Nucleotide Metabolism 1 Flashcards
Where do most of our purines and pyrimidines for nucleotide synthesis?
Synthesized from amphibolic intermediate
What is a basic difference between the order of purine and pyrimidine synthesis?
Purine - start with sugar, then build purine ring
Pyrimidine - build the pyrimidine ring, then attach sugar
What is the first reaction in purine synthesis?
Ribose-5-phosphate to
Phosphoribosyl pyrophosphate(PRPP)
Enzyme: PRPP Synthase
What five molecules are used to build the purine ring?
ATP Glutamine Tetrahydrofolate Aspartate Glycine
What molecule is the branch point for purine synthesis?
Inosine monophosphate (IMP)
What is the major site of purine synthesis?
Liver
What inhibits PRPP Synthase?
AMP and GMP
Purine nucleotides
What is the committed step of De Novo purine synthesis?
PRPP to 5-phosphoribosylamine
Enzyme: glutamine PRPP amidotransferase
(Aka PRPP Glutamyl Amidotransferase)
What are the inhibitors of Glutamine PRPP amidotransferase?
ATP, ADP, and AMP at one site
GTP, GDP, and GMP at another
What stimulates glutamine PRPP amidotransferase?
PRPP
What occurs during the purine synthesis steps involving glutamine?
The addition of a nitrogen group to the ring
What occurs during the purine synthesis steps that involve folic acid?
Addition of carbonyl to the purine ring
What is the base of IMP?
Hypoxanthine
What stimulates the production of AMP?
GTP
What stimulates the production of GMP?
ATP
What is Azaserine?
Glutamine analog that blocks purine synthesis steps involving glutamine
Primarily used in research.
What are sulfonamides and why are they used?
Inhibit folate metabolism in bacteria by competitively inhibiting PABA
What is methotrexate and what is its mechanism?
A folate analog that competitively inhibits dihydrofolate reductase
Used in cancer chemotherapy
What two disorders are caused by a folic acid deficiency?
Anencephaly
Spinal Bifida
Why does folic acid deficiency cause neural tube defects?
Rapidly dividing cells require large amounts of nucleotides, without folic acid can’t keep up with demand, causing delays in neural folding.
What reciprocal relationship exists between AMP and GMP formation?
ATP is a substrate for GMP synthesis
GTP is a substrate for AMP synthesis
What is purine salvage?
Synthesis of nucleotides from purine bases and nucleosides
What two enzymes are involved in the purine salvage pathway?
Adeninephosphoribosyltransferase
APRT
Hypoxanthine-Guanine PhosphoRibosylTransferase
HGPRT
What is Lesch-Nyhan Syndrome?
Deficiency or complete lack of HGPRT
Gout and kidney stones
Neurological problems
Self-mutilation
X-linked recessive
What is the mechanism for Lesch-Nyhan Syndrome?
Lack of HGPRT causes the build up of PRPP, leading to purine overproduction, and therefore degradation and uric acid build up
Brain relies on salvage, so decreased purine production in brain
What is the function of purine nucleoside phosphorylase
Removes sugar to yield a free base (hypoxanthine or guanine)
What is the final product of purine degradation and what is its biological significance?
Uric Acid
Can catch free radicals
However, insoluble and can percipitate
-kidney stones, gout
What causes gout?
Caused by precipitation of urate
Result of excess purine production or partial deficiency in HGPRT
What is allopurinol and what is used for?
Xanthine analog that blocks xanthine oxidase.
This prevents the formation of uric acid and can prevent gout.
What is Purine nucleoside phosphorylase deficiency?
Defect in the enzyme
Autosomal recessive disorder
Causes immunodeficiency - no T cells
Rare
What is ADA deficiency?
Lack of adenosine deaminase
Autosomal recessive
Causes Severe combined immunodeficiency (SCID)
Destruction of B and T lymphocytes
