PURINE & PYRAMIDINE METABOLISM

Overview
DNA & RNA needed for Protein synthesis & Cell proliferation Carriers of activated intermediates (CoA, FAD, NAD, NADP) Second messengers (cAMP, cGMP) Energy currency of a cell ATP  Nucleotides can be synthesized de novo or can be obtained by salvage pathways

PYRAMIDINE SYNTHESIS & DEGRADATION
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1st the pyramidine ring is formed Next the sugar moiety i.e ribose-5 po4 is added Pyramidine ring is formed by Glutamine, Aspartic acid & Co2 Carbamoyl Po4 Synthetase II present in the cytoplasm is rate limiting enzyme ATP activates & UTP inhibits CPS II

CPS I Cellular location Pathway Nitrogen source Regulators

CPS II

Mitochondria Cytosol Urea synthesis Ammonia (NH3) N- acetyl Glutamate Pyramidine synthesis Glutamine ATP activates

OROTIC ACID
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2nd step in pyramidine synthesis Defects in enzymes that convert orotic acid to UMP leads to orotic aciduria Decreased UMP  Impairs DNA synthesis  Megaloblastic anemia Orotic acid accumulates & precipitates in Urine Severe anemia not responding to Vit B12 & folates.

PURINE SYNTHESIS
Purine synthesis begins with binding of molecules over ribose sugar  Ribose 5 Po4 is present at the initiation of purine synthesis  Rate limiting step is PRPP  5 Phospho ribosylamine Enzyme is PRPP Amidotransferase  Glycine, Aspartate & Glutamine used in Purine synthesis

SALVAGE PATHWAY FOR PURINES

Salvage enzymes recycle 90% of purines 10% get converted to Uric acid and gets excreated

ADA DEFICIENCY
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Adenosine deaminase deficiency Children susceptible to Candida & PCP Gives rise to Severe combined Imunodeficiency (SCID)

SEVERE COMBINED IMMUNODEFICIENCY (SCID)
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Both Humoral & Cell mediated Immunity Wide array of pathogen infections Primary T cell defect, Secondary B cell defects. 50% are X linked 40 to 50% of Autosomal Recessive

SCID

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Cytokine receptor gene defect (IL-7 receptor) Adenosine Deaminase (ADA) gene mutation causing defective Purine metabolism Thymus is Hypoplastic. Lymphnodes, GIT, Tonsils are all atrophic Lymphocytopenia

HYPERURICEMIA & GOUT

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Over production or Reduced excretion of Uric acid Acute & chronic Gouty Arthritis Monosodiun urate crystals deposit Joints, Soft tissues  Inflammation Allopurinol inhibits Xanthine Oxidase

GOUT

Hyperuricemia does not always lead to gout But Gout is usually preceded by hyperuricemia Decreased Ph at the joints or tissues favor deposition of crystals Definitive diagnosis  Aspiration of joint and examination for crystals

PRIMARY GOUT

Most commonly due to Defective renal excretion of UA Increased production due to mutation in PRPP synthase gene Decreased salvage of Hypoxanthine & Guanine bases  More bases are metabolized by Xanthine oxidase  More UA

LESCH- NYHAN SYNDROME
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XLR Gene located on Y Chromosome Complete deficiency of HPRT Inability to salvage Hypoxanthine or Guanine More availability of PRPP and less IMP / GMP De novo purine synthesis is also increased Severe heritable form of Gout

LESCH- NYHAN SYNDROME
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Hyperuricemia Orange crystals in diapers Renal UA stones Involuntary movements Self mutilation Mental retardation Often death in 1st decade

SECONDARY HYPERURICEMIA
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Chronic Renal failure Pts undergoing chemotherapy Pts with myeloproliferative disorders Excessive alcohol consumption Purine rich foods

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