Nucleic Acid Metabolism

UNIT- IV
Nucleic Acid Metabolism
ANKUSH GOYAL
ASSISTANT PROFESSOR
MAHARAJAAGRASEN SCHOOL OF PHARMACY
MAHARAJAAGRASEN UNIVERSITY, BADDI (H.P.)

Nucleic Acids (Polymer of Nucleotides)
Nucleic acids are the polymers of nucleotides (polynucleotides) held by 3’ and 5’ phosphate
bridges. In other words, nucleic acids are built up by the monomeric units—nucleotides
Nucleotides consist of following components:
• Nitrogenous Base
• A Pentose Sugar
• A Phosphate Group
There are two types of nucleic acids, namely deoxyribonucleic acid (DNA) and ribonucleic
acid (RNA).
The pentose sugar is D-ribose in ribonucleotides of RNA while in deoxyribonucleotides
(deoxynucleotides) of DNA, the sugar is 2-deoxy D-ribose.
Nucleotides participate in almost all the biochemical processes, either directly or indirectly.
They are the structural components of nucleic acids (DNA, RNA), coenzymes, and are
involved in the regulation of several metabolic reactions.

•Nitrogenous bases
• The nitrogenous bases found in nucleotides (and, therefore, nucleic acids) are
aromatic heterocyclic compounds. The bases are of two types—purines and
pyrimidines.
• Their general structures are:
Purines Pyrimidines
Purines are numbered in the anticlockwise direction while pyrimidines are numbered in
the clockwise direction. Major Purine bases are Adenine (A) and Guanine (G) while
Pyrimidine bases are Cytosine (C), Thymine (T) and Uracil (U).

The structures of these nitrogen bases are given below:
DNA contains
Adenine,
Guanine,
Cytosine and Thymine.
RNA contains
Adenine,
Guanine,
Cytosine and Uracil.

•Pentose Sugar
The five carbon monosaccharides (pentoses) are found in the nucleic acid structure.
RNA contains D-ribose while DNA contains D-2-deoxyribose. Ribose and deoxyribose
differ in structure at C2. Deoxyribose has one oxygen less at C2 compared to ribose.
The addition of a pentose sugar to base produces a nucleoside. If the sugar is ribose,
ribonucleosides are formed. Adenosine, guanosine, cytidine and uridine are the
ribonucleosides of A, G, C and U respectively. If the sugar is a deoxyribose,
deoxyribonucleosides are produced.

•Phosphate Group
The term mononucleotide is used when a single phosphate moiety is added to a
nucleoside. Thus adenosine monophosphate (AMP) contains adenine + ribose +
phosphate.
Nucleoside monophosphates possess only one phosphate moiety (AMP, TMP).
The addition of second or third phosphates to the nucleoside results in nucleoside
diphosphate (e.g. ADP) or nucleoside triphosphate (e.g. ATP) respectively.

Biosynthesis of Purine Ribonucleotides
• Many compounds contribute to the purine ring of
the nucleotides:
1. N1 of purine is derived from amino group of
aspartate.
2. C2 and C8 arise from formate of N10- formyl THF.
3. N3 and N9 are obtained from amide group of
glutamine.
4. C4, C5 and N7 are contributed by glycine.
5. C6 directly comes from CO2.
• It should be remembered that purine bases are not
synthesized as such, but they are formed as
ribonucleotides. The purines are built upon a pre-
existing ribose 5-phosphate. Liver is the major
site for purine nucleotide synthesis.
Purine Ring

Synthesis of Purine Ribonucleotides (AMP and GMP)
Inosine monophosphate is the immediate
precursor for the formation of AMP and
GMP. Aspartate condenses with IMP in
the presence of GTP to produce
adenylsuccinate which, on cleavage,
forms AMP.
For the synthesis of GMP, IMP
undergoes NAD+ dependent
dehydrogenation to form xanthosine
monophosphate (XMP). Glutamine then
transfers amide nitrogen to XMP to
produce GMP.

Formation of deoxyribonucleotides from ribonucleotides
Reduction at the C2 of ribose moiety: This reaction is catalysed by a enzyme,
ribonucleotide reductase. The enzyme ribonucleotide reductase itself provides the H-
atoms needed for reduction from its sulfhydryl groups. The reducing equivalents, in
turn, are supplied by thioredoxin, a monomeric protein with two cysteine residues.
NADPH-dependent thioredoxin reductase converts the oxidized thioredoxin to reduced
form which can be recycled again and again.
Deoxyribonucleotides are mostly required for the synthesis of DNA.

Degradation of Purine Nucleotides
The end product of purine metabolism in humans is uric acid. The sequence of
reactions in purine nucleotide degradation is given below:
1. The nucleotide monophosphates (AMP, IMP and GMP) are converted to their
respective nucleoside forms (adenosine, inosine and guanosine) by the action of
nucleotidase.
2. The amino group, either from AMP or adenosine, can be removed to produce IMP or
inosine, respectively.
3. Inosine and guanosine are, respectively, converted to hypoxanthine and guanine
(purine bases) by purine nucleoside phosphorylase. Adenosine is not degraded by this
enzyme, hence it has to be converted to inosine.
4. Guanine undergoes deamination by guanase to form xanthine.

5. Xanthine oxidase is an important
enzyme that converts hypoxanthine to
xanthine, and xanthine to uric acid.
This enzyme contains FAD,
molybdenum and iron, and is
exclusively found in liver and small
intestine. Xanthine oxidase liberates
H2O2 which is harmful to the tissues.
Catalase cleaves H2O2 to H2O and O2.
Uric acid (2,6,8-trioxypurine) is the
final excretory product of purine
metabolism in humans.

Biosynthesis of Pyrimidine Ribonucleotides
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.

1. Formation of Carbamoyl Phosphate :
Glutamine transfers its amido nitrogen to CO2 to produce
carbamoyl phosphate. This reaction is ATP-dependent and is
catalysed by cytosomal enzyme carbamoyl phosphate
synthetase II (CPS II).
2. Conversion of Carbamoyl phosphate to Dihydroorotate :
Carbamoyl phosphate condenses with aspartate to form
carbamoyl aspartate. This reaction is catalysed by aspartate
transcarbamoylase. Dihydroorotase catalyses the pyrimidine
ring closure with a loss of H2O.
3. Formation of orotate:
The next step in pyrimidine synthesis is an NAD+ dependent
dehydrogenation catalysed by dihydroorotate dehydrogenase,
leading to the formation of orotate.

4. Conversion of orotate to orotidine monophosphate (OMP):
Ribose 5-phosphate is now added to orotate to produce orotidine
monophosphate (OMP). This reaction is catalysed by orotate
phosphoribosyltransferase.
5. Formation of Uridine Monophosphate (UMP):
OMP undergoes decarboxylation to uridine mono-phosphate (UMP).
This reaction is catalysed by OMP decarboxylase.
6. Conversion of UMP to UDP:
By an ATP-dependent kinase reaction, UMP is converted to
UDP which serves as a precursor for the synthesis of dUMP,
dTMP, UTP and CTP.
7. Final Step:
Ribonucleotide reductase converts UDP to dUDP by a
thioredoxin-dependent reaction. Thymidylate synthetase
catalyses the transfer of a methyl group from N5, N10-
methylene tetrahydrofolate to produce deoxythymidine
monophosphate (dTMP).
UDP undergoes an ATP-dependent kinase reaction to
produce UTP. Cytidine triphosphate (CTP) is synthesized
from UTP by amination. CTP synthetase is the enzyme
and glutamine provides the nitrogen.

Hyperuricemia and Gout disease
The normal concentration of uric acid in the serum of adults is in the range of 3-7
mg/dl. In women, it is slightly lower (by about 1 mg) than in men. The daily
excretion of uric acid is about 500-700 mg.
Hyperuricemia refers to an elevation in the serum uric acid concentration.
Gout is a metabolic disease associated with overproduction of uric acid. At the
physiological pH, uric acid is found in a more soluble form as sodium urate. In
severe hyperuricemia, crystals of sodium urate get deposited in the soft tissues,
particularly in the joints. Such deposits are commonly known as tophi. This causes
inflammation in the joints resulting in a painful gouty arthritis. Sodium urate and/or
uric acid may also precipitate in kidneys and ureters that results in renal damage and
stone formation.

Structure of DNA
DNA is a polymer of deoxyribonucleotides (or simply deoxynucleotides).
It is composed of monomeric units namely
Deoxyadenylate (dAMP)
Deoxyguanylate (dGMP)
Deoxycytidylate (dCMP)
Deoxythymidylate (dTMP)
Schematic representation of polynucleotides:
The monomeric deoxynucleotides in DNA are held
together by 3’,5’-phosphodiester bridges.

Chargaff’s rule of DNA composition
Erwin Chargaff observed that in all the species he studied, DNA had equal numbers of
adenine and thymine residues (A = T) and equal numbers of guanine and cytosine
residues (G = C). This is known as Chargaff’s rule of molar equivalence between the
purines and pyrimidines in DNA structure.
Single-stranded DNA, and RNAs which are usually single-stranded, do not obey
Chargaff’s rule. However, double-stranded RNA which is the genetic material in certain
viruses satisfies Chargaff’s rule.

DNA Double Helix
The double helical structure of DNA was proposed by James Watson and Francis
Crick in 1953 (Nobel Prize, 1962).
The salient features of Watson-Crick model of DNA :
1. The DNA is a right handed double helix. It consists of two
polydeoxyribonucleotide chains (strands) twisted around
each other on a common axis.
2. The two strands are antiparallel, i.e., one strand runs in the
5’ to 3’ direction while the other in 3’ to 5’ direction. This is
comparable to two parallel adjacent roads carrying traffic in
opposite direction.
3. The width (or diameter) of a double helix is 20 A° (2nm).
4. Each turn (pitch) of the helix is 34 A° (3.4 nm) with 10
pairs of nucleotides, each pair placed at a distance of about
3.4 A°.

5. Each strand of DNA has a hydrophilic deoxyribose phosphate backbone (3’-5’
phosphodiester bonds) on the outside (periphery) of the molecule while the
hydrophobic bases are stacked inside (core).
6. The two polynucleotide chains are not identical but complementary to each other due
to base pairing.
7. The two strands are held together by hydrogen
bonds formed by complementary base pairs. The A-T
pair has 2 hydrogen bonds while G-C pair has 3
hydrogen bonds. The G -C is stronger by about 50%
than A = T.

8. The hydrogen bonds are formed between a purine and a pyrimidine only. If two
purines face each other, they would not fit into the allowable space. And two
pyrimidines would be too far to form hydrogen bonds. The only base arrangement
possible in DNA structure, from spatial considerations is A-T, T-A, G-C and C-G.
9. The complementary base pairing in DNA helix proves Chargaff’s rule. The content of
adenine equals to that of thymine (A = T) and guanine equals to that of cytosine
(G = C).
10. The genetic information resides on one of the two strands known as template strand
or sense strand. The opposite strand is antisense strand. The double helix has (wide)
major grooves and (narrow) minor grooves along the phosphodiester backbone.
Proteins interact with DNA at these grooves, without disrupting the base pairs and
double helix.

Nucleic Acid Metabolism

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Nucleic Acid Metabolism