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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
 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 CPS II

Cellular Mitochondria Cytosol


location
Pathway Urea Pyramidine
synthesis synthesis
Nitrogen Ammonia Glutamine
source (NH3)
Regulators N- acetyl ATP
Glutamate activates
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.
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
 Adenosine deaminase deficiency
 Children susceptible to Candida &
PCP
 Gives rise to Severe combined
Imunodeficiency (SCID)
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
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
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
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
 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
 Hyperuricemia
 Orange crystals in diapers
 Renal UA stones
 Involuntary movements
 Self mutilation
 Mental retardation
 Often death in 1st decade
SECONDARY HYPERURICEMIA
 Chronic Renal failure
 Pts undergoing chemotherapy
 Pts with myeloproliferative disorders
 Excessive alcohol consumption
 Purine rich foods