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48 Cards in this Set
- Front
- Back
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Which amino acids contribut ring atoms to purines?
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glutamine, glycine, and aspartate (along with N10-THF)
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What is the first regulated step of purine metabolism?
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D-Ribose-5-phosphate to PRPP via PRPP synthetase
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What is the branchpoint of purine metabolism?
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IMP -> AMP or GMP
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What is the relationship between AMP and GMP synthesis?
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There is crosstalk between these two branchpoints as ATP is required from GMP synthesis and GTP is required for AMP synthesis.
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Overexpression or overactivity of which enzyme is associated with disease in gouty patients?
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PRPP synthetase
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What is the committd and rate limiting step of purine synthesis?
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PRPP -> 5-phosphoriobysyl-1-amine via amidophosphoribosyltransferase (Atase) (contributes N9 in purine ring)
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How is ATase regulated?
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Nucleotides cause an inactiving dimerization, whereas PRPP promotes an active monmerization.
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How is enzymatic efficiency in purine de novo synthesis increased?
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Some enzymes have multiple catalytic domains, others are involved in multiple reactions, and some are linked in coordinated regulation of gene transcription.
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What are some key features of purine de novo synthesis regulation?
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There is feedback regulation of PRPP, Atase and both branchpoint pathways, and there is stimulation of branch point synthesis by the end-product of the opposite branch.
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What enzyme interconverts all forms of adenosine phosphate in the steady state?
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adenylate kinase
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How is purine catabolism stimulated by increased energy demands?
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When ADP accumulates, adenylate kinase produces more molecules of ATP and AMP. AMP stimulates purine catabolism.
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What are the basic steps of purine nucleotide catabolism?
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dephosphorylation, deamination, and phosphorylysis (removal of pentose sugar)
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What enzymes in purine nucleotide catabolism have inherited deficiencies with clinical consequences?
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5'-nuleotidases (dephosphorylation); AMP deaminase and adenosine deaminase (ADA); and purine nucleoside phosphorylase (PNP)
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What aspect of purine catabolism is compensatory for an ischemic or anoxic heart?
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degradation of ATP to ADP to AMP to adenosine allows for diffusion of adenosine which acts as a potent cornoary vasodilator
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What aspect of purine catabolism is helpful to muscle tissue during periods of exertion?
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When ATP is depleted, ADP can be converted to ATP and AMP via adenylate kinase. AMP can then be broken down to IMP allowing a maximum amount of ATP produced while still leaving a pool of anabolic precursors available after the exertion has ceased.
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What is the physiological mechanism for repurfusion injury?
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Xanthine dehydrogenase (XDH) gets cleaved to xanthine oxidase (XO) when oxygen availibility is low. When oxygen once again becomes available, the hypoxanthine metabolite of AMP and GMP can be converted to Xanthine using H20 and O2 as an electorn acceptor, producing H202 in the process.
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What is the most prominent connection to nucleotide metabolism?
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gout
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What are some causes of gout?
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1. Excess urate protduction / overexpression of PRPP synthetase, underproduction of any enzyme necessary for maintaining energy balance (like G-6-PD deficiency) can trigger purine catabolism 2. Under excreation of renal urate 3. Secondary causes like drug intake or excess food intake
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How is gout managed?
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Pain dealt with using steroidal (prednisone) and non-steroidal (indomethicin) anti-inflammatory drugs. Colchicine at low levels. Increase water intake. Urate lowering therapy in chronic cases (ULT). ULT can enhance exretion or uric acid (probenecide) OR inhibit urate production with XO inhibitor (allopurinol, competitive inhibitor for xanthine).
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What are some new alternatives to alopurinol?
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febuxostat (uloric)--a XDH/XO inhibitor and pegloticase (mammalian recombinant urate oxidase--we lack this, convertis uric acid to ammonia ultimately)
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What are some immunodeficiency diseases associated with purine catabolism deficiencies?
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adenosine deaminase deficiency (ADA) and purine nucleoside phosphorylase (PNP) deficiency
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What is the primary circulating substrate for purine salvage synthesis?
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hypxanthine
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How is ribose-5-P added to a base in th epurin salvage synthesis pathway?
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Hypoxanthine or guanine are enzymatically converted using PRPP by hypoxanthine-guanine phosphoribosyltransferase (HPRT). (Goes directly from base to nucleotide--not nucleoside.)
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Which enzymes other than HPRT are used in purine salvage to converte nucleosides back to a nucleotide?
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adenosine kinase, guanosine kinase, and adenine phopshopribosyltransferase (APRT)
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Which X-linked disease associated with purine salvage is associated with aggressive behavior, self-mutilation, and mental retardation?
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Lesch-Nyhan Syndrome (LNS)--caused by a lack or very low level of HPRT
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What are some metabolic consequences of HPRT deficiency?
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1. increased hypoxanthine catabolism, and 2. hyperuricemia (and gout) 3. increase rate of denovo synthesis
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How does aspartate get fed into the TCA cycle via the purine nucleotide cycle?
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IMP can be converted to adenylosuccinaate via adenylosuccinate synthetase. When this gets reconverted to AMP, fumarate is released and converted to malate which can then be shuttled from the cytosol to the mitochondrial matrix.
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How does the catabolic arm of the purine nucleotide cycle help in meeting energy requirements during times of exertion?
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The catabolic arm converts AMP to IMP via AMP deaminase. This allows adenylate kinase to generate more ATP and AMP from ADP.
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What does a failure to produce ammonia during an ischemic excersize test indicate?
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a myoadenylate deaminase deficiency (the test can also indicate glycogen myopathies due to low production of lactate--McCardle's, etc.)
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What are some characteristics of purinergic receptors?
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P2X are ionotropic. P2Y are metabotropic (G-protein coupled--usuall to phospolipase C). P1 adenosine-preferring receptors are G-protein couple receptors (adenylate cyclase) that vasodilate coronary vessels.
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What are the three important enzymes for the pyrimidine de novo pathway?
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CAD (contains CPSII--cytosolic, is trifunctional, glutamine is the source of the amino group, rate-limitin step of de novo pyrimidine synthesis, allosterically inhibited by UTP), dihyrdo-orotate dehydrogenase (DHODH), UMP synthase
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Where is PRPP utilized in pyrimidine de novo synthesis?
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It's used to add a ribose-5-phosphate after the formation of the ring structure.
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What amino acids are used to generate the base ring structure for pyrmidine synthesis?
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glutamine and aspartic acid
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Why is the CAD protein important in patients with OTCase?
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Carbomyl phosphate that accumulates in patients with OTCase leaks into the cytosol where it is metabolized to orotic acid by the pyrimidine de novo pathway.
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Why does dysfunction of the ETC impact pyrimidine synthesis?
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DHODH, the fourth enzyme in the reaction pathway, is localized to the inner mitochondrial membrane and linked to the respiratory chain.
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How is cytosine synthesized from uridine?
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After synthesis, an amino group can be added to uridine using glutamine by CTP (cytidine triphosphate) synthetase.
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How is pyrimidine catabolism different than purine catabolism?
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Pyrimidine catoblism uses reduction reactions to degrade the ring structures into smaller components.
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What is the key difference between the salvage pathways of purines and pyrmidines?
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Pyrmidines are actually salvaged primarily from nucleoside derivatives since catabolic forms of pyrmidine bases have their ring structures opened up. Nuclesoide kinases are the key salvage enzymes wit pyrimidines. Purines can be salvaged from base derivatives since their ring structures remain intact during catabolism.
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A defect in which enzymes leads to oroticaciduria?
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UMP synthase & OTCase deficiencies--former treated with life-long oral uridine therapy.
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Which pyrimidine metabolism enzyme is important to screen for deficinicies in for Fura chemotherapy?
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DPDH (dihydropyrimidine dehydrogenase)
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How are ribonucleotides converted to deoxyribonucleotides?
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Ribonucleoside diphosphates are converted to deoxyribonucleoside diphosphate by ribonucleotide reductase.
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What are common inhibitors of ribonucleotide reductase?
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dNTPs
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Why does ADA deficiency affect dNTP synthesis?
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ADA leads to an accumulation of dATP (due to lack of deamination and catabolism) at the expense of other nucleotides. dATP prevents the formation of other dNDPs because it is the most potent inhibitor of ribonucleotide reductase. Therefore it interferes with DNA replication.
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Why does PNP deficiency affect dNTP synthesis?
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PNP deficiency leads to an accumlation of dGTP which is the second most potent inhibitor of ribonucleotide reductase. It inhibits the formation of dCDP.
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How are thymidine nucleotides generated?
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dUMP reacts with a folate derivative to add a methyl group to C-5 or uracil via the enzyme thymidylate synthase to generate thymine.
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Why is the thymidylate synthase nucleotide enzyme important clinically?
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It is the major target for 5'fluorouracil chemotherapy.
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How do the mitochondria get a nucleotide pool for nucleotide synthesis?
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Mitochondrial transporters function for a short period prior to S phase to glean dNDPs from the cytosol. The mitochodria have their own salvage enzymes for deoxynucleosides that can convert (cytosolic?) deoxynucleosides to deoxynucleotides--namely deoxyguanosine kinase (dGK) and thymidine kinase 2 (TK2).
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What are some diseases of the mitochondria related to mitochondrial nucleotide metabolism?
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MNGIE, TK2 deficiency, and dGK deficiency
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