This document summarizes biologically important nucleotides and their functions. It discusses the composition of nucleotides and their roles in DNA, RNA, and various biochemical functions. Specific nucleotides are described, including adenosine nucleotides (ATP, ADP, AMP, cAMP), guanosine nucleotides (GTP, GDP, GMP, cGMP), uridine nucleotides (UTP, UDP, UMP, UDP-G), and cytidine nucleotides (CTP, CDP, CMP). It also discusses purine and pyrimidine metabolism, including biosynthesis, degradation, salvage pathways, and disorders like hyperuricemia, gout, and Lesch-Nyhan syndrome. The regulation and enzymes involved in

1. Biologically important nucleotides and their functions
Nucleotides are composed of a nitrogenous base, a pentose sugar and a phosphate. Besides the
nucleotides which occur as integral part of DNA and RNA, there are many biologically important nucleotides
present in tissues and cells, where they have diverse biochemical functions.
A. Adenosine nucleotides: ATP, ADP, AMP and Cyclic AMP.
B. Guanosine nucleotides: GTP, GDP, GMP and cyclic GMP.
C. Uridine nucleotides: UTP, UDP, UMP, UDP-G.
D. Cytidine nucleotides: CTP, CDP, CMP and certain deoxy CDP derivatives of glucose, choline,
ethanolamine.
E. Miscellaneous: PAPS (‘active’ sulphate), active methionine (S-adenosyl methionine), certain coenzymes
like NAD+ and NADP+, FAD and FMN, Cobamide coenzyme, CoA.
A. Adenosine nucleotides: ATP, ADP, AMP and Cyclic AMP.
(a) Adenosine triphosphate (ATP)
Function: Two of the three phosphate residues are high energy “phosphates (~P)” and on hydrolysis each
releases energy (7.6 Kcal); energy is utilised for endergonic processes.
(b) Adenosine diphosphate (ADP)
Function: ADP plays an important role as a primary PO4 acceptor in oxidative phosphorylation and
photophosphorylation in addition to its effect on control of cellular respiration, muscle contraction, etc.
(c) Adenosine Monophosphate (AMP)
Function: AMP acts as an activator of several enzymes in the tissues. In the glycolytic pathway, the enzyme
phosphofructokinase is inhibited by ATP but the inhibition is reversed by AMP, the deciding factor for the
reaction being ratio of ATP and AMP.
B. Guanosine nucleotides: GTP, GDP, GMP and cyclic GMP.
(a) GTP: Guanosine Triphosphate
Function: The oxidation of succinyl-CoA in the citric acid cycle involves phosphorylation of GDP to form
GTP.
• GTP is also required for protein synthesis.
C. Uridine nucleotides: UTP, UDP, UMP, UDP-G.
Function: monophosphate (UMP) is obtained by the hydrolysis by RNAase and phosphodiesterase.
UDP-Glucuronic acid is used for:
• Conjugation and detoxication of bilirubin, benzoic acid, sterols, oestrogens and drugs.
D. Cytidine nucleotides: CTP, CDP, CMP and certain deoxy CDP derivatives of glucose,
choline, ethanolamine.
Function: CDP-choline, CDP-glycerol, and CDP-ethanolamine are involved in the biosynthesis of
phospholipids.
 CMP-Sialic acid is present in salivary glands and may be concerned with the biosynthesis of salivary
mucin.
E. Miscellaneous: PAPS (‘active’ sulphate)
(a) PAPS-Phosphoadenosine phosphosulphate: It is also known as active sulphate.
Functions
1. The sulphatases are enzymes which catalyse the introduction of a SO4 group to various biomolecules,
e.g.
• In the biosynthesis of heparin, Formation of „sulpolipids‟ (sulfatides).

2. Purine Metabolism
A. BIOSYNTHESIS OF PURINE RIBONUCLEOTIDES - Adenine and
Guanine
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.
Liver is the major site for purine nucleotide synthesis. Erythrocytes, polymorphonuclear leukocytes and
brain cannot produce purines.
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.
Ribose 5-phosphate, produced in the hexose monophosphate shunt of carbohydrate
metabolism is the starting material for purine nucleotide synthesis.
It reacts with ATP to form phosphoribosyl pyrophosphate (PRPP).

3. The initially synthesized purine derivative is , the nucleotideinosine monophosphate (IMP)
of the base hypoxanthine. AMP and GMP are subsequently synthesized from this
intermediate via separate pathways.
Series of reactions
Series of products
1. β-5-Phosphoribosylamine,
2. Glycinamide ribosyl 5-phosphate,
3. Formylglycinamide ribosyl 5-phosphate,
4. Formylglycinamidine ribosyl-5-phosphate,
5. Formylglycinamidine ribosyl-5-phosphate,
6. 5-Aminoimidazole carboxylate ribosyl 5-phosphate,
7. 5-Aminoimidazole 4-succinyl carboxamide ribosyl 5-
phosphate,
8. 5-Aminoimidazole 4-carboxamide ribosyl 5-phosphate,
9. 5-Formaminoimidazole 4-carboxamide ribosyl 5-
phosphate,
10. Inosine monophosphate

4. Salvage pathway for purines
The free purines (adenine, guanine and hypoxanthine) are
formed in the normal turnover of nucleic acids (particularly
RNA), and also obtained from the dietary sources. The purines
can be directly converted to the corresponding
nucleotides, and this process is known as ‘salvage pathway’
Inhibitors of purine synthesis
Folic acid (THF) is essential for the synthesis of purine nucleotides.
Sulfonamides are the structural analogues of paraaminobenzoic acid (PABA). These sulfa
drugs can be used to inhibit the synthesis of folic acid by microorganisms. This
indirectly reduces the synthesis of purines and, therefore, the nucleic acids.
• The structural analogues of folic acid (e.g. methotrexate) are widely used to control
cancer.
• They inhibit the synthesis of purine nucleotides and, thus, nucleic acids.
Regulation of purine nucleotide biosynthesis
The intracellular concentration of PRPP regulates purine synthesis to a large extent. This, in turn, is
dependent on the availability of ribose 5-phosphate and the enzyme PRPP synthetase.
PRPP glutamyl amidotransferase is controlled by a feedback mechanism by purine nucleotides.
That is, if AMP and GMP are available in adequate amounts to meet the cellular requirements, their
synthesis is turned off at the amidotransferase reaction.

5. DEGRADATION OF PURINE NUCLEOTIDES
• The end product of purine metabolism in humans is uric acid.
• An average of 500 to 700 mg of uric acid is excreted by human beings most of it is found
in urine.
• Its normal serum level is 3–7 mg/dL

6. DISORDERS OF PURINE METABOLISM
1. Hyperuricemia and gout
Hyperuricemia refers to an elevation in the serum uric acid
concentration. This is sometimes associated with increased uric acid
excretion.
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 result in renal damage
and stone formation.

7. Treatment Policies in Gout
i. Reduce dietary purine intake and restrict alcohol.
ii. Increase renal excretion of urate by , which decrease theuricosuric drugs
reabsorption of uric acid from kidney tubules, e.g. .probenecid
iii. Reduce urate production by , anallopurinol . Allopurinol isanalog of hypoxanthine
a competitive thereby decreasing the formation of uricinhibitor of xanthine oxidase
acid.
iv. , an anti-inflammatory agent is very useful to arrest the arthritis in gout.Colchicine
v. Use of and conversion ofPEG (polyethylene glycol)-uricase uric acid to allantoin
(more water soluble and easily excreted) is also being tried as a therapeutic measure to
reduce body uric acid pool.

8. Lesch-Nyhan syndrome
This disorder is due to the deficiency of hypoxanthine-guanine
phosphoribosyl transferase (HGPRT), an enzyme of purine salvage
pathway.
• It affects only the males and is characterized by excessive uric acid
production (often gouty arthritis), and neurological abnormalities
such as mental retardation, aggressive behaviour, learning disability
etc.
• The patients of this disorder have an irresistible urge to bite their
fingers and lips, often causing self-mutilation.
BIOSYNTHESIS OF PYRIMIDINE
RIBONUCLEOTIDES
Aspartate, glutamine (amide group) and CO2 contribute
to atoms in the formation ofpyrimidine ring.
• Pyrimidine ring is first synthesized and then attached to
ribose 5-phosphate.

9. Regulation of pyrimidine synthesis
(CPS II) isthe regulatory enzyme. It is1. Carbamoyl phosphate synthetase II
andactivated by PRPP and ATP inhibited by UDP and UTP.
2. ,OMP decarboxylase , also controls pyrimidineinhibited by UMP and CMP
formation.

10. Degradation of pyrimidine nucleotides
The pyrimidine nucleotides undergo dephosphorylation,
deamination and cleavage of glycosidic bond to liberate the
nitrogenous bases—
Cytosine, uracil and thymine.
The bases are then degraded to highly soluble products—β-alanine
and β -aminoisobutyrate. These are the amino acids which
undergo transamination and other reactions to finally produce
acetyl CoA and succinyl CoA.
Salvage pathway
• The pyrimidines -like purines- can also serve as precursors in the
salvage pathway to be converted to the respective nucleotides.
• This reaction is catalysed by pyrimidine phosphoribosyltransferase
which utilizes PRPP as the source of ribose 5-phosphate.
Eg. acts to salvage other pyrimidine bases,Orotate phosphoribosyltransferase
such as uracil and cytosine, by converting them to their corresponding
nucleotides.
Orotic Aciduria
Type I orotic aciduria: It is an autosomal recessive genetic disorder of a protein
acting as both orotate phosphoribosyltransferase and OMP decarboxylase.

11. • Orotate fails to be converted to UMP. This results in accumulation of
orotate in blood elevating its level, growth retardation and
megaloblastic anaemia.
Feeding diet rich in uridine and/or cytidine is an effective treatment for orotic
aciduria.
These compounds provide (through phosphorylation) pyrimidine nucleotides
required for DNA and RNA synthesis.