L19: purine nucleotide biosynthesis, salvage, & degradation Flashcards
Pathway for purine biosynthesis
- liver and immune cells primarily biosynthesize purines
- starts with PRPP, building a purine ring on the ribose ring
- requires great input of energy
- one-carbon transfers are provided by N10-formyl-tetrahydrofolate
- Inosine 5’P is first fully formed purine nucleotide
what is IMP?
- Inosine 5’P
- it is a key metabolic intermediate because it can readily tautomerize
why doesn’t IMP have a role in RNA or DNA?
because it has mutagenic H-bonding (acts as both an H-bond donor and an H-bond acceptor
pathway for purine biosynthesis pic
slides 106-109
conversion of IMP to AMP
IMP + aspartate + GTP -> adenylosuccinate -> AMP
key points of adenylosuccinate mechanism
- IMP tautomerizes to form -OH at C6
- GTP phosphorylates IMP to form the 6-phospho-IMP intermediate
- Aspartate amino group displaces phosphate
conversion of IMP to GMP
IMP + NAD+ + H2O -> xanthosine-5’-P
xanthosine-5’-P + ATP + Gln -> guanine-5’-monophosphate
key points of IMP dehydrogenase reaction
- enz-SH reversibly forms an adduct with inosine 5’-phosphate
- hydride is transferred to NAD+ as ring is oxidized
- H2O displaces Enz-SH to form XMP
Mechanism of GMP synthase
- adenylation of the purine -OH group
- Glutamine hydrolysis and NH3 transfer through the
tunnel - nucleophilic attack by NH3 to form GMP
control of purine nucleotide synthesis
- AMP inhibits AMP-sucsynthetase directing IMP to GMP
- high GMP directs IMP to AMP
- high IMP feedback inhibits 5’-Prib-NH2 formation
- high AMP and GMP feedback inhibit PRPP synthetase
- high AMP activates AMP-protein kinase, turning off purine pathway enzymes
what does hypoxanthine guanine-phosphoribosyl transferase (HGPRT) do?
it salvages purines from RNA and DNA degradation
what nucleic acid is not salvaged by HGPRT?
Adenine
why is adenine not salvaged by HGPRT?
it is the most abundant purine and high levels of it would block IMP and GMP re-synthesis
what is gout?
it is pathologic precipitation of excess uric acid
affects of gout
- crystals accumulate in joints
- crystals activate inflammasome response
- cause severe inflammation and pain
- white blood cells attack
how is gout treated?
it is treated with allopurinol (a xanthine oxidase inhibitor)
what is the product of ribonucleotide reductase?
2’-deoxy-ribonucleottides
what gives evidence of a transition from the RNA world to the DNA world
substrate specificity
in eukaryotes substrates are __?
di - 2
in prokaryotes substrates are ___?
tri- 3
is RNR strictly controlled?
yes, it must be to yield the right balance of dNTPs needed for DNA synthesis
RNR catalysis is controlled by ____?
allosteric specificity sites
Nucleotide-binding at specificity sites allows RNR ___?
- to sense relative abundances of NDPs
- to make the right amount of each deoxynucleotide
RNR achieves balanced production by_____?
- changing catalytic efficiency with each substrate
- preventing the overproduction of any single dNTP
