Pyrimidines and Purines
Eric Niederhoffer,
Ph.D.
SIU-SOM
Outline
• Pyrimidine and purine synthesis
• Pyrimidine and purine
salvage/degradation
• Pathway disorders
Pyrimidine and Purine Synthesis
HCO3- + Gln
R5P
CPSII
RPK
CP
Asp
PRPP
Oro
UMPS
Gln
Gly
UMP
UTP
CDP
N10fTHF
CO2
Asp
dCDP
dUMP
N5,N10-mTHF
TS
dTMP
RNA
DNA
IMP
GDP
ADP
RR
dGTP
dATP
Pyrimidine and Purine Salvage
UTP
CDP
dCDP
IMP
dUMP
N5,N10-mTHF
TS
RR
GDP
dTMP
ADP
RR
dGTP
UMP
TMP
UTPT
RNA
DNA
U
T
PRPP
HGPT
A
G
adenosine
ADA
inosine
PNP
PRPP
HX
XO
APT
urate
X
XO
dATP
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 2,8dihydroxyadenine, 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.