TOPIC: Nucleotide metabolism

By,Pillai Aswathy viswanathPG 1 BotanySt. thomas college kozhencherry

Nucleotides Nucleotides are organic molecules that

serve as the sub units of nucleic acid like DNA and RNA

Building blocks of nucleic acid. Nucleotides are composed of a sugar

molecule a phosphate unit, and a nitrogenous base.

Nucleotides contain either a purine or a pyrimidine base. 

They are found everywhere within the cells of our bodies, including the nucleus and the cytoplasm.

Functions of nucleotide Nucleotides are the activated precursors of

DNA and RNA. ATP, an adenine nucleotide, is a universal

currency of energy in biological systems. GTP is an essential carrier of chemical energy. Components of the cofactors NAD+, FAD, and

coenzyme A nucleotides function as cellular messengers

for communication from the outside to the inside of the nucleus

They are activated intermediates in many biosynthesis

Metabolism Metabolism, inclusive term for the

chemical reactions by which the cells of an organism transform energy, maintain their identity, and reproduce.

Anabolism and Catabolism Anabolism (synthesis) and

catabolism (destruction). Both processes go on throughout the life of the organism.

Nucleotide Biosynthesis:

Purines and pyrimidines are required for synthesizing nucleotide

These molecules can be synthesized either from denovo or salvaged from existing bases

Two Pathways for NucleotideBiosynthesis:

de novo pathway (a new): nucleotides are synthesised from

different small components. The synthesis of nucleotides begins with their

metabolic precursors: amino acids, ribose-5-phosphate, CO2, and one-carbon units.

salvage pathways (to save from loss): recovery and recycling of nucleotides obtained in the diet

De novo synthesis of purine

Basic pathway for biosynthesis of purine

nucleotides

occurs primarily in the liver

This pathway operates in cytoplasm.

Requires 10 steps overall

Purine ring is build up on a (R-5-P) as the

starting material step by step.

Biosynthesis of Purines

John Buchanan (1948) "traced" the sources of all nine atoms of purine

ring N-1: aspartic acid N-3, N-9: glutamine C-4, C-5, N-7: glycine C-6: CO2 C-2, C-8: one carbon units

N10-Formyltetrahydrofolate

N10-Formyltetrahydrofolate

1. Element sources of purine bases

Formation of purine ring

OH

1 ATP

AMP

1

Preliminary step or step 0:

Step 1:Addition of N9

5-磷酸核糖 ,PRA

•1 N +R-5-P=PRA

PRPP Donor of R-5-P

Gln:PRPP amidotransferase

酸

2

Step 2: in corporation of C4, C5, and N7

glycinamide synthetase

•Step 3: addition of C8

GAR transformylase

4

Step 4: addition of N3

5

苷酸

•Step 5: closing of the ring

Carboxyaminoimidazole ribonucleotide (CAIR)

6

Step 6: addition of C6

AIR carboxylase

Carboxyaminoimidazole ribonucleotide (CAIR)

Step 7: addition of N1

SAICAR synthetase

Step 8: removal of fumaric acid

adenylosuccinate lyase

Step 9: addition of C2

AICAR transformylase

Step 10: ring closure to form IMP

• Once formed, IMP is rapidly converted to AMP and GMP (it does not accumulate in cells).

AMP and GMP are Synthesized from IMP

De novo synthesis of pyrimidine

shorter pathway than for purines requires 6 steps (instead of 10 for

purine) Pyrimidine ring is made first, then

attached to ribose-P (unlike purine biosynthesis)

only 2 precursors (aspartate and glutamine, plus HCO3

-) contribute to the 6-membered ring

the product is UMP (uridine monophosphate)

1. Element source of pyrimidine base

N3 originallyfrom glutamine;C2 from HCO3

•Carbamoyl phosphate synthetase(CPS) exists in 2 types: • CPS-I, a mitochondrial enzyme, is dedicated to the urea cycle and

arginine biosynthesis. • CPS-II, a cytosolic enzyme, used here. It is the committed step in animals.

Step 1: carbamoyl phosphate synthesis

Step 2: synthesis of carbamoyl aspartate

ATCase: aspartate transcarbamoylase

Step 3: formation of pyrimidine ring

Step 4: oxidation of dihydroorot

ate to orotate

(a pyrimidine)

Step 5: formation of OMP

Step 6: decarboxylation of OMP

UDP

ADP

UTP

ATP ADP

UMP

ATP

kinase kinase

UTP and CTP biosynthesis

Summary of denovo Synthesis

Purines built up on ribosePRPP synthetase: key stepFirst, synthesis IMP

Pyrimidine rings built, then ribose addedCPS-II: key stepFirst, synthesis UMP

Salvage pathway

This pathway ensure the recovery and recycling of nucleotides from existing bases

This pathway is occure where the de novo pathway is not operating;

importance in tissue like RBCs and brain.

PRPP is the starting material in this pathway.

Salvage pathway of purines

During cellular metabolism and during digestion in animals, nucleic acids are degraded to mononucleotides, nucleosides, and free purine bases. The free purines are salvaged by 2

different enzyme: APRT (adenine phosphoribosyl transferase) for

adenine. HGPRT (hypoxanthine guanine phosphoribosyl

transferase) for guanine or hypoxanthine.

Purine Salvage Pathway

N

NN

N

NH2

O

Guanine

N

N N

O

N

Hypoxanthine

O

OHHO

2-O3POH2C

N

N N

O

N

IMP

O

OHHO

2-O3POH2C

N

NN

N

NH2

O

GMP

.

.

Adenine AMP

PRPP PPi

adenine phosphoribosyl transferase

PRPP PPi

hypoxanthine-guaninephosphoribosyl transferase

(HGPRT)

Reference Vasudevan DM,Sreekumari S

(2001).Textbook of biochemestry(for medical students).JAYPEEBROTHERS medical publishers LTD New Delhi.

Robert K Murray,Peter A Mayes, Daryle K Granner,Victor W Rodwell(1990).Harper’s biochemestry.Lange Medical publications

www.google.com, wikipedia.org

By,Pillai Aswathy Viswanath