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METABOLISM OF PURINE NUCLEOTIDES &

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Presentation on theme: "METABOLISM OF PURINE NUCLEOTIDES &"— Presentation transcript:

1 METABOLISM OF PURINE NUCLEOTIDES &
PURINE DISORDERS

2 ROLES OF NUCLEOTIDES Building blocks for DNA and RNA “Second messengers” in signal transduction cascades Energy “currency” of the cell Components of major co-enzymes

3 Purine Biosynthesis Major site – (Adenine & Guanine) in the Liver.
Synthesis starting from Ribose-5-phosphate Denova pathway: Precursors contribute to form the Purine ring: Glycine (C4, C5, N7), Glutamine ( N3, N9), THF (C2, C8 atoms) Aspartate (N1 atom), & CO2 (C6 atom). The construction of 6-membered ring forms Inosine- 5-monophosphate (IMP) – 1st Purine. Energetics – expenditure of 6 high energy bonds. Salvage pathway - Free & dietary purine can be converted into corresponding nucleotides (no need ATP). RBC, Neutrophils & Brain cannot produce Purines by de novo synthesis. But by only salvage pathway (HGPRTase).

4 Glucose-6-P pentose phosphate pathway PRPP synthetase ATP AMP 5-phosphoribosylpyrophosphate (PRPP) Ribose-5-phosphate 5-phospho-ribosylamine Glu PRPP amidotransferase Gln Inosine mono phosphate (IMP) Amino acids: Gly + Gln + Asp Cofactors: N10-formyl THF Figure 1. Synthesis of inosine monophosphate (IMP)

5 NAD+ NADH Gln + ATP Glu+AMP+PPi guanosine monophosphate (GMP) GTP GDP IMP adenosine monophosphate (AMP) aspartate + GTP ATP ADP fumarate GDP + Pi Figure 2. Formation of AMP and GMP from IMP

6 Figure 3. Allosteric inhibition of purine biosynthesis;
Ribose-5-phosphate PRPP synthetase PRPP PRPP amido-transferase 5-phospho-ribosylamine IMP GMP AMP GDP ADP allosteric inhibition Figure 3. Allosteric inhibition of purine biosynthesis; also ATP stimulates formation of AMP. Regulatory enzyme is PRPP amido transferase, controlled by feed back inhibition of nucleotides - IMP, AMP & GMP.

7 GMP, GDP or GTP AMP, ADP or ATP Adenosine Guanosine NH3 adenosine deaminase Inosine Ribose-1-P purine nucleoside phosphorylase Ribose-1-P +PRPP HGPRT GMP Guanine Hypoxanthine HGPRT +PRPP IMP Xanthine Uric acid xanthine oxidase Figure 4. Degradation of purines to uric acid and salvage of purine bases via hypoxanthine-guanine phosphoribosyl transferase

8 METABOLISM OF PURINE

9 X1a Glucose-6-P pentose phosphate pathway PRPP synthetase ATP AMP
5-phosphoribosylpyrophosphate (PRPP) X1a Ribose-5-phosphate 5-phospho--ribosylamine Glu PRPP amidotransferase Gln Inosine mono phosphate (IMP) Amino acids: Gly + Gln + Asp Cofactors: N10-formyl THF Figure 1. Hyperuricemia: Gout: X1a = PRPP synthetase defects associated with a superactive enzyme characterized by an increased Vmax or an enzyme with a reduced Km for ribose-5-P.

10 Disorder of Purine catabolism
In humans, Purine rings are degraded to the metabolically inert uric acid. Normal level of uric acid in blood is 2-7 mg/dl (Female) & 3-8 mg/dl (Male). Uric acid excretion in urine is about 500 – 700 mg/day. 1. GOUT (Hyper uricemia) An inherited metabolic disease Incidence - 3 /1000 person Defect - partial deficiency of HGPRTase or increased levels of PRPP caused by a hyperactive synthetase. Causes - ↓ Synthesis of GMP and IMP & ↑ in PRPP levels --> ↑d Purine biosynthesis by de novo pathway.

11 Gout 1. Primary gout: Inborn error of metabolism due to over production of uric acid Causes: Varient PRPP synthetase, PRPP gltamyl amido transferase, HGPRT deficiency, Glu-6-Pase defiecincy. 2. Secondary gout: Various disease causing ↑or ↓uric acid excretion. E.g.: Cancer, Psoriasis, Trauma, Starvation, Impairment in renal function leads to gout.

12 GOUT Causes Uricosuria Accumulation of sodium urate crystals in the soft tissues called Tophi -causes painful Gouty - Arthritis. Deposition of Na-urate crystals -Renal calculi Clinical finding- Red faced, Acidosis & Renal damage. Treatment Reduced dietary Purine intake & restrict alcohol is advised. Uricosuric drugs. For example – Probenecid (Benemide), Salicylates and Halofenate. Allopurinol (analog of hypoxanthine) competitively inhibits Xanthine oxidase & thus uric acid synthesis (Suicide inhibition) Coichicine is an anti-inflammatory drug to relieve pain. Other useful drugs include Indomethacin, Naproxen, Brufen, Corticosteroids etc.

13 2. LESCH-NYHAN SYNDROME X-linked recessive disorder of Purine metabolism. Incidence is 1 in 10,000 males Defect - Total lack of HGPRTase, salvage pathway Thus ↑ PRPP (de novo pathway), ↑ production of uric acid. Diagnosis - Murexide test (reddish deposit) to detect urine uric acid Clinical manifestations ↑ Production of uric acid causes severe gout, poor growth, and renal failure due to Nephrolithiasis. Neurological abnormalities such as Mental retardation, Aggressive behavior, learning disability & compulsive self-destructive behavior. Irresistible urge to bite their finger & lips (Self mutilation) It shows that abnormal behavior can be caused by absence of a single enzyme.

14 X2 X2 Purine nucleoside +PRPP GMP, GDP or GTP AMP, ADP or ATP
Guanosine Adenosine Guanine Inosine Hypoxanthine Adenosine deaminase Purine nucleoside phosphorylase Xanthine Ribose-1-P Uric acid xanthine oxidase HGPRTase IMP GMP NH3 X2 X2 Inhibited by allopurinol Figure 4. X2 = moderate defect (>50% activity) leading to gout; severe defect (very low activity) leads to Lesch-Nyhan syndrome.

15 3. Immunodeficiency diseases
Immunodeficiency diseases are associated with Purine degradation disorders. Defect: Adenosine deaminase & Purine nucleoside phosphorylase involved in uric acid synthesis. Causes: Severe combined immunodeficiency (SCID) involving T-cell & usually B-cell dysfunctions and thus impaired the immunity. Uric acid synthesis ↓& tissue level of N.S & N.T↑ Treatment: Transferring ADA gene by Gene therapy.

16 4. Hypo uricemia Hypoxanthine xanthine oxidase When serum uric acid level is less than mg/dl represents hypouricemia. A rare congenital Xanthine oxidase deficiency Incidence is 1 in 45,000. It leads to the increased excretion of Xanthine & Hypoxanthine. Causes: Excretion of xanthine in urine - Xanthinuria. Frequently causes the formation of Xanthine stones in the urinary tract. Xanthine xanthine oxidase Uric acid

17 SYNTHESIS OF PYRIMIDINE NUCLEOTIDES
& PYRIMIDINE DISORDERS

18 SYNTHESIS OF PYRIMIDINE NUCLEOTIDES
Synthesis of the Pyrimidine is less complex than that of the purines, since the base is much simpler (6 member ring). Precursors – Carbomyl phosphate & Aspartate De novo synthesis - in the Liver cytosol Energetic: Requires 2ATP

19 -  ATP, PRPP Glutamine + 2ATP + CO2 Carbamoyl-aspartate Aspartate
Carbamoyl phosphate synthetase II (gln) Glu + Pi + 2 ADP Carbamoyl-aspartate Aspartate Aspartate transcarbamoylase Carbamoyl phosphate - Orotate +PRPP OMP Orotate phosphoribosyl transferase UDP UTP +2 ATP UTP +2 ADP Gln + ATP CTP Glu + Pi + ADP UMP Orotidylic acid decarboxylase Figure1 - Biosynthesis of the Pyrimidine nucleotides UTP & CTP

20 Regulation of Pyrimidine Biosynthesis
CPS-II Asp. Trans carbomylase OMP Decarboxylase

21 CATABOLISM OF PYRIMIDINE NUCLEOTIDES
Pyrimidine degraded in the liver. The end products - are nitrogenous bases Cytosine, Uracil and Thymine. The bases are then degraded to amino acids, namely β-Alanine (from Cytosine & Uracil) & β-Amino isobutyrate (from Thymine). These amino acids undergo transamination & other reactions to finally produce Acetyl coA, Succinate & CO2. Clinical significance: β-Aminoisobutyrate is excreted in large quantity in Leukemia & when body subjected to X-ray irradiation.

22 2. Reye’s syndrome Secondary Oratic aciduria
Defect in Ornithine transcarbamoylase (in urea cycle) Causes Accumulation of Carbomyl phosphate This is then diverted for the increased synthesis and excretion of oratic acid.

23 Clinical significances of pyrimidine metabolism
Oraticaciduria Rare inherited disorders. Enzyme deficiency- Orotate phosphoribosyl transferase and OMP decarboxylase. Defect - in UMP formation & thus ↑ Oratate synthesis in blood & its excretion in the urine. Causes - Growth retardation, severe anemia caused by hypo chromic erythrocytes and megaloblastic bone marrow. Leukopenia is also common. Treatment – Diet rich in uridine & cytidine, which ↑UMP production via the action of nucleoside kinases. UMP then inhibits CPS-II, thus ↓ orotic acid production.


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