NUCLEOTIDE CHEMISTRY

Contents:
1. Introduction
2. History
3. General features of nucleotides
4. Nomenclature
5. Individual properties of bases
6. Classification
7. Synthetic analogues of biomedical importance
Introduction
• Nucleotides are organic compounds made up of a PO4
group, nitrogenous base & a sugar molecule.

• These are the building blocks of nucleic acids (DNA

and RNA).

• They serve as sources of chemical energy (ATP, GTP),

participate in cellular signalling (cAMP, cGMP) and
function as important cofactors of enzymatic reactions
(coA, FAD, FMN, NAD+).
 HISTORY

In 1869, Miescher discovered "nuclein" (DNA) in the

cells from pus & later he separated it into a protein and
an acid molecule. It came to known as nucleic acid after
1874.

1926 , Levene proposed “Tetra nucleotide theory”

which states that Nucleic acid consists of only 4 nitrides
as it gives 4 diff nucleotides on hydrolysis.
In 1950, Erwin Chargaff shows that the four
nucleotides are not present in nucleic acids in
stable proportions.

1957, Sir Alexander R.Todd of Cambridge

University gave structure of nucleotide.
General features of nucleotides
 SUGARS

 Two main sugars

 Present in furanose form

Lacks 2’-OH group

 Bases

• Purines :
– Adenine (A)
– Guanine (G)
• Pyrimidines :
– Cytosine (C)
– Uracil (U)
– Thymine (T)
 The bases are abbreviated by their first letters (A, G, C, T, U).
 The purines (A, G) occur in both RNA & DNA.

 Among the pyrimidines, Coccurs in both RNA & DNA, but

 Toccurs in DNA, and U occurs in RNA.

 DNA:A,G,C,T

 RNA: A,G,C,U
 Some minor bases:

Minor bases of DNA Minor bases of RNA

• 5-Methylcytidine occurs in DNA of animals and
higher plants.
• N6-methyladenosine occurs in bacterial DNA.
Nucleosides =Ribose/Deoxyribose +
Bases
The bases are covalently attached to the 1’ position of a
pentose sugar ring, to form a nucleoside
 Nucleotides = nucleoside + phosphate

A nucleotide is a nucleoside with one or more phosphate groups

bound covalently to the 3rd or 5th hydroxyl group of pentose sugar. Most
of nucleoside phosphate involve in biological function are 5’- phosphates.
Since 5’- phosphates are most often seen, they are written without any
prefix.
 H

Ribonucleotide Deoxy-ribonucleotide

H
Nucleoside
NOMENCLATURE:-

 Nucleosides phosphorylated on the 3’ or 5’ C of

ribose are termed ; nucleoside 3’- monophoshate &
nucleoside 5’- monophoshate.
 ‘5’ is by convention omitted when naming
nucleotide.
 Abbrevations such as AMP, GTP denotes the
phosphate is esterified to 5’ of pentose.
 Additional phosphate group is attached to preexisting
phosphate of mononucleotide ,
 - nucleotide diphosphate – ADP
 - nucleotide triphosphate – ATP
Nucleotide nomenclature:
Nucleotide nomenclature:
Individual properties :-

 PROPERTIES OF PURINE BASES:-

 Sparingly soluble in water

 Absorb light in UV region at 260 nm.

(detection & quantitation of nucleotides)

 Capable of forming hydrogen bond

Properties of pyrimidine bases :-

 Soluble at body pH

 Also absorb UV light at 260 nm

 Capable of forming hydrogen bond

Pyrimidine base :-

 Aromatic base atoms are numbered 1 to 6 for pyrimidine

 Atoms or group attached to base atoms have same

number as the ring atom to which they are bonded
Cytosine :-

 Chemically is 2-oxy ,4-amino pyrimidine

 Exist both lactam or lactim form

Thymine :-

 Chemically is 2,4 dioxy ,5-methyl pyrimidine

 Occurs only in DNA

URACIL :-

 Chemically is 2,4 dioxy pyrimidine

 Found only in RNA

PURINE BASES :-

 Aromatic base atoms numbered 1 to 9

 Purine ring is formed by fusion of pyrimidine ring

with imidazole ring

 Numbering is anticlockwise
Adenine :-

 Chemically it is 6-aminopurine
Guanine :-

 Chemically is 2-amino,6-oxy purine

 Can be present as lactam & lactim form
 CLASSIFICATION:

Adenosine ATP, ADP, AMP, Cyclic AMP

nucleotides
Guanosine GTP, GDP, GMP, Cyclic GMP
nucleotides
Uridine UTP, UDP, UMP, UDP-G
nucleotides
Cytosine CTP, CDP, CMP and certain deoxy CDP
nucleotides derivatives of glucose, choline and
ethanolamine
Miscellaneous PAPS (active sulphate), SAM (active
methionine), certain coenzymes like NAD+,
FAD, FMN, Cobamide coenzyme, CoA
ADENOSINE CONTAINING
NUCLEOTIDES
ATP (ADENOSINE TRIPHOSPHATE)

 Many synthetic reactions requires energy, e.g. arginosuccinate

synthetase reaction in urea cycle.
 ATP is required for the synthesis of Phospho creatine from
creatine, synthesis of FA from acetyl CoA, formation of
glucose from pyruvic acid, etc.
 ATP is an important source of energy for muscle contraction,
transmission of nerve impulses, transport of nutrients
across cell membrane, motility of spermatozoa.
 ATP is required for the formation of active methionine, which
is required for methylation reaction
 ATP donates phosphate for a variety of phosphotransferase
reactions e.g., hexokinase reaction.
ATP IN UREA CYCLE:
ATP IN FA SYNTHESIS:
ATP IN PHOSPHORYLATION REACTIONS:
ATP IN SYNTHESIS OF SAM:
ADENOSINE DI PHOSPHATE (ADP)

 ADP plays an important role as a primary PO4

acceptor in oxidative phosphorylation and muscle
contraction, etc

 ADP is also important as an activator of the enzyme

glutamate dehydrogenase
ACTVATION OF GLUTAMATE
DEHYDROGENASE
ADENOSINE MONO PHOSPHATE
(AMP)
 In the glycolytic pathway, the enzyme
phosphofructokinase is inhibited by ATP but the
inhibition is reversed by AMP.
 AMP can also act as an inhibitor of certain enzymes
like fructose-1-6- bisphosphatase and
adenylosuccinate synthetase.
 In resting muscles, AMP is formed from ADP, by
adenylate kinase, the AMP produced activates the
phosphorylase b enzyme of muscle and increase
breakdown of glycogen.
AMP ROLE IN REGULATION
URIDINE NUCLEOTIDES

 UTP also has the role of a source of energy or an activator of

substrates in metabolic reactions, like that of ATP, but more
specific.
 When UTP activates a substrate, UDP-substrate is usually
formed and inorganic phosphate is released. UDP- glucose
enters the synthesis of glycogen.
 UTP is used in the metabolism of galactose, where the
activated form UDP-galactose is converted to UDP-glucose
 UDP-glucuronate is used to conjugate bilirubin to a more
water-soluble bilirubin diglucuronide
UDP ROLE IN GLYCOGEN SYNTHESIS
CONJUGATION OF BILIRUBIN
UDP ROLE IN GALACTOSE METABOLISM
CYTIDINE NUCLEOTIDES
Miscellaneous :-

PAPS - Phospho Adenosine Phospho Sulphate

(active sulphate) formed in liver
 Sulfates enzymes which catalyze introduction
of SO4 group
 In biosynthesis of chondroitin sulfate
 Formation of sulpholipids

SAM:- S- Adenosyl Methionine

 Active methionine
TRANSMETHYLATION REACTIONS
PHOSPHO ADENOSINE PHOSPHO SULPHATE
SYNTHESIS OF GAG’S FROM PAPS
C AMP
Contd.
Cyclic AMP mediated activationcascade
C GMP
FUNCTIONS

 c-GMP is second messenger in photo transduction

in the eyes.
 It has been claimed that c-GMP as second
messengers regulate the closing and opening of Na+
channels. In the dark there are high levels of c-GMP
which bind to Na+ channels causing them to open.
Reverse occur in light.
INOSINE MONOPHOPHATE

 Hypoxanthine ribonulcleotide, usually called IMP

is a precursor of all purine nucleotide synthesized
de-novo
 Inosinate can also be formed by de amination of
AMP, a reaction which occurs particularly in
muscles as a part of purine nucleotide cycle
SYNTHETIC ANALOGUES OF
BIOMEDICAL IMPORTANCE
 Synthetic analogues of nucleobases, nucleosides
and nucleotides are recently of wide use in medical
sciences and clinical medicine.
 The heterocyclic ring structure or the sugar moiety
is altered in such a way as to induce toxic effects
when the analogues get incorporated into cellular
constituents of the body.
 Theophylline

Azapurine
Azathiopurine

SOME IMPORTANT SYNTHETIC DERIVATIVES

 Uses of some Synthetic analogues of
nucleotides:-

Allopurinol is a purine analogue. This drug is an inhibitor of the enzyme

xanthine oxidase, which inhibit uric acid formation. The drug is widely used
for the treatment of gout
AZT-(azydothymidine):- thymidine analogue treatment of AIDS
(terminates DNA synthesis catalysed by reverse transcriptase of retrovirus
such as HIV)
NUCLEOSIDE ANALOGUES AS
DRUGS
ANALOGUES DRUGS USES
Deoxyadenosine Didanosine HIV
analogues , Chemotherapy
Vidarabine
Deoxycytidine analogues Cytarabine, Chemothrapy
Emtricitabin HIV
e Hepatitis B
Lamivudine HIV
Zalcitabine
Deoxyguanosine Abacavir HIV
analogues Entecavi Hepatitis B
r
Deoxy- Stavudine HIV
thymidine analogues Telbivudine Hepatitis B
Zidovudine HIV
Deoxyuridine analogues Idoxuridine HIV
Trifluridine HIV
NUCLEOTIDE ANALOGUES AS
DRUGS
 Tenofovir, also called 'prodrug‘. It is approved in
the USA for the treatment of both HIV and hepatitis
B.

 Adefovir, has trade names Preveon and Hepsera. It

was not approved by the FDA for treatment of HIV
due to toxicity issues, but a lower dose is approved
for the treatment of hepatitis B.
Thank you..