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Transcript of Nucleotide Metabolism 2556 - si.mahidol.ac.th · Function of Nucleotide 1....
Nucleotide Metabolism 2556
Chalermchai Mitrpant
Outline • Structure of nucleotide
• Biosynthesis of pyrimidine nucleotide
• Function of nucleotide
• Biosynthesis of purine nucleotide
De novo and Salvage pathway and its regulatory mechanism
De novo and Salvage pathway and its regulatory mechanism
• Diseases relating to nucleotide synthesis
• Biosynthesis of deoxynucleotide and its regulatory mechanism
• Catabolism of pyrimidine nucleotide and related diseases
• Catabolism of purine nucleotide and related diseases
• Biosynthesis of Coenzymes
• Medication related to nucleotide metabolism
Structure and function of Nucleotide
Structure of Nucleotide
Function of Nucleotide
1. เปนหนวยยอย (monomeric unit) ใชในการสรางกรดนวคลอคซงในรางกายแบงไดเปน 2 พวก คอ DNA (deoxyribonucleic acid) และ RNA (ribonucleic acid)
2. Adenosine triphosphate (ATP); เปนสารใหพลงงานสง มความส าคญ ในการขบเคลอนปฏกรยาตางๆทจ าเปนตองใชพลงงาน โดยปฏกรยาสลาย ATP (ATP hydrolysis) จะสงผานพลงงานเสร เพอเปลยนสมดลของปฏกรยาใหเกดไดงายขน (ATP coupling)
3. เปนสอกลาง (mediator) ของขบวนการตางๆในรางกาย เชน cyclic AMP (cAMP),
cyclic GMP (cGMP)
4. เปนสารตนในการสงเคราะห cofactor บางชนด เชน GTP ใชในการสงเคราะห
tetrahydrobiopterin
5. เปนสวนประกอบของโคเอนไซม เชน NAD (nicotinamide adenine dinucleotide), FAD (flavin adenine dinucleotide) และ coenzyme A
Function of Nucleotide
6. ชวย น า สาร intermediates ในปฏกรยาบางอยาง เชน UDP-glucose (Glycogen synthesis), CDP-choline, และ CDP-diacylglycerol
(glycolipid synthesis)
7. เปน allosteric effector ทควบคมการท างานของเอนไซมหลายชนด
8. AMP ท าหนาท metabolic sensor ควบคมเมแทบโบลซมในเซลล ท างานสมพนธกนกบ adenylate kinase (AK) และ AMP kinase (AMPK)
9. ADP ท าหนาทเกยวของกบการเกาะกลมของเกลดเลอด ภายหลงจากเกลดเลอดถกกระตน จะหลง ADP และ ADP นเองจะจบกบ adenosine receptor P2Y12 บนผวของเกลดเลอดน า ไปสการเกาะกลมของเกลดเลอด
AMP as a metabolic sensor
ADP as a mediator for platelet activation
ADP
Clopidogrel
Biosynthesis
Biosynthesis of nucleotide
Purine nucleotide Pyrimidine nucleotide
• De novo
• Salvage
• De novo
• Salvage
Synthesis of PRPP
Voet Biochemistry 3e © 2004 John Wiley & Sons, Inc.
The metabolic pathway for the de novo
biosynthesis of IMP
Voet Biochemistry 3e © 2004 John Wiley & Sons, Inc.
IMP is converted to AMP or GMP in
separate two reactions
Voet Biochemistry 3e © 2004 John Wiley & Sons, Inc.
The biosynthetic origins of purine ring atoms
IMP
De novo Purine synthesis
Voet Biochemistry 3e © 2004 John Wiley & Sons, Inc.
IMP is converted to AMP or GMP in
separate two reactions
Regulation of de novo Purine synthesis
Salvage purine synthesis
Salvage purine synthesis
De novo Pyrimidine synthesis
Salvage pyrimidine synthesis
Uracil
Uracil
Uridine
Uridine
Biosynthesis of deoxynucleotide
Substrate for RNA synthesis
Deoxyadenosine triphosphate dATP
dGTP
dCTP
dTTP
Substrate for DNA synthesis
Biosynthesis of deoxynucleotide
Biosynthesis of deoxynucleotide
Substrate for RNA synthesis
Deoxyadenosine triphosphate
dATP
dGTP
dCTP
dTTP
Substrate for DNA synthesis
dUTP
Biosynthesis of deoxynucleotide (dTTP)
1. From dCDP
2. From dUDP
1. 2.
Biosynthesis of deoxynucleotide (dTTP)
Regulation of deoxynucleotide biosynthesis
Diseases related to biosynthesis of nucleotide
Purine Pyrimidine
1. Lesch nyhan syndrome 1. Orotic aciduria
2. Renal lithiasis
(APRT deficiency)
Lesch Nyhan syndrome
• X-linked recessive inherited disorder • Neurological dysfunction
• Cognitive and behavioral disturbance;
self-mutilation • Uric acid overproduction
How does Lesch Nyhan syndrome causes hyperuricemia
• Excess of hypoxanthine and guanine
• Reduced IMP and GMP
Management
• Symptomatic treatment; benzodiazepine (reduced anxiety)
• Medication to reduce uric acid; Allopurinol & Probenecid
• SAM supplement (still in clinical research)
Lesch Nyhan syndrome
Guanine Deaminase
How does Lesch Nyhan syndrome
causes hyperuricemia
(Guanase)
How does Lesch Nyhan syndrome
causes hyperuricemia
Role of SAM supplement in
patient with Lesch Nyhan syndrome
APRT deficiency
Excess adenine
8-hydroxy adenine
2,8-dihydroxy adenine
Xanthine oxidase
Xanthine oxidase
• Renal lithiasis
• Renal failure
Orotic aciduria
• Orotate decarboxylase
or Orotate Phosphoribosyltransferase
• Growth Retardation
• Megaloblastic anemia
Symptoms
Management
• Uridine supplement
• Autosomal recessive
Uridine
Catabolism
Catabolism of purine nucleotide
Catabolism of purine nucleotide
Diseases related to catabolism of purine
2. Severe combined immune deficiency (Adenosine
deaminase)
1 .Purine nucleotide phosphorylase
3. Gout
Purine nucleotide phosphorylase deficiency
• Defect in T-lymphocyte related immunological defense
(2/3 of cases)
• Excess 1,2 & 3 can be excreted by kidney
• Excess of 1. inosine, 2. deoxyinosine, 3. Guanosine and
4. deoxyguanosine
• Deoxyguanosine -------> dGTP
Purine nucleotide phosphorylase deficiency
PNP
dGTP
Purine nucleotide phosphorylase deficiency
dATP
Overall Inhibition of RNR
Inhibit DNA synthesis
Specific activation of RNR
Loss in mitochondrial membrane potential
Apoptosis of thymocyte in Thymus
Effect on number and function of T-lymphocyte
Adenosine deaminase deficiency
• Defect in both T- and B-lymphocyte related
immunological defense
• Excess deoxyadenosine -------> dATP
• Severe combined immunodeficiency (SCID)
• Inhibit RNR and inhibit Lymphocyte proliferation
Adenosine deaminase deficiency
Overall Inhibition of RNR Inhibit DNA synthesis
Hyperuricemia and Gout
• Uric; Final degradative product of purine in human
• Deposition of urate crystal causes Gout (Gouty arthritis)
• Not well-dissolved in water
• Increased purine synthesis
• Increased purine catabolism;
patient with cancer prescribed on chemotherapy
• Genetic disease; Lesch Nyhan syndrome and PRPS hyperactivity
• Decreased Excretion
Cause of Hyperuricemia
• Glucose-6-phosphatase deficiency
Excess G-6-P promotes Pentose phosphate pathway
• Polymorphism on urate transporter ATP binding G2 (ABCG2)
decreases rate of urate transport and then decrease urate secretion
Catabolism of purine nucleotide
and uric acid excretion
Probenecid
Allopurinol
Voet Biochemistry 3e © 2004 John Wiley & Sons, Inc.
Mechanism of competitive inhibitor of Allopurinol on xanthine oxidase
Catabolism of pyrimidine nucleotide
Nucleotidase
Nucleotidase
Nucleotidase
1. 5’-Nucleotidase deficiency
2. Lead poisoning
Diseases related to catabolism of pyrimidine
Disease relating to Catabolism of pyrimidine
5’-Nucleotidase deficiency
• Hemolytic anemia
• Basophilic strippling
Nucleotidase
PNP
• Increased CMP and UMP
Blood smear is similar to lead poisoning associated hemolytic anemia
How can lead inhibit 5’Nucleotidase?
Decreased 5’-Nucleotidase activity in patient with lead poisoning
5’-Nucleotidase inhibition in Lead poisoning
Medications related to nucleotide metabolism
and coenzyme synthesis
Antitumour drug in clinical used
1. Antimetabolite
• 5 Fluorouracil (5-FU)
• 6 Mercaptopurine (6-MP)
• Inhibit Thymidylate synthase (dUMPdTMP)
2. Antifolate
• Metrothexate
• Aminopterin
• Interfere on gene splicing
• DNA damage
• Inhibit Amidophosphoribosyl transferase
• Inhibit IMP dehydrogenase
• Inhibit Adenylosuccinate synthetase
Inhibit Thymidylate synthase (dUMPdTMP)
Tetrahydrofolate
Mechanism of action of
Antimetabolite and antifolate
Mechanism of action of 6-MP
Antitumour drug in clinical used
3. Glutamine antagonist
• Inhibit reactions required glutamine
IMP GMP conversion
UTP CTP conversion
PRPP synthesis and CPSII
Antiproliferation drug
Hydroxyurea
Antiviral drug
Acyclovir (Acycloguanosine)
• Active form “Acycloguanosine triphosphate”
• AcycloGTP is the specific substrate for HSV DNA polymerase causing DNA chain termination
• Metabolised to AcycloGMP only by Thymidine kinase of HSV (herpes simplex virus)
• Treatment for Herpes Zoster
Antiviral drug
AZT (Zidovudin)
• Active form “AZT triphosphate”
• Inhibitory effect of AZT triphosphate on HIV DNA polymerase is 100 fold more sensitive than human DNA polymerase
• Metabolised to AZT-triphosphate by Thymidine kinase of host cell
• Treatment for Human immune deficiency viral infection
Biosynthesis of Nicotinamide adenine
dinucleotide
Biosynthesis of flavin adenine dinucleotide
Biosynthesis of Coenzyme A
1. หลงปรบเพมขนาด ตวอกษรบน slide ยงคงมขนาดเลก
2. มองไมเหนความเชอมโยงระหวางเนอหา ของ lecture แตละสวน
3. อาจารยบรรยายเรว ไมสามารถท าความเขาใจเนอหาไดทน
4. อาจารย บรรยายโดยไมชประเดนเนนจดส าคญของเนอหา
Response 2555