Chapter 8 Nucleic Acids Metabolism

CHE220 - Introduction to Biochemistry

Dr. Rola Abboud

 GENERAL, ORGANIC, AND
• 11TH Edition BIOCHEMISTRY
• Katherine J. Denniston
• Danaè R. Quirk
• Joseph J. Topping
• Robert L. Caret

•Chapter 20
•Introduction to Molecular
Genetics

© McGraw Hill LLC. All rights reserved. No reproduction or distribution without the prior written consent of McGraw Hill LLC.
 20.1 The Structure of the Nucleotide
• DNA is deoxyribonucleic acid and RNA is
ribonucleic acid.
• Long polymers whose monomer units are called nucleotides.
• A nucleotide consists of:
1. Nitrogen containing heterocyclic base
• Purine.
• Pyrimidine.
2. Five-carbon sugar ring
• Ribose.
• Deoxyribose.
3. Phosphoryl group

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Functions of Nucleotides
• The availability of
nucleotides is essential to
all cells, because.
• Nucleotides are:
– precursors of nucleic acids
(The monomeric unit of nucleic
acid)
– The central molecules in
energy metabolism
– Intermediates in many
biosynthetic pathways
– Essential components of
signal transduction
pathways (cAMP)
• Hence the importance of
nucleotide synthesis
pathways to all living
cells.
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Functions of Nucleic Acids

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 Structure of the nucleotides making up nucleic acids.

The chemical structure of a nucleotides. A nucleotide comprises a five-carbon sugar molecule:

deoxyribose in DNA (A) and ribose in RNA (B). The carbon atoms on the sugar molecule are
numbered in red.
Deoxyribose (A) is different from ribose (B) in that it lacks an –OH group at carbon 2’. The 5’-
carbon atom is attached to a phosphate group (here a monophosphate in orange) and the 1’-carbon
is attached to a base (blue).
The main difference between nucleotides from DNA and those from RNA is the nature of the
sugar. Nucleotides making up RNA (B) contain ribose, making them ribonucleotides. In DNA,
however, the sugar lacks an –OH group at the 2’-carbon, making it deoxyribose and the
corresponding nucleotides deoxyribonuleotides.
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Nucleoside and Nucleotide Structures
• Nucleosides have only the base and the sugar
(no phosphate).
• Ring structures are found in both the base and
the sugar.
• Base rings are numbered as usual.
• Sugar ring numbers are given the designation′ or
prime.
• Bond between the base and the sugar is a
• β-N-glycosidic linkage joining the 1′-carbon of
• the sugar and a nitrogen atom of the base.
• Nucleotides also have a covalent bond Adenosine triphosphate, often abbreviated to ATP.
between the sugar and the phosphoryl group -
a phosphoester bond.

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Nucleotide Sugars

• Access the text alternative for slide images.

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Numbering of Base and Sugar

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 Major Purine Bases
• Nitrogenous bases are heterocyclic amines.
• Cyclic compounds with at least 1 nitrogen atom
in the ring structure.
• Purines are a double ring structure.
• A 6-member ring fused to a 5-member ring.

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 Major Pyrimidine Bases
• Pyrimidines consist of a single 6-membered
ring.

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 Nucleotides
• A nucloetide is the repeating
unit of the DNA or RNA
polymer.
• Ribonucleotides are in RNA.
• Deoxyribonucleotides are in DNA.
• The nitrogen base is attached β
to the 1′ carbon.
• Ribose (RNA).
• Deoxyribose (DNA).
• The sugar is phosphorylated at
the 5′ carbon.

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 Ribonucleotides of Adenosine
• Adenosine is the name of
the molecule that has
adenine attached to the 1′-
carbon of ribose.
• The ribonucleotide forms
differ by the number of
phosphate groups joined to
5′-carbon of the ribose.

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 Nomenclature: Base and Nucleoside
Nomenclature: Base and Nucleoside

Adenosine

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14
Ribonucleotides and Deoxynucleotides Containing
Adenosine
• TABLE 20.1 Names and Abbreviations of the Ribonucleotides and
Deoxyribonucleotides Containing Adenine.

Nucleotide Abbreviation
Deoxyadenosine monophosphate dAMP
Deoxyadenosine diphosphate dADP
Deoxyadenosine triphosphate dATP
Adenosine monophosphate AMP
Adenosine diphosphate ADP
Adenosine triphosphate ATP

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 20.2 The Structure of DNA
and RNA
• Nucleotides combine to form a
chain or polymerize in a series of
3′ to 5′ phosphodiester bonds.
• The terminal 5′ unit retains the
phosphate.
• Backbone of the polymer (in blue)
is called the sugar-phosphate
backbone because it is composed
of alternating units of deoxyribose
and phosphoryl groups.

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 Phosphodiester
Nucleic acid – polymer of nucleotides – directionality 5’ à 3’
linkage (link the 3'
carbon atom of one
sugar molecule and
the 5' carbon atom
of another (hence
the name 3', 5'
phosphodiester
linkage used with
reference to this
kind of bond in DNA
and RNA chains) 17
Nomenclature: Ribonucleotide

ATP: adenosine 5’-triphosphate

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Nomenclature: Deoxyribonucleotide

dAMP: deoxyadenosine 5’-monophosphate

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Nucleic Acid Structure

• Covalent bonds formed

via phosphodiester
linkages
üNegatively charged
backbone.
• Linear polymers
üNo branching or cross-
links.
• Directionality
ü5’ end is different from 3’
end.
üWe write/read the
sequence from 5’ to 3’.
The primary structure of DNA and RNA proceeds in 5’ —–> 3’

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 Helical Structure of DNA
• DNA consists of two chains of
nucleotides coiled around one
another in a right-handed
double helix.
• Sugar-phosphate backbones of the
two strands spiral around the outside
of the helix like the handrails on a
spiral staircase.
• Nitrogenous bases extend into the
center at right angles to the acids of
the helix as if they are the steps of
the spiral staircase.

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 Hydrogen Bonding of the
DNA Helix
• A noncovalent attraction aiding in maintaining
the double helix structure is hydrogen bonding
between base pairs.
• Adenine forms 2 H-bonds with thymine A=T.
• Cytosine forms 3 H-bonds with guanine G=C.
• This H bonding pattern is called base pairing.
• Diameter of the double helix is 2.0 nm.
• Distance dictated by the dimensions of the purine-
pyrimidine base pairs.

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 Complementary DNA Strands
• The two DNA strands are complementary strands.
• The sequence of bases on one automatically determines the
sequence of bases on the other strands.
• The chains run antiparallel.
• Only when the 2 strands are antiparallel can the base pairs
form the H bonds that hold them together.

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DNA Double Helix Structural Specifics

• Access the text alternative for slide images.

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 RNA Structure
• Sugar-phosphate backbone for ribonucleotides is
also linked by 3′–5′ phosphodiester bonds.
• RNA molecules usually single-stranded.
• Ribose replaces deoxyribose.
• Uracil replaces thymine.
• Base pairing between U - A and G - C can still
occur.
• This H bonding results in portions of the single-strand
that become double-stranded.

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Synthesis of Nucleic Acid

• Nucleotide biosynthetic pathways are the major targets of chemotherapeutic agents,

particularly the pathway leading to the synthesis of DNA precursors.

• There are two types of pathways for the synthesis of nucleic acids:
– De novo pathways
– Salvage pathways

• De novo pathway is a metabolic pathway that begins with small molecules and synthesizes new
complex molecules (synthesizes nucleotides from amino acids and glucose) but using different
strategies for pyrimidines and purines.

• In pyrimidine biosynthesis, the framework of the base is first synthesized then attached to
ribose while in purine biosynthesis the framework of the base is synthesized onto a ribose-
based structure.

• The salvage pathway recovers nucleosides or bases formed during DNA or RNA
degradation.

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Synthesis of Nucleic Acid

• In purine
• In pyrimidine biosynthesis the
biosynthesis, the framework of the
framework of the base is synthesized
base is first onto a ribose-based
synthesized then structure.
attached to
ribose.

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Synthesis of Nucleic Acid
• Both the de novo and salvage
pathways lead to the synthesis of
ribonucleotides.
• All deoxyribonucleotides are
subsequently synthesized
through reduction of the ribose
of the corresponding
ribonucleotides.
• The methyl group that
distinguishes Thymine from
Uracil is added at the last step
of the pathway for synthesis of
thymine deoxyribonucleotides.

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The De novo synthesis of Pyrimidine Nucleotides

• The synthesis of pyrimidines is a much simpler process compared to that of

purines. Aspartate, glutamine (amide group) and CO2 contribute to atoms in the
formation of pyrimidine ring.

• Pyrimidine ring is first synthesized and then attached to ribose 5-phosphate.

This is in contrast to purine nucleotide synthesis where in purine, ring is built
upon a pre-existing ribose-5 phosphate.

Sources of individual atoms in Pyrimidine ring

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The De novo synthesis of Pyrimidine Nucleotides

• Pyrimidine rings, during their de novo synthesis, are assembled from

bicarbonate, aspartic acid and ammonia (generated from the hydrolysis of the
side chain of glutamine).

• The first step in the de novo pyrimidine synthesis pathway is the generation
of carbamoyl phosphate from bicarbonate and ammonia in a reaction catalyzed
by carbamoyl-phosphate synthetase and at the cost of 2 molecules of ATP.
glutamine as amino group donor

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The De novo synthesis of Pyrimidine Nucleotides

• In the second step of the pathway, carbamoyl phosphate reacts with

aspartate to form carbamoylaspartate in a reaction catalyzed by aspartate
transcarbamoylase.

• Carbamoylaspartate then cyclizes into dihydroorotate which is subsequently

oxidized by NAD+ to form orotate.

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The De novo synthesis of Pyrimidine Nucleotides

• At this point, orotate (a pyrimidine),

couples to ribose in the form of 5-
phosphoribosyl-1-pyrophosphate
(PRPP) to form orotidylate in a
reaction catalyzed by pyrimidine
phosphoribosyltransferase.

• PRPP is synthesized from ribose 5-

phosphate, formed through the
pentose phosphate pathway, to
which pyrophosphate is added from
ATP.

• Orotidylate is then decarboxylated

to form uridylate (Uridine
monophosphase; UMP) in a reaction
catalyzed by orotidylate
decarboxylase
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The De novo synthesis of Pyrimidine Nucleotides

• Uridine Monophosphate (UMP) is then converted to Uridine triphosphate

(UTP) before serving as the precursor for synthesis of cytosine triphosphate
(CTP).

• CTP is synthesized from UTP by the replacement of a carbonyl group by an

amino group in an ATP-dependent reaction that uses glutamine as amino group
donor.

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Salvage pathway for Purine Nucleotides

Salvage pathway of purine nucleotide synthesis

refers to the process of synthesizing
nucleotides from purine bases and purine
nucleosides. Purine bases and purine
nucleotides are constantly produced in the cells
as a result of the metabolism of nucleotides
such as polynucleotide degradation. Moreover,
these bases and nucleosides also enter our body
by the food we consume.

Purine synthesis via the salvage pathways

occurs in all tissues. It is especially important
in the brain and the bone marrow.
•Substrates: Hypoxanthine; PRPP; guanine;
adenine.
•Products: GMP; AMP; IMP.
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Salvage pathway for Purine Nucleotides
Bases from degraded nucleic acids can be converted
back into purine nucleotides via the salvage pathways.
•Hypoxanthine can be combined with PRPP (which acts
as the donor of ribose-5 phosphate) to form IMP in a
reaction catalyzed by Hypoxanthine-guanine
phosphoribosyl transferase (HGPRT).
•IMP can subsequently be transformed into AMP or
GMP.
•HGPRT also catalyzes the reaction which combines
PRPP with guanine to form GMP.
•Adenine phosphoribosyl transferase converts
adenine and PRPP to form AMP.

Important enzymes and Regulation

•HGPRT: Inhibited by IMP and GMP.
•Adenine phosphoribosyl transferase: Inhibited by
AMP. 35
Significance of Purine Synthesis
1.Purines serve as building blocks of nucleic acids.
2.ATP plays an important role in energy transformation.
3.ATP, ADP, and AMP may function as allosteric regulators and participate in
regulation of many metabolic pathways.
4.ATP involves in covalent modification of enzymes.
5.cGMP are secondary messengers.
6.Salvage pathways are used to recover bases and nucleosides that are formed
during degradation of RNA and DNA.
7.In comparison to de novo pathway, salvage pathway is energy-saving.

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What are the Similarities Between De Novo and Salvage
Pathways?
•De novo and salvage are two pathways of nucleotide synthesis.
•Moreover, both assemble ribonucleotides that can be used to
synthesize deoxyribonucleotides for DNA.
•Furthermore, feedback inhibition regulates both pathways.

What is the Difference Between De Novo and Salvage Pathways?

De novo pathway utilizes small molecules to produce nucleotides,
while salvage pathway utilizes preformed bases and nucleosides to
produce nucleotides. So, this is the key difference between de
novo and salvage pathway.

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