The document discusses nucleic acids, specifically DNA and RNA, covering their structure, synthesis, properties, and roles in protein synthesis. It outlines the history of DNA as the genetic material, experiments that led to its discovery, and the differences between RNA and DNA. Additionally, it highlights the importance of nucleotides, their analogues in clinical applications, and the primary and secondary structures of nucleic acids.

1. Nucleic Acids
Prepared by
Nathan Kiboi
Ph. D. (c) MMUST
1

2. Objectives
• Hx and Introduction of Nucleic Acids
• To classify Nucleic acids and learn the structural
differences of different groups
• To discuss the physical and chemical properties of
Nucleic acids
• To discuss the synthesis and degradation of
Nucleic acids in brief.
• Application & Clinical Relevance in brief
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3. Introduction
• Nucleic acids are molecules that store
information for cellular growth and reproduction
• There are two types of nucleic acids:
- deoxyribonucleic acid (DNA) and ribonucleic
acid (RNA)
• These are polymers consisting of long chains of
monomers called nucleotides
• A nucleotide consists of a nitrogenous base, a
pentose sugar and a phosphate group:
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4. DNA
• Stands for Deoxyribonucleic acid
• Made up of subunits called
nucleotides
• Nucleotide made of:
1. Phosphate group
2. 5-carbon sugar
3. Nitrogenous base
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5. History of DNA
• Early scientists thought protein was
the cell’s hereditary material because
it was more complex than DNA
• Proteins were composed of 20
different amino acids in long
polypeptide chains.
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6. • Transformation
• Fred Griffith worked with virulent S and
nonvirulent R strain Pneumoccocus
bacteria
• He found that R strain could become
virulent when it took in DNA from heat-
killed S strain
• Study suggested that DNA was probably
the genetic material
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7. Griffith Experiment
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8. Hx of DNA cont…
• Chromosomes are made of both
DNA and protein
• Experiments on bacteriophage
viruses by Hershey & Chase
proved that DNA was the cell’s
genetic material
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Radioactive 32P was injected into bacteria!

9. Genes are composed of DNA
 A gene is a specific sequence of nucleotides along
the DNA strand
 Consists of a promotor, coding and terminator
region
 A gene can code for
 mRNA (used to make proteins from amino acids at
ribosomes)
 rRNA (synthesized in the nucleolus in eukaryotes)
 tRNA (brings specific single amino acids to the ribosomes)
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Binds RNA-polymerase Indicates end of gene
Promoter Terminator
Coding region

10. What is DNA?
• Sequence of nucleotides
– Base: Adenine, thymine,
cytosine, and guanine
– Deoxyribose (sugar)
– Phosphate
• Double helix associated with
proteins
• Strands held together by
hydrogen bonds between AT
and CG
• Strands antiparallel
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11. DNA
• Two strands coiled called a double helix
• Sides made of a pentose sugar Deoxyribose
bonded to phosphate (PO4) groups by
phosphodiester bonds
• Center made of nitrogen bases bonded
together by weak hydrogen bonds
• Most DNA has a right-hand twist with 10 base
pairs in a complete turn
• Hot spots occur where right and left twisted
DNA meet producing mutations
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12. DNA DOUBLE HELIX
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“Rungs of ladder”
Nitrogenous
Base (A,T,G or C)
“Legs of ladder”
Phosphate &
Sugar Backbone
Double Helix

13. Antiparallel Strands
• One strand of DNA goes
from 5’ to 3’ (sugars)
• The other strand is
opposite in direction going
3’ to 5’ (sugars)
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14. Characteristics of DNA
• Both alkali and heat cause the two strands of
the DNA helix to separate (denature).
• Many techniques employed to study DNA or
to produce recombinant DNA molecules make
use of this property.
• Although alkali causes the two strands of DNA
to separate, it does not break the
phosphodiester bonds.
• In contrast, the phosphodiester bonds of RNA
are cleaved by alkali.
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15. • Therefore, alkali is used to remove RNA from
DNA and to separate DNA strands before, or
after, electrophoresis on polyacrylamide or
agarose gels.
***Effect of alkali on DNA and RNA.
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16. Properties of DNA
• Heat alone converts double-stranded DNA to
single-stranded DNA.
• The separation of strands is called melting,
and the temperature at which 50% of the DNA
is separated is called the Tm.
• If the temperature is slowly decreased,
complementary single strands can realign and
base-pair, re-forming a double helix essentially
identical to the original DNA.
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17. Hybridization
• This process is known as renaturation,
reannealing, or hybridization.
• The process by which a single-stranded DNA
anneals with complementary strands of RNA is
also called hybridization.
• Hybridization is used extensively in research
and clinical testing.
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18. Hybridization of DNA and
complementary RNA.
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19. General Features of RNA
• RNA is similar to DNA.
• Like DNA, it is composed of nucleotides
joined by 3’- to 5’-phosphodiester bonds, the
purine bases adenine and guanine, and the
pyrimidine base cytosine.
• However, its other pyrimidine base is uracil
rather than thymine.
• Uracil and thymine are identical bases except
that thymine has a methyl group at position 5
of the ring. Sugar is ribose.
• Ribose sugar in DNA lacks hydroxyl group at 2’
19

20. Comparison of the structures of
Uracil and thymine.
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21. RNA vs. DNA
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*Ribose sugar in DNA lacks hydroxyl group at 2’
Carbon
*RNA more abundant than DNA molecules

22. General Features of RNA
• RNA chains are usually single-stranded and
lack the continuous helical structure of
double-stranded DNA.
• However, RNA still has considerable secondary
and tertiary structure because base pairs can
form in regions where the strand loops back
on itself.
• As in DNA, pairing between the bases is
complementary and antiparallel.
• But in RNA, adenine pairs with uracil rather
than thymine
• RNA molecules are smaller than those of DNA
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23. RNA Types
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24. RNA types
• Ribosomal RNA; Ribosomes are the sites of
protein synthesis
- they consist of ribosomal DNA (65%) and
proteins (35%)
- they have two subunits, a large one and a
small one
Messenger RNA; carries the genetic code to the
ribosomes
- they are strands of RNA that are
complementary to the DNA of the gene for the
protein to be synthesized
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25. • Transfer RNA; translates the genetic code
from the messenger RNA and brings specific
amino acids to the ribosome for protein
synthesis
-Each amino acid is recognized by one or more
specific tRNA
-tRNA has a tertiary structure that is L-shaped
- one end attaches to the amino acid and the
other binds to the mRNA by a 3-base
complimentary sequence
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26. RNA Polymerase
• During transcription, RNA polymerase moves
along the DNA template in the 3’-5’direction to
synthesize the corresponding mRNA
• The mRNA is released at the termination point
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27. Protein synthesis
• The two main processes involved in protein synthesis are
- the formation of mRNA from DNA (transcription)
- the conversion by tRNA to protein at the ribosome
(translation)
• Transcription takes place in the nucleus, while translation takes
place in the cytoplasm
• Genetic information is transcribed to form mRNA much the
same way it is replicated during cell division
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28. Discovery of DNA Structure
• Erwin Chargaff showed the amounts of the
four bases on DNA ( A,T,C,G)
• In a body or somatic cell:
 A = 30.3%
 T = 30.3%
 G = 19.5%
 C = 19.9%
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29. Chargaff’s Rule
• Adenine must pair with Thymine
• Guanine must pair with Cytosine
• The bases form weak hydrogen bonds
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T A G C

30. Nitrogenous Bases
• The nitrogen bases in nucleotides consist of two
general types:
- Purines: adenine (A) and guanine (G)
- Pyrimidines: cytosine (C), thymine (T) and
Uracil (U)
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31. Nitrogenous Bases
• Double ring PURINES
Adenine (A)
Guanine (G)
• Single ring PYRIMIDINES
Thymine (T)
Cytosine (C)
NB; Other purines (Hypoxanthine and Xanthine)
-Other Pyrimidines (Orotic acid)
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32. Base-Pairings
• Purines only pair with Pyrimidines
• Three hydrogen bonds required to bond
Guanine & Cytosine
• Two hydrogen bonds required to bond
Adenine & Thymine
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C
G
3 H-bonds
T A
2 H-bonds

33. DNA Nucleotide
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Nitrogenous base
(A, G, C, or T)
N
C1
C2
C3
C4
O
CH2
5
Sugar
(deoxyribose)
Phosphate
Group
O
O=P-O
O
O
O=P-O
O

34. Pentose Sugars
• There are two related pentose sugars:
- RNA contains ribose
- DNA contains deoxyribose
• The sugars have their carbon atoms numbered
with primes to distinguish them from the
nitrogen bases
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35. Pentose Sugars
D-Ribose and 2’-Deoxyribose
*Lacks a 2’-OH group
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36. Pentose Sugars
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NB; Carbons are numbered clockwise 1’ to 5’
CH2
C1
C2
C3
C4
5
Sugar
(deoxyribose)
O

37. Nucleosides and Nucleotides
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•A nucleoside consists of a nitrogen base linked by a glycosidic
bond to C1’ of a ribose or deoxyribose.
•Nucleosides are named by changing the the nitrogen base
ending to -osine for purines and –idine for pyrimidines
•Nucleotides result from linking a phosphate to a nucleoside
onto the C5’ OH group of ribose or deoxyribose by esterification.
•Nucleotides are named using the name of the nucleoside
followed by 5’-monophosphate

38. • linking one of the sugars with a purine or
pyrimidine base through an N-glycosidic
linkage
• Purines bond to the C1’ carbon of the sugar at their
N9 atoms
• Pyrimidines bond to the C1’ carbon of the sugar at
their N1 atoms
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39. Names of Nucleosides and Nucleotides
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40. Ribonucleosides
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41. Bases, nucleosides, and nucleotides
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42. Phosphorilation (AMP, ADP & ATP)
• Additional phosphate groups can be added to the
nucleoside 5’-monophosphates to form diphosphates
and triphosphates
• Phosphates can be bonded to either C3 or C5 atoms of
the sugar.
• ATP is the major energy source for cellular activity
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43. Importance of Nucleotides
(1). Are the sources of energy that drive most of our reactions.
• ATP- is the most commonly used source (energy
currency)
• GTP- is used in protein biosynthesis as well as a
few other reactions.
• UTP - is the source of energy for activating
glucose and galactose.
• CTP - is an energy source in lipid metabolism.
• AMP- is part of the structure of some of the
coenzymes like NAD and Coenzyme A.
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44. 1/22/2023 44
(2). Nucleotides are part of nucleic acids.
• Neither the bases nor the nucleotides are
required dietary components.
• Humans synthesize both of them thro’ de novo
and salvage pathways and reuse. The major
site of purine synthesis is in the liver.
(3) Many nucleotide analogues are chemically
synthesized (Synthetic nucleotide analogues)
and used for their chemotherapeutic potential.
• The nucleotide analogues can be utilized to
inhibit specific enzymatic activities.

45. • Synthetic analogs of purines, pyrimidines,
nucleosides, and nucleotides altered in either
the heterocyclic ring or the sugar moiety have
numerous applications in clinical medicine.
• Their toxic effects reflect either inhibition of
enzymes essential for nucleic acid synthesis or
their incorporation into nucleic acids with
resulting disruption of base-pairing.
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46. • Analogues are used as anti-tumor (cytotoxic)
agents because they interfere with the synthesis
of DNA. eg 5- Fluorouracil, Dactinomycin etc..
• NB; Oncologists employ:
• 5-fluoro- or 5-iodouracil,
• 3-deoxyuridine,
• 6-thioguanine and 6-mercaptopurine,
• 5- or 6-azauridine, 5- or 6-azacytidine,
• and 8-azaguanine which are incorporated into
DNA prior to cell division.
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47. *Selected synthetic pyrimidine and
purine analogs.
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48. *Selected synthetic pyrimidine and
purine analogs.
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49. (4). Second messenger (adenosine
derivatives)
• The most common adenosine derivative is the
cyclic form, 3'-5'-cyclic adenosine
monophosphate, cAMP. cAMP is a second
messenger in body cells.
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50. (5). Coenzymes (NAD+ and NADP+), Coenzyme A
• Nicotinamide adenine dinucleotide (NAD+) and
nicotinamide adenine dinucleotide phosphate
(NADP+ ) are important electron acceptors in
cellular respiration.
• The two coenzymes play a role in reactions
involving transfer of hydrogen atoms.
– NAD+ + 2H+ NADH + H
– NADP+ + 2H+ NADPH + H
• The two coenzymes are derived from niacin
(vitamin B3)
• Nicotinic acid and nicotinamide can serve as the
dietary source of vitamin B3.
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51. Forms of Niacin
• NB; Nicotinic acid and nicotinamide can serve as
the dietary source of vitamin B3.
• Vit B3 ;It is resistant to heat and light and to
both acid and alkali environments.
• Deficiency may cause pellagra, dermatitis, 51
Nicotinic Acid Nicotinamide

52. Structure of NAD+
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The - OH phosphorylated in
NADP+ is indicated by the red
arrow.
NADH

53. Primary Structure of Nucleic Acids
• The primary structure of a nucleic acid is the nucleotide
sequence
• The nucleotides in nucleic acids are joined by phosphodiester
bonds
• The 3’-OH group of the sugar in one nucleotide forms an ester
bond to the phosphate group on the 5’-carbon of the sugar of
the next nucleotide
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54. Reading Primary Structure
• A nucleic acid polymer has
a free 5’-phosphate group
at one end and a free 3’-OH
group at the other end
• The sequence is read from
the free 5’-end using the
letters of the bases
• This example reads
5’—A—C—G—T—3’
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55. Example of RNA Primary Structure
• In RNA, A, C, G, and U are linked by 3’-5’ ester
bonds between ribose and phosphate
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56. Example of DNA Primary Structure
• In DNA, A, C, G, and T are linked by 3’-5’ ester
bonds between deoxyribose and phosphate
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57. Secondary Structure: DNA Double Helix (review)
• In DNA there are two strands of nucleotides that wind together
in a double helix
- the strands run in opposite directions
- the bases are are arranged in step-like pairs
- the base pairs are held together by hydrogen bonding
• The pairing of the bases from the two strands is very specific
• The complimentary base pairs are A-T and G-C
- two hydrogen bonds form between A and T
- three hydrogen bonds form between G and C
• Each pair consists of a purine and a pyrimidine, so they are the
same width, keeping the two strands at equal distances from
each other
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58. Nucleotide Biosynthesis/Metabolism
A) De novo pathway
De novo is a Latin
phrase, meaning
"from the new," anew,
from scratch, or from
the beginning.
De novo synthesis refers
to the synthesis of
complex molecules
from simple molecules
such as sugars or
amino acids, as
opposed to their
being recycled after
partial degradation
1/22/2023 58
B) Salvage pathway
Is a pathway in which
nucleotides are
synthesized from
intermediates in the
degradative pathway for
nucleotides
The salvage pathways
are a major source of
nucleotides for synthesis
of DNA, RNA and
enzyme co-factors.

59. Nucleotide metabolism
• PURINE RIBONUCLEOTIDES: formed De novo
– i.e., purines are not initially synthesized as free
bases
– First purine derivative formed is Inosine Mono-
phosphate (IMP)
• The purine base is hypoxanthine
• AMP and GMP are formed from IMP
• Purine Nucleotides
-Get broken down into Uric Acid (a purine)
• Ingested nucleic acids are degraded to
nucleotides by pancreatic nucleases, and
intestinal phosphodiesterases in the intestine
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60. • NB: Most ingested nucleic acids are degraded and
excreted.
• Group-specific nucleotidases and non-specific
phosphatases degrade nucleotides into
nucleosides.
• Nucleotides broken into nucleosides by action
of 5’-nucleotidase (hydrolysis reactions).
• Purine nucleoside phosphorylase (PNP)
– Inosine  Hypoxanthine
– Xanthosine  Xanthine
– Guanosine  Guanine
– Ribose-1-phosphate splits off
• Adenosine is deaminated to Inosine (ADA)
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Intracellular purine catabolism

61. • Xanthine is the point of convergence for the
metabolism of the purine bases
• Xanthine  Uric acid
• Xanthine oxidase; A homodimeric protein
• Contains electron transfer proteins (Transfers electrons
to O2  H2O2)
– H2O2 is toxic
– Disproportionated to H2O and O2 by catalase
• Xanthine oxidase catalyzes two reactions;
– 1) Hypoxanthine is converted to Xanthine by
Xanthine Oxidase
– 2) Xanthine gets converted to Uric Acid by Xanthine
Oxidase
61

62. Uric Acid Excretion
• Nucleotidase; an enzyme that catalyses
hydrolysis of nucleotide to a nucleoside &
phosphoric acid.
• Catabolism of the purine nucleotides leads
ultimately to the production of uric acid
• Humans; Uric acid is insoluble & excreted in
urine as sodium urate crystals.
• Uric Acid  Allantoin  Allantoic Acid  Urea
 Ammonia (Final degradation to ammonia)
• Birds, terrestrial reptiles, some insects – excrete
insoluble crystals in paste form (conserves H20)
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63. Clinical significance of Purine metabolism
• Clinical problems associated with nucleotide
metabolism in humans are predominantly the result of
abnormal catabolism of the purines.
This is manifested in three disorders below:-
(i) Severe combined immunodefficiency – SCID (Due
to adenosine deaminase (ADA) deficiency which
catalyzes the deamination of adenosine to inosine).
(ii) Lesch-Nyhan syndrome - (results from loss of
functional HGPRT gene. Patients have severe
symptoms of gout but also a severe malfunction of the
nervous system.
(iii) Gout –Excess purine production & partial
deficiency in salvage enzyme (HGPRT; Hypoxanthine-
Guanine phosphoribosyl transferase (HGPRT)
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64. Gout
• Impaired excretion or overproduction of uric
acid
• Uric acid crystals (urate) as monosodium urate
(MSU) or calcium pyrophosphate dihydrate
(CPPD) crystals in the synovial fluid of the joints,
leading to severe inflammation and arthritis.
• Xanthine oxidase inhibitors inhibit production of
uric acid, and treat gout
• Allopurinol treatment – structural hypoxanthine
analog that binds to and strongly inhibits
Xanthine Oxidase to decrease uric acid
production
• NB; The salvage of pyrimidine bases has less
clinical significance than that of the purines
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65. Structure of Allopurinol
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ALLOPURINOL IS A XANTHINE OXIDASE INHIBITOR
A SUBSTRATE ANALOG IS CONVERTED TO AN
INHIBITOR, IN THIS CASE A “SUICIDE-INHIBITOR

66. Storage of DNA
• In eukaryotic cells (animals, plants, fungi) DNA is
stored in the nucleus, which is separated from the rest
of the cell by a semipermeable membrane
• The DNA is only organized into chromosomes during
cell replication
• Between replications, the DNA is stored in a compact
ball called chromatin, and is wrapped around proteins
called histones to form nucleosomes
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67. The flow of genetic information
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68. DNA Replication
• Involves transfer of the genetic information to
the next generation.
• When a eukaryotic cell divides, the process is
called mitosis
- the cell splits into two identical daughter cells
• 1 strand remains the parent strand, 1 strand is
newly synthesized.
• Mistakes only in 1/ 1010 bases!
• Direction
– In eukaryotes: uni-directional
– In prokaryotes: circular genome and bi-directional
replication
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69. • DNA replication involves several processes:
- first, the DNA must be unwound, separating the two
strands
- the single strands then act as templates for synthesis
of the new strands, which are complimentary in
sequence
- bases are added one at a time until two new DNA
strands that exactly duplicate the original DNA are
produced
• The process is called semi-conservative replication
because one strand of each daughter DNA comes from
the parent DNA and one strand is new
• The energy for the synthesis comes from hydrolysis of
phosphate groups as the phosphodiester bonds form
between the bases
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70. -Semi-Conservative DNA Replication
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71. -Direction of Replication (summary)
• The enzyme helicase unwinds several sections of parent
DNA
• At each open DNA section, called a replication fork,
DNA polymerase catalyzes the formation of 5’-3’ester
bonds of the leading strand
• The lagging strand, which grows in the 3’-5’ direction, is
synthesized in short sections called Okazaki fragments
• The Okazaki fragments are joined by DNA ligase to give
a single 3’-5’ DNA strand
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72. **Break-down (DNA Replication)
• Begins at Origins of Replication
• Two strands open forming Replication Forks (Y-
shaped region)
• New strands grow at the forks
• DNA is copied during the S or synthesis phase of
interphase
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Replication
Fork
Parental DNA Molecule
3’
5’
3’
5’

73. • Enzyme Helicase unwinds and separates the 2
DNA strands by breaking the weak hydrogen
bonds.
• Single-Strand Binding Proteins attach and keep
the 2 DNA strands separated and untwisted.
• Enzyme Topoisomerase attaches to the 2 forks
of the bubble to relieve stress on the DNA
molecule as it separates
• Before new DNA strands can form, there must
be RNA primers present to start the addition
of new nucleotides
• Primase is the enzyme that synthesizes the
RNA Primers
1/22/2023 73

74. 1/22/2023 74
• DNA polymerase can then add the new
nucleotides
• DNA polymerase can only add nucleotides to
the 3’ end of the DNA
• This causes the NEW strand to be built in a 5’ to
3’ direction
Direction of Replication
RNA
Primer
DNA Polymerase
Nucleotide
5’
5’ 3’

75. -Synthesis of new DNA strands
• The Leading Strand is synthesized as a
single strand from the point of origin
toward the opening replication fork
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RNA
Primer
DNA Polymerase
Nucleotides
3’
5’
5’

76. -Synthesis of new DNA strands
• The Lagging Strand is synthesized
discontinuously against overall direction of
replication
• This strand is made in many short segments & is
replicated from the replication fork toward the
origin.
76
RNA Primer
Leading Strand
DNA Polymerase
5’
5’
3’
3’
Lagging Strand
5’
5’
3’
3’

77. -Lagging strand segments
• Okazaki Fragments - series of short
segments on the lagging strand
• Must be joined together by an enzyme
1/22/2023 77
Lagging Strand
RNA
Primer
DNA
Polymerase
3’
3’
5’
5’

78. -Joining of Okazaki fragments
• The enzyme Ligase joins the Okazaki
fragments together to make one strand
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Lagging Strand
Okazaki Fragment 2
DNA ligase
Okazaki Fragment 1
5’
5’
3’
3’

79. -Replication of strands
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Replication
Fork
Point of Origin

80. Proofreading new DNA
• DNA polymerase initially makes about 1 in
10,000 base pairing errors
• Enzymes proofread and correct these
mistakes
• The new error rate for DNA that has been
proofread is 1 in 1 billion base pairing
errors
• Mistakes only in 1/ 1010 bases!
• Nb: DNA Poymerase; synthesizes DNA,
proofreads and repairs DNA. 80

81. Semiconservative Model of Replication
• Idea presented by Watson & Crick
• The two strands of the parental molecule
separate, and each acts as a template for a new
complementary strand
• New DNA consists of 1 PARENTAL (original) and
1 NEW strand of DNA
•
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Parental DNA
DNA Template
New DNA

82. Change in the genetic material
-Mediated by;
• Mutations
• Gene transfer and recombination
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83. Mutations
• Not-corrected errors during DNA replication
• Occur spontaneously rarely at 1/109 replicated base
pairs
• Lead to permanent changes in genotype
– If coupled to changes in proteins with altered function:
changes in phenotype
• Base substitutions (point mutations) can lead to
– Missense: one amino acid change with major consequences
• A T leads to glutamic acid  valine in hemoglobin:
sickle cell disease (SCD)
– Nonsense: can lead to stop of transcription
• Deletion or insertion of a few base pairs
– Frame shift mutation: shift translational reading frame,
major alterations in amino acid sequence, almost always
dysfunction protein results
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84. Types of mutations
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85. Consequences of Mutations in the
Microbial World
• Increased antibiotic resistance or loss
of antibiotic resistance
• Increased pathogenicity or loss of
pathogenicity
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86. DNA Damage and Repair
• Chemicals & ultraviolet (uv) radiation
damage the DNA in our body cells
• Cells must continuously repair DAMAGED
DNA
• Excision repair occurs when any of over 50
repair enzymes remove damaged parts of
DNA
• DNA polymerase and DNA ligase replace
and bond the new nucleotides together
1/22/2023 86

87.  Natural mutation rate is ~ 1 in
109 replicated base pairs (or in
106 replicated genes)
 Mutagens increase the rate of
mutations by factor 10 – 1000
 Chemical
 Point mutations
▪ Nitrous acid
▪ Nucleoside analogs
 Frame shift mutations
▪ Benzpyrene (smoke)
▪ Aflatoxin (Aspergillus flavus
toxin)
 Physical
 UV Radiation (Thymine
dimerization) 87

88. Vital enzymes for DNA replication
and repair
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89. Enzymes and Proteins Involved in DNA Replication
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90. 1/22/2023 90

91. THANK YOU……
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