PURINE & PYRAMIDINE METABOLISM

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

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 location

Mitochondria Cytosol

Pathway Urea synthesis

Pyramidine synthesis

Nitrogen source

Ammonia (NH3)

Glutamine

Regulators N- acetyl Glutamate

ATP activates

Co2

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 isPRPP 5 Phospho ribosylamineEnzyme 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