lecture 11 Flashcards
two biosynthesis pathways
De novo and Salvage
de novo synthesis
“new” synthesis
precursors for de novo
amino acids, ribose 5P, CO2, NH3
salvage pathway
endproducts made from “scavenged” components
how does the salvage pathway get precursors
Recycling of free bases and nucleosides from nucleic acid breakdown
what does de novo synthesis begin with
5-phosphoribosyl 1-pyrophosphate (PRPP)
what does de novo end with
inosinate (IMP)
biosynthesis of AMP and GMP:
IMP is an important precursor
arm 1 of IMP to AMP
add aspartate and GTP
take out fumerate
make adenylate
arm 2 of IMP to GMP
add H2O and reduce NAD
add amino group of glutamine and use ATP
make GMP
3 major inhibition mechanisms
- ribose phosphate pyrophosphokinase
- glutamine-PRPP amidotransferase
- AMP inhibiting adenylosuccinate synthetase
bacterial carbamoyl phosphate synthetase
3 active sites
substrate channeling
important in limiting substrate/intermediates diffusion
when is substrate channeling critical
if intermediates are unstable
aspartate transcarbamolyase
in charge of bacterial pyrimidine biosynthesis
ATCase
first enzyme in pyrimidine de novo synthesis pathway
what does ATP prevent
CTP-induced change in ATCase activity
CTP
causes extreme decline in ATCase activity
ribonucleotides
are precursors of deoxyribonucleotides
E coli ribonucleotide reductase
enzyme acts on ribonucleotide diphosphate
what does the reduction involve
replacement of 2OH with H
slide 12
where does regulation of ribonucleotide reductase occur
at primary AND substrate specificity sites
why does ribonucleotide reductase have 2 sites of regulation
idea is to provide a balanced pool of precursors for DNA synthesis
both activity and substrate specificity are regulated by
effector building
enzyme activity
ATP activates
dATP inactivates
substrate specificity
when ATP or dATP is bound
favors reduction of UDP and CDP
substrate specificity
when dTTP or dGTP is bound
favors reduction of GDP or ADP
thymidine is derived from
dCDP and dUMP
what does the degradation of purines and pyrimidines produce
uric acid and urea
what exctretes allantoin
most mammals
what excretes allantoate
bony fishes
whats the difference between allantoin and allantoate
extra H2O
catabolism of thymidine results in
methylmalonyl semialdehyde-> succinyl coa
how are free purine and pyrimidine bases released
metabolic degradation of NTs
adenine + PRPP
AMP +PPi
where does the pyrimidine pathway exist
bacteria POSSIBLY mammals
defect in which salvage pathway enzyme could cause Lesch- Nyhan syndrome
hypoxanthine-guanine phosphoribosyltransferase HGPRT
lesch nyhan
almost exclusively male children
symptoms: mental retardation, self mutilation
what do defects in HGPRT result in
elevated de novo purine synthesis & increases in uric acid
gout
excess uric acid
allopurinol
inhibitor of xanthine oxidase
what is a strong inhibitor of xanthine oxidase
oxypurinol
chemotherapeutics attack
nucleotide biosynthetic pathways
two targets
thymidylate synthase, dihydrofolate reductase
thymidilate synthase
FdUMP
dihydrofolate reductase
methotrexate, aminopterin, trimethoprim
suicide inhibitors (FdUMP)
reactive flourine binds to enzyme and makes dead end covalent complex
