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Structure and function of Nucleotide

Nucleotide Metabolism
2019

Chalermchai Mitrpant

Outline Structure of Nucleotide

• Structure of nucleotide
• Function of nucleotide
• Biosynthesis of purine nucleotide
 De novo and Salvage pathway and its regulatory mechanism 
• Biosynthesis of pyrimidine nucleotide
 De novo and Salvage pathway and its regulatory mechanism 
• Biosynthesis of deoxynucleotide and its regulatory mechanism
• Diseases relating to nucleotide synthesis
• Catabolism of purine nucleotide and related diseases
• Catabolism of pyrimidine nucleotide and related diseases
• Medication related to nucleotide metabolism
• Biosynthesis of Coenzymes
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Function of Nucleotide Function of Nucleotide

4. cAMP and cGMP is mediator downstream to receptor for hormones 
1. Function of nucleotide: monomeric unit to synthesise nucleic 
(glucagon or epinephrine)
acid (DNA or RNA)

2. ATP is a high energy molecule critical to drive reactions by 
means of transfering high energy by ATP hydrolysis and ATP

Function of Nucleotide Function of Nucleotide

3. Composition of coenzyme i.e. Coenzyme A, NAD and FAD used in  5. GTP is used for biosynthesis of biopterin which is a cofactor 
enzyme for hydroxylation of Phenylalanine, Tyrosine and Tryptophan
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Function of Nucleotide Function of Nucleotide

6. Allosteric control to regulate many enzymes
Clopidogrel

ADP

9. ADP is required for platelet activation; Once activated, platelet will 
release ADP to have a paracrine effect promoting platelet aggregation 

Function of Nucleotide Biosynthesis

7. AMP is the metabolic sensor to control metabolism by using 
different isoforms of adenylate kinase and AMP‐kinase (AMPK)

ATP
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De novo Purine synthesis

Biosynthesis of nucleotide

Purine nucleotide Pyrimidine nucleotide

• De novo • De novo
• Salvage • Salvage IMP  Adenylosuccinate
dehydrogenase synthetase

Gunosine monophosphate Adenosine monophosphate

(GMP) (AMP)

De novo Synthesis Precursors Synthesis of PRPP

Ribonucleotides!
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Regulation of de novo Purine synthesis

Synthesis of 5-phosphoribosyl amine (PRA)

P‐Pi
Glutamine
N 2

GMP AMP

IMP is converted to AMP or GMP in Salvage purine synthesis

separate two reactions

IMP 
NAD+ Aspartate+GTP
dehydrogenase (AMP)
Adenylosuccinate
NADH+H+ GDP synthetase

(IMP)

Glutamine+ATP
Adenylosuccinate
Glutamate+ADP Fumarate
(GMP)

AMP
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Salvage purine synthesis Salvage pyrimidine synthesis

(UMP)
Uracil

(Uridine)
Uracil

De novo Pyrimidine synthesis

Biosynthesis of deoxynucleotide

Orotate

Deoxyadenosine triphosphate dATP

dGTP
dCTP
dTTP

Substrate for RNA synthesis Substrate for DNA synthesis

UMP
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Biosynthesis of deoxynucleotide Biosynthesis of deoxynucleotide (dTTP)

1. From dUDP
2. From dCDP

dUDP

Biosynthesis of deoxynucleotide Regulation of deoxynucleotide biosynthesis

Deoxyadenosine triphosphate dUTP

dATP
dGTP
dCTP
dTTP

Substrate for RNA synthesis Substrate for DNA synthesis


Diseases related to biosynthesis of nucleotide
Purine
Lesch nyhan syndrome
(HGPRT deficiency)
Lesch Nyhan syndrome
• X-linked recessive inherited disorder
• Cognitive and behavioral disturbance;
self-mutilation
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Lesch Nyhan syndrome
How does Lesch Nyhan syndrome causes hyperuricemia
Pyrimidine
• Excess of hypoxanthine and guanine
Orotic aciduria
• Reduced IMP and GMP
(IMP)
(GMP)
Management
• Symptomatic treatment; benzodiazepine (reduced anxiety)
• Medication to reduce uric acid; Allopurinol & Probenecid
How does Lesch Nyhan syndrome
causes hyperuricemia
• Neurological dysfunction Guanine Deaminase
(Guanase)
• Uric acid overproduction
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How does Lesch Nyhan syndrome

causes hyperuricemia Catabolism

Orotic aciduria Catabolism of purine nucleotide

Symptoms

• Autosomal recessive

• Orotate decarboxylase
or Orotate Phosphoribosyltransferase

• Growth Retardation

• Megaloblastic anemia

Uridine
Management

• Uridine supplement
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Catabolism of purine nucleotide Purine nucleotide phosphorylase deficiency

• Defect in T-lymphocyte related immunological defense

(2/3 of cases)

• Excess of 1. inosine, 2. deoxyinosine, 3. Guanosine and

4. deoxyguanosine

• Excess 1,2 & 3 can be excreted by kidney

• Deoxyguanosine -------> dGTP

Diseases related to catabolism of purine Purine nucleotide phosphorylase deficiency

1 .Purine nucleotide phosphorylase

2. Severe combined immune deficiency
(Adenosine deaminase)

3. Gout

PNP
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Purine nucleotide phosphorylase deficiency Adenosine deaminase deficiency

dGTP Overall Inhibition of RNR Inhibit DNA synthesis

Specific activation 
of RNR

dATP
Loss in mitochondrial 
membrane potential

Overall Inhibition of RNR

Inhibit DNA synthesis
Apoptosis of thymocyte in Thymus

Effect on number and function of T‐lymphocyte

Adenosine deaminase deficiency Hyperuricemia and Gout

• Acute/recurrent monoarthritis (commonly found on the 1st
• Defect in both T- and MTP)
B-lymphocyte related
immunological defense • Deposition of urate crystal causes Gout (Gouty arthritis)

• Uric; Final degradative product of purine in human
• Severe combined
immunodeficiency
(SCID)

• Excess deoxyadenosine
and dATP

• Inhibit RNR and inhibit Lymphocyte proliferation

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Cause of Hyperuricemia Catabolism of purine nucleotide

and uric acid excretion
• Increased purine synthesis
Allopurinol
• Genetic disease; Lesch Nyhan syndrome and PRPS hyperactivity

• Increased purine catabolism;

patient with cancer prescribed on chemotherapy

• Glucose-6-phosphatase deficiency Probenecid

Excess G-6-P promotes Pentose phosphate pathway

• Decreased Excretion

• Polymorphism on urate transporter ATP binding G2 (ABCG2)

decreases rate of urate transport and then decrease urate secretion

How glucose 6 phosphatase deficiency Mechanism of competitive inhibitor of 

causes of Hyperuricemia Allopurinol on xanthine oxidase

Voet Biochemistry 3e
© 2004 John Wiley & Sons, Inc.
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Medications related to nucleotide metabolism Mechanism of action of

Antimetabolite and antifolate

Interfering 
pre‐mRNA splicing

Antitumour drug in clinical used Mechanism of action of 6-MP

Azathioprine

1. Antimetabolite
• 5 Fluorouracil (5‐FU)
• Inhibit Thymidylate synthase (dUMPdTMP)
• Interfere on gene splicing
• DNA damage
• 6 Mercaptopurine (6‐MP) and Azathioprine
• Inhibit Amidophosphoribosyl transferase
• Inhibit IMP dehydrogenase Tetrahydrofolate
• Inhibit Adenylosuccinate synthetase
2. Antifolate
• Metrothexate
• Inhibit Thymidylate synthase 
(dUMPdTMP)

Antiviral drug
Anti-herpes simplex virus drugs
O
Virion entry into the cell
viral gene expression
viral DNA replication
primary envelope formation
Egress
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Antiviral drug
Anti-HIV medications
NRTIs (Nucleoside)
Zidovudin: 3’‐azido‐2’,3’‐dideoxythymidine (AZT)
Didanosine: 2’,3’‐dideoxyinosine (ddI)
Zalcitabine : 2’,3’‐dideoxycytidine (ddC)
Stavudine: 2’3’‐dideoxy‐2’,3’‐didehydrothymidine (d4T)
Lamivudine: (‐‐)‐b‐L‐3’‐thia‐2’,3’‐dideoxycytidine (3TC)
Abacavir: 2‐amino‐6‐cyclopropylaminopurine‐9‐yl‐2‐cyclopentene (ABC)
Emtricitabine: (‐‐)‐b‐L‐3’‐thia‐2’,3’‐dideoxy‐5‐fluorocytidine ((‐‐)‐FTC)
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Antiviral drug Biosynthesis of Coenzymes and applications

AZT (Zidovudin)
• Treatment for Human immune deficiency viral infection
• NAD • FAD • Coenzyme A
• Active form “AZT triphosphate”
• Metabolised to AZT‐triphosphate by Thymidine kinase of 
host cell Question NAD FAD Coenzyme A
• Inhibitory effect of Reverse transcription of HIV RNA virus Can human synthesize it in our body?
Diagram to demonstrate how can it be 
synthesized?
Can the knowledge of this metabolism 
be used for antimicrobial medication? 

Anti-HIV medications

NRTI