nucleotide metabolism Flashcards
what is nucleotide structure?
nitro base + sugar+ phosphate
what is nucleoside structure?
nitro base + sugar
How are purines synthesized?
- They can be made in the liver or cytosol: purine base formed on r5p from ppp
- Salvage: r5p to purine base
How are pyrimidines synthesized?
- They can be made in the liver or cytosol: pyramidine ring, ribose phosphate added
- Salvage: pyrimidine nucleotides made from bases in RNA/DNA
4 Phases of purine synthesis?
Phase 1: Activation of r5p
Phase 2: PRPP to PRA
Phase 3: IMP is formed
Phase 4:IMP made into AMP or GMP
What happens in phase 1 of purine syn? + and -?
r5p to prpp (PRPP synthetase), needs ATP
+P
-Purine nucleotides
What happens in phase 2 of purine syn? + and -?
COMMITTED STEP!!
PRPP to PRA (glutosamine: phosphoribyl pyrophosphate)
-Needs Gln
+ PRPP
-Nucleotides
What happens in phase 3 of purine syn? + and -?
PRA to IMP
- 9 steps to make ring
- uses ATP to make ring
-methotrexate
What happens in phase 4 of purine syn? + and -?
IMP to
dATP (adenylylsuccinate ynthetase)
-AMP
or
dGTP (IMP dehydrogenase)
- needs GTP
- GMP
How is Purine synthesis regulated?
*Own products inhibit synthesis
- AMP stopped by GTP
- GMP stopped by ATP
4 steps of pyrimidine synthesis?
Phase 1: pyrimidine ring made as orotate
Phase 2: orotate attaches to PRPP to become UMP
Phase 3: UMP becomes TMP or dCTP
What is phase 1 of pyrimidine synthesis? what + and -? whats significance?
GLN uses HCO3 and ATP to make carbamoyl aspartate (carbamoyl phosphate synthetase 2)
+PRPP
-UTP
- Cytosol and mito
- too much carbamoyl aspartate: orotic aciduria
What is phase 2 of pyrimidine synthesis?
Orotate attached to PRPP to become UMP, OMP is in rxn too
UMP synthetase
What is phase 3 of pyrimidine synthesis?
UMP made into dCTP and DTTP
Regulatory steps of pyrimidine synthesis?
Carbamoyl Synthetase:
- Inhibited to UMP/UTP
- stimulated by PRPP
ATCase:
-stopped by CTP
Pentose phosphate pathway?
produces rp5 and nadph
uses nadph to maintain reducing environment
makes Gluthione
What is the significance of methotrexate?
prevents oxidation of NADPH
Targets DHFR, cant make folate into tetrahydrofolate
disrupts DNA replication
What do sulfa drugs too?
disrupt DNA synthesis in bacteria
inhibits enzyme that puts paba into folate
What does depriving cells of GMP and dGTP do?
conversion of IMP to XMP
inhibits IMP dehydrogenase
Deprives them of adequate supplies of GMP, dGTP
disrupting this helps prevent rejection
What is purine catabolism?
Ribose is removed from guanosine and inosine, makes guanine and hypoxanthine
converges at xanthine formation
converted to uric acid
what is ADA, what does it do?
hydrolytic deamination, adenosine to inosine
overproduction makes anemia
underproduction leads to scid
xantine oxidase? what does it do?
hypoxantine to xantine to uric acid
target for gout
oxidation levels of purines, explain it
become more and more oxidized, uric acid is most oxidized
What is SCID and how does it happen?
B and T cells compromised
Due to ADA deficiency , high levels of adenosine which is converted to dATP, blocks formation of other dNDPs, impairs DNA synthesis
what is gout?
Overproduction of uric acid, under excretion of uric acid
Deposits of sodium urate
Due to xanthine oxidase, treatment inhibits this
uric acid is a marker for gout
How are pyramidines catabolized?
uracil/cytosine becomes malonyl CoA
thymine becomes methylmalonyl coA or succinyl coA
What is the salvage pathway used for and how?
nucleotides which are recovered can be reused for purines
APRT: makes AMP
HGPRT: makes GMP or IMP
what is Lesch-Nyhan
Defects in HGPRT of purine salvage pathway
self mutiliation!!
Excess purines
Severity depends on HGPRT excess
What does Acyclovir do?
acyclovir gets phosphorylated by Thymidine kinase at higher rate than cellular kinase
becomes acyclovir dGTP, incorporated into dividing viral cells, used to help heal sores
“false nucleotide, blocks dna synthesis
