P1246990938jBRTr

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Overview of Purine Metabolism
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Purine Biosynthesis Both de novo and salvage
pathways are used -De novo synthesis occurs
primarily in the liver -Peripheral tissues use
salvage pathways to recycle Liver-released
products
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Conversion of PR to PRPP and thence to PRNH2
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N5-formyl THF
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Glutamine is the N donor
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Spontaneous
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N10-formyl THF
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Note driven by GTP hydrolysis
Adenylosuccinate Synthase
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Xanthylate Synthase
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Note driven by ATP hydrolysis
Glutamine is the N donor
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Adenine Phosphoribosyltransferase
Adenine PRPP
AMP
Hypoxanthine / Guanine Phosphoribosyltransferase
Hypoxanthine / Guanine
IMP / GMP
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Feedback regulation in Purine Biosynthesis
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Glutamine PRPP amidotransferase
5-phosphoribosyl pyrophosphate synthetase
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Adenylosuccinate Synthase
Xanthylate Synthase
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Purine Degradation
Excess bases are converted to Urate, released to
the circulation and excreted through the Kidney
GMP
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Adenosine Deaminase
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Molecular Oxygen Is the electron acceptor
Cofactors Molybdenum Iron Riboflavin (Vit. B2)
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Diseases of Purine Metabolism
Most common Gout Caused by excessive Urate
Urate has low solubility, high concentrations
precipitate faster than they can be cleared in
Kidney Leads to painful deposits in joints
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Gout
Multiple causes usually not due to defects in
the degradation pathway but rather increased
flux through the pathway. Examples 1)Salvage
pathway defects (Partial deficiency in
hypoxanthine-guanine prtase) 2) Increased
de novo synthesis (upregulated PRPP synthase)
3)Alcohol-induced Gout symptoms In
alcoholics conversion of ethanol to acetate
loads up NADH Liver lacks sufficient
NAD to oxidize Lactate to Pyruvate
Leads to Lactic Acidosis Lactate
competes Urate uptake in Kidney --leads to
Gout symptoms
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Gout
Treatment Allopurinol
(hypoxanthine analog)
Acts in at lease two ways 1) suicide inhibitor
of Xanthine Oxidase 2) coupled to
PRPP (decreases de novo synthesis)
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Rarer, but more severe diseases
-Lesch-Nyan Syndrome caused by severe defect
in HGPRTase Symptoms Self-mutilation/Mental
Retardation/Spasms Also Kidney Stones -- Gout
occurs later Circulating Urate levels are
high Allopurinol decreases circulating urate
but doesnt relieve the neurological
symptoms. -Severe combined immunodeficiency
(SCID) caused by Adenosine Deaminase deficiency
adenosine buildup indirectly leads to block
in DNA synthesis -- loss of rapidly
proliferating cell types e.g immune
cells. ADA is a chemotherapeutic target
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Overview of Pyrimidine Metabolism
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Synthesis As with Purines, there are both de novo
and salvage pathways
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De novo synthesis pathway
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First step Production of Carbamoyl
Phosphate (as in the urea cycle)
Glu
Gln
Carbamoyl Phosphate Synthetase II
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Aspartate Transcarbamylase
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(UMP)
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UMP, similar to IMP in purine biosynthesis,
serves as the precursor to other pyrimidine
nucleotides
UMP
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Feedback Regulation of Pyrimidine Biosynthesis
Inhibited by UTP
Inhibited by CTP
CPSII
Gln CO2 ATP
ATCase
Carbamoyl Phosphate
Carbamoylasparate
UMP
CTP
UTP
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Conversion of NTPs to dNTPs
dNTPs are synthesized from the corresponding
NTP by the action of the enzyme Ribonucleotide
Reductase
Removes the 2 hydroxyl group on the Ribose
moiety of the NTP General Reaction NTP
NADPH dNTP NADP H20
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Conversion of NTPs to dNTPs
Ribonucleotide reductase has a variety of
substrates (ATP, GTP, CTP, UTP) and is subject to
complex allosteric regulation
1)Regulation of overall activity (dNTP/NTP
ratio) dATP decreases activity ATP increases
activity
2) Regulation of specificity (balance of
nucleotide pools) ATP increases activity on UTP
GTP dTTP increases activity on GTP decreases
activity on UTP CTP dGTP increase activity on
ATP
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Synthesis of dTTP
Thymidilate is used only for DNA synthesis.
Made only in the deoxy form.
Formed by the methylation of dUMP
N5,10 methylene THF
DHF
dUMP
dTMP
Thymidilate Synthase
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Reaction Mechanism is complex. Important point
Tetrahydrofolate is oxidized to
Dihydrofolate and must be recycled.
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Need to recycle DHF to THF creates a cycle that
is the target of chemotherapeutic drugs
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Need to recycle DHF to THF creates a cycle that
is the target of chemotherapeutic drugs
These drugs lead to depletion of dTTP pools and
a block to DNA replication. Therefore, rapidly
dividing cells, e.g cancer cells, are
more sensitive.
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Other products derived from Purines/Pyrimidines
Nucleotide sugars e.g. UDP-Glucose or GDP
Mannose Coenzyme A (Adenine) NAD
(Adenine) NADP (Adenine FAD
(Adenine) Vitamin B12 (Adenine) Biopterin
(Guanine)