Biochemistry Exam 4 - Purine & Pyrimidine Metabolism

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Lesch-Nyhan Syndrome

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-Absence of HPGRTase
-X-linked (occurs primarily in males)
Characterized By:
-increased uric acid
-spacticity
-neurological defects
-aggresive behavior
-self mutilation

-nerve cells rely on salvage pathway

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Pro-drugs

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-many pro-drugs need to go through the salvage pathway to be activated
-Ex. 6-Mercaptopurine & 6-Thioguanine --> antitumor agents

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6-Mercaptopurine & 6-Thioguanine

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-antitumor agents
-act as inhibitors of adenylsuccinate synthase & IMP dehydrogenase
-also act as feedback inhibitors of PRPP amidotransferase

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Purine Nusleoside Phosphorylase Deficiency

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-PNP deficiency causes
decreased T cells and
lymphopenia, but does not
appear to effect B-cells
-Decrease in uric acid
formation, combined with
increased levels of purine
nucleosides and nucleotides.
-dGTP is the major nucleotide
that accumulates in red cells.
-Treatment: bone-marrow
transplantation.

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Adenosine Deaminase Deficiency

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-Causes severe combined
immunodeficiency (SCID)
involving T-cell and usually
B-cell dysfunction.
-Extremely large buildups of
dATP in red cells have been
observed. (dATP is an
inhibitor of ribonucleotide
reductase, and therefore, of
DNA synthesis)
-ADA-deficient children
usually die before 2 years of
age from overwhelming
infection.
-Treatment: bone-marrow
transplantation.

-wipes out entire immune system --> think bubble boy

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Gout

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-Characterized by
hyperuricemia, with recurrent
attacks of acute arthritic joint
inflammation caused by
deposition of Sodium Urate
-Primary gout (hyperuricemia)
is the form of the disease
that is attributable to an
inborn error metabolism (i.e.
over production of uric acid)
-Secondary hyperuricemia
may be caused by other
diseases (e.g. cancer,
chronic renal insufficinecy,
HGPRT deficiency, etc.)
-Treatment: allopurinol
inhibits xanthine oxidase,
which results in an
accumulation of more
soluble hypoxanthine and
xanthine-compounds.

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Main Differences Between Purine & Pyrimidine Synthesis

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-Pyrimidine rings are assembled as a free base before attached to the ribose ring. The purine ring is assembled on the ribose.
-Purine synthesis follows a branched pathway --> AMP & GMP are synthesized from IMP
-Pyrimidine Synthesis follows an unbranched pathway --> CTP is synthesized from UTP

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Carbamoyl Phosphate Synthetase II

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-The enzyme CPS II shows a long solvent-protected channel running through the center of the enzyme.
-This allows the highly reactive intermediate to travel from one active site to the other.
-CPS II channel helps isolate from water

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CPS II Inhibition/Activation

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-inhibition (allosterically regulated) by UTP, a product of the pathway
-activated (allosterically regulated) by ATP & PRPP

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Aspartate Transcarbamylase Reugulation

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-allosterically regulated by CTP in some microorganisms (but not eukaryotes)

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NAD+

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-a 2 electron acceptor (H+)
-mostly used as a cofactor for catabolic enzymes

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beta-aminoisobutyrate found in blood

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-is a sign of DNA degradation/turnover

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Pyrimidine Salvage

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-Can also be salvaged by reactions with PRPP
-Catalyzed by Pyrimidine phosphoribosyltransferase (PPRTase)
-Degredation pathways are quite distinct for purines and pyrimidines, but salvage pathways are quite similar

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Synthesis of deoxyribonucleotides

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-coversion of ribonucleotides to deoxyribonucleotides
-catalyzed by ribonucleotide reductase

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Ribonucleotide Reductase

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-2 R1 subunits (small subunits)
-2 R2 subunits (large subunits)
-catalyzes the reduction of ribinucleotides to deoxyribonucleotides