purine & pyramidine met
DESCRIPTION
Molecular BiochemistryTRANSCRIPT
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PURINE & PYRAMIDINE METABOLISM
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Overview
DNA & RNA needed forProtein synthesis & Cell proliferationCarriers 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
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PYRAMIDINE SYNTHESIS & DEGRADATION
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
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CPS I CPS II
Cellular location
Mitochondria Cytosol
Pathway Urea synthesis
Pyramidine synthesis
Nitrogen source
Ammonia (NH3)
Glutamine
Regulators N- acetyl Glutamate
ATP activates
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Co2
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OROTIC ACID 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.
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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 isPRPP 5 Phospho ribosylamineEnzyme is PRPP Amidotransferase Glycine, Aspartate & Glutamine
used in Purine synthesis
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SALVAGE PATHWAY FOR PURINES
Salvage enzymes recycle 90% of purines
10% get converted to Uric acid and gets excreated
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ADA DEFICIENCY
Adenosine deaminase deficiency Children susceptible to Candida &
PCP Gives rise to Severe combined
Imunodeficiency (SCID)
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SEVERE COMBINED IMMUNODEFICIENCY (SCID)
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
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SCID
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
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HYPERURICEMIA & GOUT
Over production or Reduced excretion of Uric acid
Acute & chronic Gouty Arthritis Monosodiun urate crystals deposit Joints, Soft tissues Inflammation Allopurinol inhibits Xanthine
Oxidase
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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
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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
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LESCH- NYHAN SYNDROME
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
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LESCH- NYHAN SYNDROME
Hyperuricemia Orange crystals in diapers Renal UA stones Involuntary movements Self mutilation Mental retardation Often death in 1st decade
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SECONDARY HYPERURICEMIA
Chronic Renal failure Pts undergoing chemotherapy Pts with myeloproliferative disorders Excessive alcohol consumption Purine rich foods