Studied by 14 peopleWhat are the roles of nucleotides?
Precursors of nucleic acids
Drive energetic reactions
Biosynthetic processes
Signal transduction pathways
What does the de novo pathway do?
Synthesizes nucleotides from scratch
What does the salvage pathway do?
Synthesizes nucleotides from existing compounds and remains
Where does purine de novo synthesis occur?
Cytosol
In what state is the purine ring synthesized in de novo synthesis?
While attatched
In what state is the pyrimidine ring synthesized in de novo synthesis?
Free base (not attached)
Which de novo pathway is branched?
Purine synthesis
Which de novo pathway is linear?
Pyrimidine synthesis
What is the regulated step of de novo purine synthesis?
The formation of phosphoribosylamine from PPRP
What upregulates de novo purine synthesis?
High concentrations of PRPP
What downregulates de novo purine synthesis?
High concentrations of IMP, AMP, and GMP
What is the activation step in de novo purine synthesis?
Ribose-5-phosphate is activated and produces PRPP
1 ATP used
activates 1' carbon
How many ATPs are needed to make IMP?
5 ATPs
What energy source does XMP use to transform into GMP?
ATP
What kinase phosphorylates GMP to GDP?
GMP kinase
What energy sources does adenylosuccinate use to transform into AMP?
GTP
releases fumarate in process as also uses aspartate with the GTP
What kinase phosphorylates AMP to ADP?
Adenylate kinase
What enzyme phosphorylates both ADP and GDP (not specific)?
NDPK
How do we obtain an appropriate balance of ATP and GTP?
GMP will shut off the GMP branch when needed, and AMP will shut off the AMP branch when needed.
What is the regulated step of de novo pyrimidine synthesis?
Carbamoyl phosphate synthetase step
What inhibits the regulated step of de novo pyrimidine synthesis?
CTP
What activates the regulated step of de novo pyrimidine synthesis?
ATP
What is the initial nucleotide in de novo pyrimidine synthesis?
OMP (orotidine monophosphate)
How do prokaryotes form carbamoyl phosphate?
One enzyme that uses ammonia as the nitrogen donor
How do eukaryotes form carbamoyl phosphate?
The mitochondrial enzyme (resembles bacterial enzyme) uses ammonia as nitrogen donor; product goes to urea cycle The cytosolic enzyme uses glutamine as a nitrogen donor; product dedicated for pyrimidine synthesis
When do de novo pyrimidines get the ribose phosphate attached?
After dihydroorotate is oxidated to orotate
Orotate + ribose phosphate = OMP
What molecule is OMP converted to via decarboxylation?
UMP
How does UTP get converted to CTP?
Replace C=O at C4 with amino group from glutamine
What is the regulation step of de novo pyrimidine synthesis in prokaryotes?
Aspartate transcarbamoylase (later in pathway) because product dedicated to pyrimidine synthesis
What is the regulation step of de novo pyrimidine synthesis in eukaryotes?
Carbamoyl phosphate synthetase (earlier than prokaryotes) bc carbamoyl phosphate dedicated to pathway
What inhibits/activates CPS II?
Inhibited by UTP (product) and activated by PRPP
What are the three types of salvage enzymes/pathways?
Nucleoside kinases
Nucleoside phosphorylases
Phosphoribosyl transferases
What would be the effect of blocking the salvage pathway in protozoan parasites?
Since they cannot synthesize purines de novo, blocking the salvage pathway would kill them
What is the basic reaction for nucleotide kinases?
Nucleoside + ATP --> nucleotide + ADP
What is the basic reaction for nucleotide phosphorylases?
What is the basic reaction for phosphoribosyl transferases?
Base + PRPP --> nucleotide + PPi
What is the fate of pyrimidine catabolism?
Catabolized to beta-ureidopropionic acid and excreted
What is the fate of purine catabolism?
Hypoxanthine, guanine, and xanthine are converted to urate and excreted into liver and kidney
At what level does deoxyribonucleotide synthesis occur?
Occurs at the diphosphate level
What is the carbon group donor for DNA synthesis?
N5,N10-methylene tetrahydrofolate
What dead-end molecule is N5,N10-methylene tetrahydrofolate converted to in TMP synthesis?
DHF (dihydrofolate)
How can we form DNA from RNA?
Reduce the 2' carbon
What inhibits ribonucleotide reduction?
Binding dATP to enzyme activity site
What activates ribonucleotide reduction?
Binding ATP to activity site
What two routes can generate dUMP?
UDP reduction and phosphorylation
CDP reduction, dephosphorylation, and deamination (preferred route)
How is tetrahydrofolate regenerated?
NADPH donates electrons
Note
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