Purine and Pyrimidine Metabolism Flashcards
purine source of atoms
aspartate, glycine, glutamate
*also needs THF for synthesis
pyrimidine source of atoms
aspartate
Purine de novo synthesis important enzymes
GLutamine Phosphoribosyl Pyrophosphate Amidotransferase
PRPP synthase: activated by Pi, Inhibited by IMP, GMP, AMP
Pyrimidine de-novo synthesis important enzymes
carbamoyl phosphate synthase II (cytosol): activated by PRPP, Inhibited by UTP
Purine Breakdown Products
uric acid = closed base ring
excreted in urine
pyrimidine breakdown products
open base ring
water soluble products used in other reactions
Purine synthesis steps
- glutamine phosphoribosyl pyrophosphate aminotransferase
PRPP + Glutamine –> PRPP + first nitrogen
- PRPP synthase
Ribose 5 phosphate –> PRPP
*involves several AA, CO2, THF, and ATP
Bases Produced:
IMP–> GMP
IMP–>AMP
failure of enzymes involved in AMP synthesis
associated with autism
feedback loop purine synthesis
IMP, GMP, AMP inhibit enzymes acting early in pathway
Pyrimidine synthesis steps
- carbamoyl phosphate synthase II
PRPP + Glutamine –> PRPP + first nitrogen
Nucleotides:
First: UMP, to make cysteine nucleotides converted to triphosphate form
UMP–> UTP–> CTP
UMP synthase Deficiency
orotic aciduria
severe anemia, poor growth, orotate excreted in urine
Treat: feed synthetic uridine to supply pyrimidine nucleotides needed for DNA/RNA synthesis
Purine Breakdown steps
- remove free base from sugar –> free base (adenosine/guanine)
- free bases –> uric acid –> urine
pyrimidine breakdown steps
- remove base ring from ribose
- open base ring
Breakdown products: h20 soluble and used in other pathways (succinyl CoA, malonyl Co-A, acetyl Co-A)
important enzyme in purine breakdown
Xanthine Oxidase:
Hypoxanthine –> Xanthine –> Uric Acid
base specific nucleoside monophosphate kinases
Produces diphosphates: M–>D *bi-directional reactions
adenylate kinase
AMP + ATP –> 2ADP
Guanylate kinase
GMP + ATP –> GDP + ADP
nucleoside diphosphate kinase
produces triphosphates: D–>T
GDP + ATP –> GTP + ADP
CDP + ATP –> CTP + ADP
what enzyme converts ribose to deoxyribose?
ribonucleotide reductase
operates on diphosphate
Regulation based on Primary Regulation Site and Substrate specificity site
regulation of conversion of ribose to deoxyribose
Ribonucleotide Reductase
Primary Regulation Site: On/ Off, Active= ATP, Inactive = dATP
Substrate specificity Site: Dial: sensitive to concentrations of dNTPs
–> makes sure that equal and adequate amounts of each NDP–> dNDP then to dNTPs
ribonucleotide reductase reactions
GDP –> dGDP *Purine
ADP –> dADP *Purine
UDP –> dUDP *Pyrimidine
how to make what is needed for DNA
dUDP dephosphorylated to make dUMP
Thymidylate synthase: dUMP –> dTMP
Kinases: dTMP–> dTDP –> dTTP
SCID
Cause: mutated adenosine deaminase (of purine degradation pathway)
Description: imbalances pool nucleotide feedback inhibition of ribonucleotide reductase through dATP buildup; dNTPs are not made
Prevents DNA synthesis; lowers lymphocyte count
Gout
cause: abnormal purine degredation pathway
description: uric acid builds up in blood; monosodium rate crystal deposit –> inflammation in joints
Gout Treatment
Under Excrete: Increase excretion
Uricosuric drugs: probenecid or sulfinpyrazone
Over Producers:
allopurinol
Both Types:
anti-inflammatory: NSAIDS
Colchicine: stops polymerization of microtubules: inhibits neutrophil migration
Lesch- Nyhan Syndrome
X linked recessive
Cause: deficient enzymes in purine salvage pathway (HGPRT): higher de novo rates of purine synthesis, excessive acid production
Description: HGPRT Hyperuricemia Gout Pissed off (aggression, self-mutilation) Retardation T: DysTonia
6-mercaptopurine/ prodrug azathioprine
anticancer
inhibits PRPP–> IMP
*purine
Mycophenolate
immunosuppressive
¬ Inhibit IMP dehydrogenase
¬ Inhibits IMP GMP
¬ Reduces proliferation of T and B cells
¬ Prevents organ transplant rejection
*purine
Sulfonamides
Inhibit bacterial purine synthesis
¬ Analogs of PABA
¬ Competitively inhibit folic acid synthesis by bacteria
¬ Inhibits synthesis of THF
¬ Slows purine synthesis pathway in microorganisms
¬ Humans do not synthesize folic acid: source= diet
Allopurinol
Inhibits Xanthine Oxidase
¬ Increase in hypoxanthine and xanthine = more soluble than uric acid
Azidothymide (AZD)
anti HIV
inhibits DNA polymerase
acyclovir
anti herpes simplex virus
targets viral DNA polymerase & reverse transcriptase
Acivicin
mostly GMP, anti Cancer
Gln Analog; inhibits nucleotide synthesis
leflunomide
¬ Inhibits dihydroorate dehydrogenase
¬ Inhibits carbamoyl phosphate orotic acid
hydroxyurea
inhibits ribonucleoside reductase
5-FU
¬ Inhibits thymidylate synthase
¬ Inhibits dUMP dTMP
Methotrexate
¬ Inhibits dihydrofolate reductase
¬ Decreased dTMP
¬ Inhibits growth of cancer cells and bacterial growth
¬ Inhibits synthesis of THF and slows purine synthesis pathway
Toxic for all dividing cells
RR activators and inhibitors
RR promotes the production of DNA nucleotides to balance RNA:
- RNA nucleotides activate: ATP, GTP, UTP, CTP
- DNA Nucleotides inhibit: dATP, dGTP, dTTP, dCTP
CPS II: role, activators and inhibitors
CPS II: regulated step pyrimidines
Activated: PRPP, ATP
Inhibited: UTP, CTP
PRPP Synthase Activators and inhibitors
Activators: Pi
Inhibitor: IMP, AMP, GMP
End products Purine and pyrimidine synthesis
Purine:
ATP; dATP
GTP; dGTP
Pyrimidine:
UTP; dTTP
CTP; dCTP
In what disorder is PRPP activity increased?
Lesch-Nyhan: HGPRT Defective
can’t convert
hypoxanthine–> IMP
guanine –> GMP
-IMP and GMP normally inhibit PRPP
In what disorder is PRPP elevated?
Lesch-Nyhan: HGPRT Defective
can’t convert
hypoxanthine–> IMP
guanine –> GMP
-IMP and GMP normally inhibit PRPP
What drug might inhibit the urine detection of OTC disorder? *my personal theory, not tested
Leflunamide:
-excess carbamoyl phosphate from OTC becomes substrate in pyrimidine synthesis –> increased orotic acid production and urinary excretion
Leflunamide inhibits carbamoyl phosphate –>orotic acid so could theoretically decrease urine production
