Chapter 41
Purine and Pyrimidine Metabolism
Purines
1. What does alkaline phosphatase do in the intestines?
 dephosphorylates nucleotides to nucleosides
2. What is the first commited step of purine synthesis? Enzyme? What is added afterwards? What
is the product after all these reactions?
 PRPP + glutamine’s amino group
[glutamine is the mean glue that holds it together]
i. catalyzed by glutamine phosphoribosyl amidotransferase
ii. PRPP = 5-PhosphoRibosyl-1-PyroPhosphate
 Glycine, N10-formyl-FH4,glutamine, CO2, Aspartate, and another N10-formyl-FH4
i. 6 molecules of ATP are needed
 Inosine monophosphate (IMP)
3.
4.
How is AMP made from IMP? How is GMP different (2 steps)?
 Aspartate + GTP is added by adenylosuccinate synthase, then fumarate is subtracted by
adenylosuccinase
 IMP dehydrogenase turns IMP into xanthosine monophosphate;
 then Glutamine + ATP is added by GMP synthetase
What four enzymes are regulated? How are they regulated?
First 2 steps of IMP synthesis: PRPP synthetase, glutamine phosphoribosyl amidotransferase
i. PRPP synthetase inhibited by ADP and/or GDP (2 allosteric sites)
ii. The other enzyme is dimerized and inactivated by GMP and AMP
 First step of either AMP and GMP synth: Adenlyosuccinate synthetase, IMP dehydrogenase
i. inhibited by AMP or GMP, respectively

5. SALVAGE. Occurs after 5’ nucleotidase digests DNA into nucleosides. What does purine
nucleoside phosphorylase do? What is the second stage—how are nucleotides IMP or GMP
reformed? What is special about the Adenine/AMP/Adenosine pathway?
 Replaces a purine base for a phosphate group, creating a free base:
i. Guanosine is converted to guanine
ii. Inosine to hypoxanthine (adenosine is first deaminated to inosine)
 Then, a phosphoribosyl transferase (HGPRT) takes phosphate from PRPP to reform the
nucleotide, IMP or GMP
i. The reactions in #3 convert IMP to AMP
 Adenosine can also be directly converted back to AMP by adenosine kinase
6.
What happens when purine nucleoside phosphorylase is deficient due to a mutation? What do
you call the condition caused by defective HGPRT? Clinical presentation?
 T cell immunity is compromised
 Lesch-Nyhan syndrome: mental retardation and self-mutilation
 Speculation: since de novo synthesis occurs in liver, brain, and leukocytes…maybe
overactivation of this pathway is harming these tissues?
Pyrimidines
7. What molecules are combined to make pyrimidines? What enzyme catalyzes the synthesis of
Glutamine, CO2, and ATP into carbamoyl phosphate? What activates this reaction and where
does it take place?
 Aspartate and carbamoyl phosphate
 CPSII: Carbamoyl phosphate synthetase II
 PRPP; Cytosol
i. a MAP kinase makes CPSII more sensitive to PRPP approaching S phase
8.


9.
What is the last mainline product, and what provides feedback inhibition to CPSII?
UDP
UTP
How is CTP made?
 UTP + glutamine’s amino group
[the glue of nucleotide synthesis]
 Does not work with anything but UTP
10. What does pyrimidine nucleoside phosphorylase do? What is the next step?
 Non-specific enzyme that converts pyrimidine bases into their respective nucleosides
i. NOTE: purine version runs in opposite direction
 Nucleoside kinases make nucleosides into nucleotides
 Much simpler salvage than w/purines! Base=> nucleoside=> nucleotide
11. What is hereditary orotic aciduria, what causes it, and how is it cured? [test Q]
 Lack of enzymes converting orotate to UMP (defective orotate phosphoribosyltransferase
and orotidine 5’ phophate decarboxylase)
 pyrimidines can’t be synthesized—synthesis is stuck at the intermediate orotate
 Administer uridine, which can be converted to UMP by other enzymes
12. What is another way that orotic aciduria can occur? [test Q]
 OTC (urea cycle) deficiency leaves too much carbamoyl phosphate floating around; this is
used in pyrimidine production, bypassing the rate controlled step; lots of orotate is produced
along this route, it just can’t be converted quickly enough to nucleotides
13. What does ribonucleotide reductase do? How does an accumulation of dTTP change its activity?
How does an accumulation of dGTP change its activity?
 converts the ribose of a nucleotide (diphosphate nucleotides only!) into deoxyribose
 favors reduction of GDP to dGDP
Teegax
 Favors reduction of ADP to dADP
cycle of favor: T=> G=> A=> C or U
14. What can generally stimulate purine synthesis, and thereby cause gout?
 PRPP accumulation (used in first commited step), perhaps caused by lack of the enzyme
glucose 6-phosphatase
15. What can be radiolabeled to determine if purines are being overproduced?
 15N-labeled glycine
16. What does allopurinol inhibit?
 Suicide inhibitor of xanthine oxidase
 Also decreases synthesis by decreasing levels of PRPP (salvage of xanthine requires PRPP)
17. What happens when adenosine deaminase is deficienct?
 SCID
[path: this is actually the less common variant of SCID]