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BIOC 801 Dr. Tischler

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Hyperuricemia: Gout: X1a = PRPP synthetase defects associated with a ... Gout: X1b = PRPP synthetase defect associated with resistance to feedback inhibition. ... – PowerPoint PPT presentation

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Title: BIOC 801 Dr. Tischler


1
BIOC 801 - Dr. Tischler Lecture 20 February
10, 2006
METABOLISM NUCLEOTIDE SYNTHESIS DISORDERS
2
CLINICAL PREMISE S.G., a 45-year-old Caucasian
male, presented to your office complaining of
foot pain. The pain began approximately one week
ago when he noticed one morning that his right
big toe was swollen and painful to touch. He
attributed the pain to stubbing his toe two
days earlier on a coffee table. He initially took
aspirin and Tylenol with some minimal improvement
in the pain, but over the past week the pain has
increased and now the big toe is red. Further
history reveals that S.G. is an accountant, has
had a weight problem most of his life, doesnt
exercise and is a wine connoisseur. Physical
examination reveals an obese, middle-aged white
male. His vital signs are normal with the
exception of elevated BP. His right toe is
swollen and the skin over the joint is inflamed
and tender to touch. His left big toe is swollen
but is not inflamed. A complete blood count is
normal. His blood chemistry values were normal
except for uric acid of 14.5 mg/dl (nl 3-9
mg/dL). Urinalysis reveals a crystalluria.
Analysis of RBC enzymes relevant to uric acid
metabolism shows normal activity and normal
regulation of the metabolic pathway.
3
ROLES OF NUCLEOTIDES
  • building blocks for DNA and RNA
  • second messengers in signal transduction
    cascades
  • energy currency of the cell

4
Glucose-6-P
pentose phosphate pathway
Ribose-5-phosphate
Figure 1. Synthesis of inosine monophosphate
(IMP)
5
IMP
Figure 2. Formation of AMP and GMP from IMP
6
PRPP synthetase
PRPP amido-transferase
IMP
GMP
AMP
GDP
ADP
Figure 3. Allosteric inhibition of purine
biosynthesis also ATP stimulates stimulates
formation of AMP.
7
GMP, GDP or GTP
AMP, ADP or ATP
Adenosine
Guanosine
adenosine deaminase
NH3
Inosine
purine nucleoside phosphorylase
Ribose-1-P
Ribose-1-P
Guanine
Hypoxanthine
Figure 4. Degradation of purines to uric acid and
salvage of purine bases via hypoxanthine-guanine
phosphoribosyl transferase (HGPRT).
8
Glucose-6-P
pentose phosphate pathway
X1a
Ribose-5-phosphate
Figure 1. Hyperuricemia Gout X1a PRPP
synthetase defects associated with a superactive
enzyme characterized by an increased Vmax or an
enzyme with a reduced Km for ribose-5-P.
9
X1b
PRPP synthetase
PRPP amido-transferase
IMP
GMP
AMP
GDP
ADP
Figure 3. Gout X1b PRPP synthetase defect
associated with resistance to feedback inhibition.
10
X2
X2
Inhibited by allopurinol
Figure 4. X2 moderate defect (50 activity)
leading to gout severe defect (very low
activity) leads to Lesch-Nyhan syndrome.
11
GOUT AND LESCH-NYHAN SYNDROME
Gout hyperuricemia due to a variety of causes
Lesch-Nyhan syndrome excessive hyperuricemia
leads to self-mutilation
Urate crystals appearing in a diaper often
found in synovial fluid of joints
12
Incan Mask Depicting An Individual Presumably
with Lesch-Nyhan as Evidenced by the
Self-Mutilation
13
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14
? ATP, PRPP
carbamoyl phosphate
-
UDP UTP
Figure 5. Biosynthesis of the pyrimidine
nucleotides UTP and CTP.
15
Figure 6. Biosynthesis of deoxyribonucleotides
by ribonucleotide reductase and of thymidine
monophosphate (TMP) by thymidylate synthase.
16
Suicide inhibitor
DHF reductase
THF
DIETARY FOLIC ACID
Figure 7. Metabolism of dietary folic acid to
its various cofactor forms.
X3 site at which cobalamin (B12) deficiency
causes folate to be trapped as N5-methyl THF
X4 fluorodeoxyuridylate (F-dUMP), synthesized
from 5-flurouracil, acts as chemotherapeutic
agent
X5 site at which methotrexate (MTX) acts as a
chemotherapeutic agent
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