Nucleotides Flashcards
Basic synthesis
PRPP (Purines)/glutamate (pyrimidines) –>–>5’ nucleoside monosphosphates
Basic salvage
nucleoside monosphosphates <–> nucleosides <–> purines and pyrimidines
basic catabolism
purines and pyrmidines –> uric acid
basic interconversion
triphosphates (RNA, ATP, GTP) <–> diphosphates (deoxy –> DNA) <–> monophosphates
purine de novo biosynthesis
Ribose 5 –> PRPP –> phosphoribosylamine ———> IMP
IMP –> AMP
IMP –> GMP
phosphoribosylamine synthesase
PRPP –> phosphoriboslyamine
in presence of AMP, IMP, GMP - shift curve to the right
commited step of purine biosynthesis
regulation of purine de novo synthesis
amount! IMP, AMP, GMP inhibit phosphoribosylamine synthetase to regulate overall amt
balance:
GMP and AMP each reg own synthesis - specific purine amts
each purine nt monosphophosphate synthesis consumes the other triphosphate
pyrimidine de novo synthesis
gln = substrate
CPS II –> carbamoyl aspartate –> orotic acid –> UMP –> UDP –> UTP –> CTP (using Gln again)
UTP = building block for RNA - bad if it’s too high
gln substrate
CPS II in cytosol - inhibited by UTP
salvage
(d)AMP and (d) GMP
dAMP –> dAdenosine –> d(inosine) –> hypxanthine
AMP –> IMP –> Inosine –> hypoxanthine
(d) GMP –> (d) guanosine –> Guanine
PNP - hypoxanthine and guanine back to insoine and guanosine
HGPRT - hypoxanthine to IMP, IMP to AMP or GMP
guanine to GMP
HGPRT
salvage
hypoxanthine to IMP then to AMP or GMP
guanine to GMP
xanthine oxidase
hypoxanthine –> xanthine –> uric acid
also guanine
Allopurinol
gout treatment, inhibit XO and excrete hypoxanthine and guanine sinstead
reduced xanthine oxidase downregulates de novo purine synthesis because more hypoxanthine and guanine –> more salvage –> more IMP, AMP, GMP –> inhibit
Lesch-Nyan
no XO
can’t do salvage
make a ton of uric acid
purine nucleotide phosphorylase
hypoxanthine –> inosine/adenosine
guanine –> guanoside
primary gout
HGPRTase
Lesch-Nyhan
G6Pase
metabolism issues
secondary gout
generation of excess purines
chemo
colchicine
inhibits MT polyperization - inhibits phagocyte function and inflammation?
ribonucletode reductase
ADP, GDP, UDP, CDP –> dADP, dGDP, dUDP, dCDP
made for DNA repolication from RNA rep!
not constituently active
regultion:
A - active site, NDP + thiredoxin-SH –> dNDP + thiredoxin-SS (need NADPH to regenerate
O - overall activity site - ATP activates, dATP binding inhibits - overall amount! signal that cell has the E to replicate
S - specificity - ATP, dGTP, dTTP binding - modulates sbstrate preference for active site, modifices and changes activities for balance!
nucleoside diphosphate kinase
dADP, dGDP, dUDP, dCDP –> dATP, dGTP, dUTP, dCTP
kinase, reversible, need another P for repair and polymerase!!
dUTP is bad - can’t be incorporated into DNA synthesis
valtrex
Acyclovir
herpes virus needs own kinase to replicate whenever, if our cells aren’t dividing
aciclivir is different - stops growth
phosphorylated bt viral nucleoside kinase but NOT cell kinase - block repolication
2 ways to get rid of U (don’t want for DNA)
dUDP –> dCMP –> dUMP –> TMP (dCMP kinase, dCMP deaminase)
dUTP –> dUMP –> TMP (dUTP diphosphoryhydrolase)
thymidylate synthase
dUMP –> TMP
needs 1 C donor - N5,N10 methylene FH4 –> dihidrofolate! needs to regenerate
fluorodeoxyuridyate
suicide inhibitor of thymidylate synthase
dUMP –> dTMP
uses C donor from folate
target bc cells not replicating don’t have this enzyme - only in S phase
FH2 reductase
regenerate FH4 - so can continue making TMP
Methotrexate
inhibits dihidrofolate reductase - regerates tetrahydrofolate to make TMP
on dTMP synthesis more than purine synthesis
dNA are made to order in small concentrations, but ribonucleotides (ATP) are made all the time in larger concentrations
