Eric Niederhoffer, Ph.D.

SIU-SOM

Pyrimidines and Purines

Outline

• Pyrimidine and purine synthesis

• Pyrimidine and purine salvage/degradation

• Pathway disorders

Pyrimidine and Purine SynthesisHCO3

- + Gln

CP

CPSII

Asp

Oro

R5P

PRPP

RPK

UTP

TSN5,N10-mTHF

dTMP

DNARNA

dGTP dATPRR

GDP ADP

IMP

Gln

Gly

CO2

Asp

N10fTHFUMP

UMPS

CDP

dCDP

dUMP

Pyrimidine and Purine Salvage

U TPRPP

UMP TMP

RR

UTPT

GPRPP

HGPT

A

APTX

XO

adenosine

inosineADA

HXPNP

urateXO

UTP

CDP

dCDP

dUMPTSN5,N10-mTHF

dTMP

RNA DNA

IMP

GDP ADP

dGTP dATPRR

Pathway Disorders

Rare autosomal recessive disorders• UMP synthase – deficiency in either orotate

phosphoribosyltransferase or OMP decarboxylase leads to hereditary orotic aciduria, megaloblastic anemia appearing weeks to months after birth that does not respond to cobalamin, folic acid, or iron, orotic crystalluria and nephropathy, cardiac malformations, strabismus, and recurrent infection. Urine orotic acid overexcretion. Enzyme assay of RBC. Treatment with oral uridine.

• Adenosine deaminase – (Severe combined immunodeficiency disorder) variety of clinical phenotypes, history of infections, diarrhea, dermatitis, and failure to thrive, ribs and vertebrae abnormalities (defects in cartilaginous structures). Lymphopenia, B and T cell production affected. Enzyme assay of RBC/WBC. Treatment by bone marrow/stem cell transplantation or enzyme replacement.

• Purine nucleotide phosphorylase – (Immunodeficiency) lymphopenia, thymic deficiency, recurrent infections, and hypouricemia, developmental delay, ataxia, or spasticity. T cell production affected. Enzyme assay of RBC, lymphocytes, fibroblasts. Treatment by bone marrow/stem cell transplantation.

• Adenine phosphoribosyl transferase – frequent infections, renal colic, renal failure. Elevated urine levels of 2,8-dihydroxyadenine, 8-hyroxyadenine, and adenine; serum uric acid normal. Enzyme assay. Treated with dietary purine restriction, high fluid intake, and avoidance of urine alkalinization, Allopurinol to prevent oxidation of adenine.

Pathway Disorders

X-linked recessive disorder• Hypoxanthine-guanine phosphoribosyl transferase –

(Lesch-Nyhan syndrome) usually presents at 3 to 12 months with orange sandy urine precipitate, dystonia, intellectual disability, self-mutilation (lips, tongue, fingers), and gout. Elevated serum and urine uric acid levels. Enzyme assay on RBC, lymphocytes, fibroblasts. Molecular genetics of gene. Treated supportively with low-purine diet, allopurinol, and plenty of hydration.