Drugs and Diseases: Purine, Pyrimidine metabolism Flashcards
derivatives of purine C’s and N’s
N1: Asp amino C2, C8: C1-THF N3, N9: Gln amide C6: HCO3- C4, C5, N7: Gly
what causes Lesch-Nyhan syndrome?
HGPRT deficiency
how is Lesch-Nyhan inherited?
x-linked
symptoms of Lesch-Nyhan?
- increased uric acid, xanthine
- increased purine synthesis to compensate
- neuro disease: athetosis, chorea, dystonia, self mutilation
- urate nephrolithiasis
- hyperuricemia
how do you treat Lesch-Nyhan?
allopurinol - competitive inhibitor of xanthine oxidase (suicide inhibitor)
what causes gout?
high serum uric acid
symptoms of gout
-tophus lesion (deposit of uric acid crystals + inflam) in extremities, at night (temp related)
3 known metabolic causes of gout
- increased PRPP synthetase activity
- HGPRT deficiency
- G-6-phosphatase deficiency (von Gierke’s) - indirect
treatment of gout
- allopurinol (lower uric acid)
- colchicine (no neutrophil migration)
- decreased alcohol (increase lactate = lower pH = decreased uric acid solubility)
- NSAIDS (no excretion of urate)
- uricase (urate -> allantoin)
what is correlated with gout attacks?
fructose
what causes SCID?
ADA (adenosine deaminase deficiency)
symptoms of SCID
- no B or T cells
- recurrent infections
- increased dATP in lymphocytes -> decreased ribonucleotide reductase -> less trans-methylation
what does purine nucleoside phosphorylase deficiency cause?
- no T cell fxn
- accumulation of inosines, guanosines
- recurrent infections
what are two targets for chemo? which chemos target each?
- thymidylate synthase - fluorodeoxyuridylate (suicide inhibitor)
- DHFR - aminopterin and MTX (amethopterin)
2 antiviral agents that are purine analogs?
- acyclovir (acycloguanosine)
2. ganciclovir
what activates acyclovir and ganciclovir?
activated to mono-phosphate by viral HSV-thymidine kinase
mechanism of action of acyclovir and ganciclovir?
tri-phosphate is substrate for HSV-specific DNA pol -> causes DNA chain termination of viral gene products
what is ganciclovir used to treat?
cytomegalovirus infections in HIV patients
2 antiviral agents that are pyrimidine analogs?
- AZT (azido-d’-deoxythymidine)
2. DDI (2’,3’-dideoxyinosine)
activation of AZT?
phosphorylated by cellular kinases
action of AZT?
blocks HIV replication - inhibits HIV-DNA pol, which is RNA-dependent
action of DDI?
chain termination mechanism
what is an antiviral agent used to treat HepB?
FIAU (fialuridine/ 1-(2-deoxy-2-fluro-arabinosyl)-5-iodouracil)
- added into mito DNA via DNA pol gamma -> no mito division
- lactic acidosis from increased anaerobic glycolysis
caused liver failure in one patient
what is used to estimate DNA turnover?
beta-aminoisobutyrate (increased in chemo/rad patients)
name 4 chemo agents?
- 5-fluorouracil/ FUra/ 5-FU
- AraC (cytosine arabinoside)
- MTX (methotrexate)
- hydroxyurea
what is 5-fluorouracil and what is it used to treat?
- uracil analog
- treat solid tumors (ovary, cervix, prostate, colorectal)
- inhibits precursor rRNA from dividing (5’ tri-P inserted in RNA)
- inhibits thymidylate synthase -> DNA breaks
what is AraC and what is it used to treat?
- antileukemic
- inhibits DNA synthesis (5’ tri-P inserted into DNA)
what is MTX and what is it used to treat?
- inhibits DHFR (inhibits THF formation)
- treats human cancer (leukemia)
what rescues normal cells in leukemia treatment w/ MTX?
leucovorin
what is hydroxyurea and what does it treat?
- inhibits DNA synthesis but not RNA/protein synthesis
- acts on ribonucleotide reductase
- limited clinically (rapid clearance, need [high])
