B6.038 Metabolism of Purine and Pyrimidine Nucleotides Flashcards
purines
adenine
guanine
pyrimidines
thymine (DNA)
cytosine
uracil (RNA)
starting substrate for de novo purine synthesis
ribose 5-P
manifestations of gout in clinic
acute gouty arthritis
nephropathy
what causes symptoms of gout?
crystal deposition in joints and/or kidneys
urate crystal formation in urine
at low pH: uric acid predominates in urine and uric acid crystals precipitate (common)
at high pH: urate predominates and Na+ urate crystals precipitate (rare)
urate crystal formation in joints
urate predominates and Na+ urate crystals precipitate in synovial fluid and auricles
who is most likely to develop gout?
adult men
95% are under-excreters
diseases w associations w gout
hypertriglyceridemia
hypertension
metabolic syndrome
all related to obesity
factors that lead to chronic urate underexcretion
decreased glomerular filtration in patients with renal failure
inhibition of excretion by organic acids (ketoacidosis, aspirin, excessive alcohol)
chronic dehydration
anything that can decrease amt of urine excreted in general
diagnosis of gout
aspirating fluid from affected joint and finding negatively birefringent crystals under polarizing microscope
benefits of urate
normally in body @ 7-10% concentration
antioxidant properties
when this conc increases in when symptoms emerge
hyperuricemia
too much urate in blood
due to:
-urate overproduction
-under excretion
chronic hyperuricemia
gout
- acute arthritis
- kidney stones
where is ribose-5-p for purine synthesis derived from
pentose phosphate pathway
from glucose-6-p
general overview of de novo synthesis of ATP and GTP
ribose-5-P > PRPP > IMP > AMP or GMP
enzyme which converts ribose-5-p to PRPP
PRPP synthase
- inhibited by ADP
- activated by phosphate
enzyme which converts PRPP to IMP
glutamine-PRPP amidotransferase
- non-reversible
- inhibited by AMP and GMP (feedback)
- activated by PRPP
molecules needed for conversion of PRPP to IMP
folate molecules (N10-formyl-THF)
mycophenolic acid in purine synthesis
inhibits conversion of IMP to GMP
acts as an immunosuppressant
reduces synthesis of DNA/RNA in lymphocytes (primary cells that utilize de novo purine synthesis)
degradation of GMP
GMP > guanine > xanthine (taken up by liver) > urate
degradation of AMP
AMP > hypoxanthine (taken up by liver) > urate
salvage of GMP
guanine from GMP breakdown travels through blood to new cell
guanine > GMP
salvage of AMP
hypoxanthine from AMP breakdown travels through blood to new cell
hypoxanthine > IMP > AMP
what % of production of IMP is de novo?
3%
97% salvage
how is salvage preferred over de novo synthesis?
enzyme controls HGPRT (salvage enzyme) -greater affinity for PRPP -higher max activity glut PRPP amidotransferase (rate limiting enzyme in de novo synthesis) -cooperativity toward PRPP -only active at high PRPP concentrations
HGPRT activity in Lesch-Neyhan
<2% of normal activity
little ability to salvage
enzyme used to degrade hypoxanthine to urate
xanthine dehydrogenase (oxidase)
drug used to increase excretion of urate
probenecid
inhibits reuptake of urate
lifestyle modifications in gout treatment
reduce purine load by avoiding liver, kidney, sweetbreads limit sugar intake limit ethanol (particularly beer)
urate lowering drugs
xanthine dehydrogenase (oxidase) inhibitors uricase (less common)
xanthine dehydrogenase (oxidase) inhibitors
allopurinol
febuxostat
lesch-nyhan syndrome
X-linked recessive HGPRT deficiency -recycle almost no hypoxanthine -increased de novo synthesis -increased urate production
symptoms of lesch-nyhan syndrome
mental retardation
profound motor disability
self mutilation
gout
what is UMP
uridine monophosphate
precursor for all pyrimidine nucleotides
pyrimidine nucleotides in DNA
dCTP
dTTP
pyrimidine nucleotides in RNA
UTP
CTP
pyrimidine nucleotides in phospholipids
CTP
pyrimidine nucleotides in glycogen
UTP
where does pyrimidine synthesis occur
liver
dividing cells
general process of UMP synthesis
PRPP + orotate > UMP > uridine
synthesis for UTP and CTP from UMP
UMP + 2ATP > UTP
UTP + ATP + glutamine > CTP
what is UTP used in
RNA
glycogen
what is CTP used in
DNA
RNA
phospholipids
reduction of ribonucleotides to deoxyribonucleotides
NTP (UDP,CDP,ADP, or GDP) > dNTP
enzyme: ribonucleoside diphosphate reductase
inhibitors of ribonucleoside diphosphate reductase (ribonucleotide reductase)
hydroxyurea
gemcitabine
dATP
dUDP, dCDP, dADP, dGDP
hydroxyurea mechanism
leads to a decreased rate of deoxyribonucleotide production
reduces a protein tyrosyl radical that is crucial for enzyme activity
gemcitabine mechanism
leads to a decreased rate of deoxyribonucleotide production
2 mechanisms:
1. dephosphorylated inhibits enzyme irreversible
2. triphosphorylated is incorporated into DNA and chain terminates
synthesis of dTTP
dUMP > dTMP
enzyme: thymidylate synthase
enzyme 2: dihydrofolate reductase regenerates THF for reaction
what is clinically significant about the synthesis of dTTP
DNA replication and repair are the only processes that depend on production of dTTP
-persons who are folate deficient do not make enough dTTP (not as big of an issue in AMP and GMP bc of the possibility of salvage)
what happens if you deprive cells of dTTP
inhibit tumor synthesis
5-FU and premetrexed inhibit thymidylate synthase
MTX inhibits reduction of DHF to THF
how does 5-FU inhibit dTTP synthesis
integrates into the molecule and acts as a suicide substrate
drugs metabolized into 5-FU
capecitabine
tegafur
mechanism of pemetrexed
inhibits thymidylate synthase directly
mechanism of MTX
competitive inhibitor with a similar structure of DHF
breakdown of UMP
liver dephosphorylates UMP to uridine
in the blood, uridine is salvaged and re-phosphorylated to UMP
-CTP made from UTP
-dTMP synthesis requires thymidylate synthase and DHF reductase
result of RNA and DNA degradation
break down into pyrimidine mononucleotides that can be re-phosphorylated and reused
