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29 Cards in this Set
- Front
- Back
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what is inosine?
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hypoxanthine with ribose
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what is AMP
dGTP |
the base sugar and phosphate
deoxy sugar |
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How do we get ribose?
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hexose monophosphate shunt
G6P --G6P dehydrogenase**-> NADPH and product oxidizing portion of pathway |
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NADH and NADPH comparison
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NADH ox-phos
NADPH used in other things: biosynthetic rxns |
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glutathione
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protects against ROS using NADPH
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Making purine nucleotides: first step
What regulates this? |
activate the ribose at the anomeric Carbon.
ribose 5P + ATP ---Mg2+ and PRPP synthetase--> PRPP high free P = + ADP, GDP = - |
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PRPP disorders
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Arts Syndrome retardation, optic atrophy
deficiency of PRPP means lack of purine nt (X-linked) Gout: pain swelling in joint- elevated PRPP makes too much uric acid (this is rarer, usually it's excretion problems) |
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purine nt synthesis 2nd step
regulatory |
committed step
PRPP + Gln --amidotransferase--> PRA + Glu + PRPP (feed forwards on this enzyme; Km is much greater than normal concentration, so if PRPP raises at all, this amidotransferase starts working) - AMP GMP IMP |
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purine nt synthesis 3rd step
which amino acids? |
PRA + ATP +2 vit B9 (folate) + caroxylation + nitrogen (Gly, Gln, Asp)**
emerges as IMP |
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disrupting purine synthesis
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Antibacterial: sulfa drugs. competitive inhibitor for PABA --> folate -DHFR-> tetrahydrofolate
we don't try to make folate, so it does not affect us at all trimethoprim: dihydrofolate reductase. can also affect us, but bacteria are making tetrahydrofolate a lot faster antineoplastic agents: methotrexate also disrupts DHFR because cancer rapidly divides |
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Have IMP. Now what?
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transformation into the purines we use AMP GMP. Two step process for each.
Branch point: gets regulated at first step. IMP --> AMP enzyme regulated by AMP (-) and GTP used as energy donator. IMP --> GMP regulated by GMP (-) and ATP used as energy donor. Process includes oxidizing |
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Reversing GMP and AMP to IMP
Why? |
AMP and GMP can go back to IMP
AMP --AMP deaminase--> IMP (reg +ATP, -GDP, -GTP) GMP --GMP reductase--> IMP (reg +GTP) Note that A series outweighs G series |
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NMP to NDP to NTP
what about dNMP? |
each NMP has it's own specific 'nucleotide monophosphate kinase'
NDP there is a nucleotide diphosphate kinase that does whatever one same scheme for dNMP |
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Summary of all regulation going on in these purines
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PRPP + to PRA synthetase
IMP AMP GMP - to PRA synthetase IMP --> AMP or GMP AMP and GMP - to each respective enzyme AMP or GMP --> IMP regulated by NMP's AMP -AMP deaminase-> IMP (+ATP -GTP -GDP) GMP-GMP reductase-> IMP (+GTP) |
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Purine Salvage Pathways
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2
taking free purine bases -> nucleotides using PRPP and transferases to attach to 5' phosphoribose or conversions of nucleosides to nucleotides using ATP and kinases for each base |
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saving free bases
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adenine --APRT--> AMP
hypoxanthine or guanine -HPRT-> IMP or GMP both need PRPP because it has the ribose |
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Defects in purine salvage
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defect in APRT (saving adenine). 2,8-dihydroxyadenine urolithiasis. Kidney stones made of 2,8 DHA (adenine gets oxidized a few times). Also, because PRPP isn't being used by APRT rxn, it makes that amidotransferase in front of it work more, making more nucleotides.
Lesch-Nyhan Syndrome: hyperuricemia hyperuricosuria (get gout and kidney stones, self-mutilation). X-linked, AR leads to defect in HPRT. High levels g and hypx give uric acid and PRPP stimulates amidotransferase for more purines |
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6-mercaptopurine
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cancer druge. inhibits several enzymes.
-negative amidotransferase making PRA -inhibits IMP to GMP (IMP dehydrogenase) or AMP (adenylosuccinate synthetase) -inhibits xanthine oxidase uses HPRT to activate it into a nucleotide form |
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how do you get nucleotides to deoxynucleotides
enzyme. substrate. process. regulation. |
done by ribonucleotide reductase for all but only on NDP's
takes off that 2' OH. NADPH. has two allosteric sites: on/off site (ATP up; dATP down) specificity site (balances relative proportions of dNTP types) |
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ribonucleotide reductase inhibitor
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hydroxyurea
scavenges free radicals during NDP to dNDP stops cancers, myeloproliferative diseases, psoriasis, AIDS |
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RNA/DNA catabolism
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Endogenous DNA involves lysosomal enzymes
nucleases cleave polymer. nucleotidases take off phosphate. nucleosidases take off ribose. dietary get denatured in stomach, absorbed in small intestine. |
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how do you go from adenosine to inosine?
Why does this matter? What happens next? and next? |
adenosine deaminase ADA
A has to go to I to be degraded. guanosine doesn't become Inosine purine nucleoside phosphorylase PNP puts inosine to hypoxanthine and guanosine to guanine guanine gets made into xanthine by guanase hypoxanthine by xanthine oxidase goes to xanthine xanthine by xanthine oxidase makes uric acid |
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ADA
what's it do? why? disorders |
Makes A go to I
helps balance purines overproduction in erythrocyte makes hemolytic anemia (A gets changed to I too much, run out of ATP to maintain Na/K pumps, cell explodes) underproduction makes SCID (B cells and T cells ruined; lymphocytes use ADA the most and without they build up A levels go to (AMP ADP-> dADP->dATP-> inhibits ribonucleotide reductase used for other dNDP's->not enough dNTP's for DNA replication) |
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PNP
what's it do? |
purine nucleoside phophorylase
takes nucleoside (I and G) and splits into the base and sugar by phosphorylating the sugar. phosphoglucomutase (promiscuous enzyme) makes ribose 5P. |
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Xanthine oxidase
what it does. disorders. |
hypoxanthine gets oxidized -> xanthine -oxidized-> uric acid/urate
xanthinuria (not xanthemia). without xanthine oxidase, xanthine and hypoxanthine builds up- can't be rescued. Hypouricemia, renal failure. Need low purine diet and high fluid. |
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gout
causes diseases causing gout |
high uric acid in blood and urine.
primary hyperuricemia: PRPP synthetase where Km is lower for ribose5P and so are active when normally they wouldn't or HPRT salvage pathway issue Lesch-Nyhan syndrome so accumulate guanine or hypoxanthine secondary hyperuricemia: (90% of cases): under excretion. renal problems, reabsorption of urate, urate binding to plasma proteins, beer, HFI and Von Gierke's Disease |
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HFI
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hereditary fructose intolerance
aldolase B deficiency so fructose 1P accumulates taking up all the phosphates, ATP declines, adenine rise -> uric acid |
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Von Gierke's Disease
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don't have glucose-6-phosphatase. Liver can't export Glc anymore and it stays as G6P. This gets sent down the hexose monophosphate shunt to make purines which get made into urate
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gout drugs
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symptoms: NSAID's corticosteroids
Recurrent attacks: allopurinol (xanthine oxidase competitve inhibitor) or uloric (inhibits channel for active site of xanthien oxidase) |
