Lecture 12 Flashcards
What is the sequence of NDP conversion for RNR?
1) UDP/CDP
2) GDP
3) ADP
When dATP levels high enough the enzyme is switched off
How many enzymes do you need for biosynthesis of dTTP from UMP?
5 enzymes. dTTP specific for DNA synthesis.
1) ribonucleotide kinase (UMP kinase)
2) ribonucleotide reductase (RNR)
3) nucleotide diphosphate kinase (NDP Kinase)
4) dUTP phosphatase (dUTPase)
5) thymidylate synthase
Why not go straight from dUTP to DTTP?
It is a fast conversion, this is bad because there is a potential for error
What is important about dUTPase?
It is a very active diphosphorylase. Takes dUTP to dUMP and PPi. Keeps dUTP concentration low and prevents incorporation of dUTP into DNA by DNA polymerase. Energy is used to prevent errors!
What do the hydrophilic residues in loop do?
Provide info about what is bound at each site, modulate conformation of that loop, and adjust conformation of that catalytic site to determine what happens
Gout
Painful condition caused by high circulating levels of uric acid
Lesch-Nyhan syndrome
Deficiency in purine salvage
complete loss of hgprt activity is severe (x linked recessive)
guanine and hypoxanthine are consistently produced due to turnover of nucleic acids
No salvage of either, increased de novo synthesis of purines
excess production of uric acid- severe gouty arthritis
NS disorders- motor disabilities, learning disabilities and behavioral disorders
severe aggression and self-mutilation
adenosine deaminase deficiency
severe combined immunodeficiency syndrome
B and T lymphocytes can’t proliferate
Nucleotide metabolism provides targets for clinical intervention
chemotherapy- goal is to selectively target a metabolic process that is specific to the disease. can also use to treat certain infections. adults don’t have many rapidly dividing cells so these can be effective.
rapidly proliferating cells- susceptible to disruptions in nucleotide metabolism, require nucleotides for growth and DNA synthesis
selectively target cancer cells, bacterial and viral infections
in mature adults, most cells are not dividing and will not be affected as much- nucleotide metabolism is a great place to intervene
notable exceptions: bone marrow cells (blood and immune cells), hair cells, intestinal mucosa
chemo approaches affect rapidly dividing human cells
Inhibitors of Glutamine amidotransferases are potent drugs
prevent liberation of ammonia from side chain of glutamine- these pathways are great targets
These compounds interfere with reactions that require glutamine as nitrogen donor (Gln amidotransferases)
at least half a dozen reactions require Gln during the synthesis of purest and pyrimidines
azaserine has antibiotic and anti tumor properties
acivicin is an anti-tumor agent
