chromosomes, usually Chromosome 21, instead of a pair.

10. FAMILIAL HYPOCHOLESTEREMIA

A mutation of a gene on chromosome 19 results in high cholesterol levels that leads to early CoronaryHeart Disease in people 30-40 years old.

11. HUNTINGTONS DISEASE (HD)

Appearing in middle age, affects the nervous system, leading to total physical impairment. It is theresult of a mutation in a gene on chromosome 4, which can now be mapped to test people in families

with HD.

12. TAY-SACHS DISEASE

Hexosamindase A is defective, causing an accumulation of gangliosides resulting in mental retardation,loss of motor control, and early death.

TREATMENT OF GENETIC DISEASES:1. Correct the metabolic consequences of the disease by supplying the missing product.2. Replace the missing enzyme or hormone.3. Remove excessive stored substances4. Correct the major genetic abnormality.


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