Term
| Addition of a pentose sugar to a base produces... |
|
Definition
|
|
Term
| linked to sugar by B (1'-9) N-glycosidic linkage |
|
Definition
|
|
Term
| linked to sugar by B (1'-1) N-glycosidic linkage |
|
Definition
|
|
Term
|
Definition
| from the bottom N, clockwise |
|
|
Term
|
Definition
| From top left N counter-clockwise then 7, 8 on top, bottom (respectively) N of pentose ring |
|
|
Term
| Xanthine and Hypoxanthine are intermediates in the biosynth and breakdown of... |
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Definition
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Term
| Natural ribo- and deoxy- nucletodides have ___ PO4 linkages, while degradation products have ___, ___, or ___ PO4 linkages |
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Definition
|
|
Term
| Nucleotide cellular level: ATP is highest; rNTP, rNMP >> ____, ____ |
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Definition
|
|
Term
|
Definition
| energy carrier; nucleic acid compnt; coenzyme compont; acceptors in oxidative phosphorylation;allosteric regulation; substrate activation |
|
|
Term
| Energy for purine synth comes all from ____ except for energy for changing IMP -> AMP which is ____. |
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Definition
|
|
Term
| The ribose-phosphate component of both purine and pyrimidine nucleotides comes from _____ which is synthesizied from _______ and ______ by ________. |
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Definition
| PRPP; ATP, ribose-5-phosphate; PRPP synthetase |
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Term
| Purine biosynth: control step is formation of _________ catalyzed by ________ which is feedback inhibited by ___ and ___ or ___. |
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Definition
| 5-phosphoribosyl-1-amine; glutamine-PRPP amidotransferase; AMP; IMP; GMP |
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Term
| Purine biosnyth: steps using Gln as substrate can be inhibited by using Gln analogues such as ______ and ______. |
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Definition
|
|
Term
| Purine biosynth: the first purine base made is _______ but its nucleoside and nucleotide forms are ____ and ______, respectively. |
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Definition
| hypoxanthine; inosine, IMP |
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Term
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Definition
|
|
Term
| Purine ring: #3-N and #9-N source |
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Definition
|
|
Term
| Purine ring: #4-C, #5-C, #7-N source |
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Definition
|
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Term
| AMP formed from IMP: Aspartate is added to IMP by ___ enzyme and this rxn is stimulated by ___ and feedback inhibited by ___. |
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Definition
| adenylsuccinate synthase; GTP, AMP |
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Term
| GMP formed from IMP:IMP oxidized to XMP by ____. XMP + ___ and ___ -> GMP which is stimulated by ___ and inhibited by ___ and this step can be inhibited by the Gln analogues ___ and ___. |
|
Definition
| IMP dehydrogenase; Gln, GMP synthetase; ATP, GMP; azaserine, DON. |
|
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Term
| At physiologically high levels(von Gierke's disease), ____ stimulates PRPP production, overriding the inhibitory effects of ___ and ___. |
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Definition
| ribose-5-phosphate; ADP, GDP |
|
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Term
| Glutamine-PRPP-amidotransferase is regulated by feedback inhibition by ___, ___, ___ but higher levels of ___ can override this feedback inhibition. |
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Definition
|
|
Term
| Azaserine and DON are _____ antagonists and they inhibit ______. |
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Definition
| glutamine; formylglycinamide ribotide amidotransferase |
|
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Term
| 6-mercatopurine is ___ antagonist, 6-thioguanine is ___ antagonist and 8-asaguanine is ___ antagonist and all these inhibit ___. |
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Definition
| IMP, GMP, GMP; purine nucleotide synthesis |
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Term
| In contrast to purine snth, pyrimidine ring is ___. ___ is donor of C-atoms, while ___ is donor of C and N atoms; ___ is donor of ribose and alpha-PO4. ___ is energy source. |
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Definition
| assembled first; CO2, amino acids, PRPP; ATP |
|
|
Term
| First pyrimidine base is ____ which receives ____ from PRPP to form ____, the first pyrimidine nucleotide, which is decarboxylated to ___. |
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Definition
| orotic acid; R-P; OMP; UMP. |
|
|
Term
| Pyrm Synth 1. Carbamoyl phosphate synthetase II (CPS II) is located in ____ and is feedback inhibited by ____. |
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Definition
|
|
Term
| Pyrm Synth 2. The control step is catalyzed by ____ (can be therapeutically inhibited by ___) which is stimulated by ___ but inhibited by ___, the end product of this (pyrimidine) pathway. |
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Definition
|
|
Term
| Pyrm Synth 3. Enzyme is ____. |
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Definition
|
|
Term
| Pyrm Synth 4. Enzyme is ____. |
|
Definition
| Dihydroorotate dehydrogenase |
|
|
Term
| Pyrm Synth 5. enzyme is _____. |
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Definition
|
|
Term
| Pyrm Synth 6. Enzyme is ___ which is feedback inhibited by ____. |
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Definition
|
|
Term
| Pyrm synth 7. CTP is produced by ___, which is feedback inhibited by ___ which also feedback inhibits ___. |
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Definition
| CTP synthetase; CTP; committed step enzyme ATCase. |
|
|
Term
| Enzymes 1+2+3 are called multifxnl enzyme ____ |
|
Definition
|
|
Term
| Enzymes 5 & 6 are called multifxnl enzyme ____, the deficiency of which leads to ___, (an orotate excess caused by lack of UMP feedback inhibition and a deficiency of pyrimidines) |
|
Definition
| UMP synthase; orotic aciduria |
|
|
Term
| Pyrimidine ring:#2 C comes from ___ |
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Definition
|
|
Term
| Pyrimidine ring: #3 N comes from ___. |
|
Definition
|
|
Term
| Pyrimidine ring: #5, #6 C's come from ____. |
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Definition
|
|
Term
| ATCase/asp binding affinity stimulated by ___ and inihibited by ___ which affects levels of ___, the product of this rxn. |
|
Definition
| ATP; CTP; N-carbamoyl aspartate. |
|
|
Term
| Pyrimidine biosynthesis can be therapeutically down-regulated by treatment with ___ or with ___. |
|
Definition
| PALA (it resembles carbamoyl aspartate, inhibits ATCase) ;pyrimidine analogs |
|
|
Term
| The triphosphate form of the nucleotides is needed for use in most biological reactions. Only ___ (which requires ___ as substrate) is made de novo as an NTP. The biosynthesis of adenylate, guanylate and uridylate generates the NMP. |
|
Definition
| cytidylate (requires UTP, not UMP as substrate) |
|
|
Term
| Nucleotide phosphorylation (kinase) rxns. are reverisble/irreversible? |
|
Definition
|
|
Term
| The NMP->NDP rxns are catalyzed by the ____ which is specific/non-specific for the ribose/deoxyribose forms. Note that the TMP kinase is attached only to the ___, never the ___. |
|
Definition
| UMP, CMP, or GMP Kinase; non-specific; deoxyribose sugar, ribose sugar |
|
|
Term
| A single enzyme ___ converts all (d)NDPs to (d)NTPs except the ___ enzyme which is base (adenine) specific only but does the transfer for the PO4 to either the mono- or di-phosphate forms with ribose or deoxyribose forms. |
|
Definition
| nucleoside disphosphate kinase; adenylate kinase |
|
|
Term
| The single enzyme ___ catalyzes the reduction of all rNDPs to dNDPs. |
|
Definition
|
|
Term
| Ribo R'tase is kept in reduced form by ____ or the ___/___ electron donors in which the electrons are transferred from the NADPH + H+ to the ___ of ribo r'tase |
|
Definition
| thioredoxin, glutathione/glutaredoxin; catalytic site sulfhydryl groups |
|
|
Term
| Ribo R'tase (B1) has activity site that regulates overall enzyme activity that binds ___ for activation and ___ for inhibition. |
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Definition
|
|
Term
| ATP in the specificity site favors ___ or ___ in catalytic site -> ___ or ___. |
|
Definition
|
|
Term
| dCDP, dUDP ->->___->___->->___. |
|
Definition
|
|
Term
| dTTP occupies specificity site, favoring ___ or ___ in catalytic site. Then GDP -> dGDP -> ___ which favors ___ in catalytic site which leads to incr levels of ___ -> ___ which displaces ATP at activity site and thus Ribo R'tase is turned on/off. |
|
Definition
| GDP; ADP; dGTP; ADP; dADP, dATP; OFF |
|
|
Term
| In tumor lysis sydrome, the efficient salvage of dA->-> ___ leads to ___ by upsetting balance of cellular ___ needed for DNA replctn. in lymphocytic and other stem cells. |
|
Definition
| dATP; immune suppression; dNTP |
|
|
Term
| Another cause of immune suppression is ___. |
|
Definition
| adenosine deaminase deficiency |
|
|
Term
| Salvage of orotate and uracil + PRPP --> OMP, UMP by ____ ____ ____ enzyme (normally used in de novo prymidine synth) |
|
Definition
| orotate phosphoribosyl transferase; |
|
|
Term
| To salvage T to deoxynucleoside form use _____ ______ enzyme |
|
Definition
|
|
Term
TMP is generated from thymidine by the
deoxynucleoside-specific enzyme ____ ____. |
|
Definition
|
|
Term
| Nucleoside rxns use kinases that are specific for the base and/or the sugar; they use ___ as the phosphate donor |
|
Definition
|
|
Term
| Nucleoside salvage rxn enzymes include ___ for rU and rC, ___for dT and ___ for dC, dA and dG. |
|
Definition
| uridine- and cytidine- kinase; thymidine kinase; deoxycytidine kinase |
|
|
Term
| EXCEPTION: Adenosine kinase is specific for __, but it is not sugar-specific; can phosphorylate both __ and __. |
|
Definition
|
|
Term
| _____ and _____ salvage free purine bases directly to the NMP forms in a reaction using PRPP as the ribose-phosphate donor |
|
Definition
| Adenine phosphoribosyl transferase (APRTase) ;hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) |
|
|
Term
SAVINGS:
__~P/base needed for salvage to its (d)NTP.
__~P/nucleoside need for salvage its (d)NTP. |
|
Definition
|
|
Term
| ____ and ____ can be transported into cells; ____ can not. Thus, these drugs are administered as bases or nucleosides, then metabolically activated intracellularly. |
|
Definition
| Bases, nucleosides; nucleotides |
|
|
Term
| Pyrimidines that are not salvaged or those from the diet are degraded to β-alanine and β-aminoisobutyrate, which are highly soluble And may be ________ or _______. Thus, there are no metabolic problems associated with normal degradation of pyrim |
|
Definition
|
|
Term
| In humans, unsalvaged purines are converted to ___, then to ___, both of which have solubility problems and may cause ___. |
|
Definition
| Xanthine; Uric Acid; gouty arthritis |
|
|
Term
| The enzymes for conversion of AMP or adenosine to hypoxanthine include the _____ and ______. |
|
Definition
| adenosine deaminase (ADA); purine nucleoside phosphorylase |
|
|
Term
| Enzymes for converting GMP, guanosine and guanine to xanthine also include ___ ___ ___. |
|
Definition
| purine nucleoside phosphorylase |
|
|
Term
| Note, that mis-regulaton of Ribo. R’tase leading to an imbalance of ___ is an essential part of each of these diseases which include ____, ____ and ____. |
|
Definition
| dNTPs; ADA Def, Gout, Purine nucleoside phosphorylase deficiency |
|
|
Term
| Hypoxanthine conversion to xanthine and xanthine to uric acid are catalyzed by ___ ___. |
|
Definition
|
|
Term
| Uric acids (____ form) can ionize to urate. |
|
Definition
|
|
Term
| Since the solubilities of uric acid, hypoxanthine or xanthine increase at higher/lower pH, temporary mild alkalinization of urine PLUS forcing fluids will: ____, ____, and ____. |
|
Definition
higher; increase the excretion of urate, xanthine and hypoxanthine;
decrease urate crystal formation and precipitation;more rapid decrease in tissue urate levels. |
|
|
Term
| _____ is a therapeutic analog of hypoxanthine and is used to reduce body urate levels. |
|
Definition
|
|
Term
| ______ degrades urate to allantoin, which is 5-10 times more soluble that urate. |
|
Definition
|
|
Term
| Lesch-Nyhan syndrome is a complete deficiency in_____ ______ and is a rare X-linked chromosome disorder. Symptoms include ____, ____, and ____. |
|
Definition
| functional HGPRTase; severe gouty arthritis, mental retardation and aggressive, self-mutilation. |
|
|
Term
| _____ leads to an accumulation of rA and dA; the dA is salvaged to ___ that impairs the immune system by preventing immune cell multiplication. The excessive dATP inhibits ___ ___, causing a deficiency in ___, ___, and ___. This leads to ___ ___ ___ synd |
|
Definition
| Adenosine deaminase (ADA) deficiency; dATP; Ribo. R’tase; dCTP, dTTP and dGTP; Severe Combined Immonodeficiency (SCID) |
|
|
Term
| ___ deficiencies (von Gierke’s disease) increase levels of___ , overriding the feedback inhibition by ADP & GDP. (This is a type of glycogen storage disease and may lead to gout). |
|
Definition
| Glucose-6-phosphatase; ribose-5-PO4 |
|
|
Term
| Gout can also be caused by alterations in ___ ____ ____. |
|
Definition
| Gln PRPP amidotransferase |
|
|
Term
| Gout is also caused by decreased ___ and/or ____ activity resulting in decr feedback inhibition of de novo biosynthesis plus generation of excess ___ for degradation. |
|
Definition
| HGPRTase, APRTase; purines |
|
|
Term
| Renal lithiasis is a complete deficiency of ___ enzyme and is inherited in a(n) ___ pattern. |
|
Definition
| adenine phosphoribosyltransferase; autosomal recessive. |
|
|
Term
| Thiopurine is metabolically activated by ___. |
|
Definition
| TPMT-thiopurine S-methyltransferase |
|
|
Term
| Lesch-Nyhan syndrome is a complete deficiency in functional ___ and is a rare X-linked chromosome disorder. |
|
Definition
|
|
Term
| Adenosine deaminase (ADA) deficiency leads to an accumulation of ___ -> ___ which inhibits Ribo R’tase, causing a deficiency in ___. Thus, ADA deficiency leads to ___. |
|
Definition
| dA; dATP; DNA synthesis; Severe Combined Immunodeficiency (SCID) Syndrome |
|
|
Term
| Gout caused by elevated PRPP synthetase can be due to loss of feedback inhibtion by ___ and by ___ deficiencies (Von Gierke's Disease) that incr levels of ribose-5-PO4 which override feedback inhibition of ADP and GDP and cause a decreased ___ for ribose- |
|
Definition
| purine nucleoside diphosphates; glucose -6-phosphatase; Km |
|
|
Term
| Gout: also caused by alterations in ___ enzyme can be caused by two things: (1) An excess of ___ overriding the feedback inhibition or (2) incr/decr sensitivity to feedback inhibition by AMP, GMP or IMP. |
|
Definition
| Gln PRPP amidotransferase; PRPP; decreased |
|
|
Term
| Gout: also caused by decreased ___ and/or ___ activities resulting in less feedback inhibition of de novo biosynthesis, plus generation of excess ___ for degradation. |
|
Definition
| HGPRTase and/or APRTase; purines |
|
|
Term
| mutations to the pyrimidine catabolic enzyme ___ can generate toxic levels of 5-FU activation products; mutations in ___ are important in the catabolic inactivation of thiopurine and may lead to toxic levels of some administered drugs. |
|
Definition
| DPD; thiopurine S-methyltransferase (TPMT) |
|
|
Term
| Adenosine deaminase (ADA) deficiency treatments: Include (1)___ from HLA-identical sibling or haplo-identical donor, (2) exogenous ___, and (3) ___ into peripheral lymphocytes and bone marrow erythropoetic stem cells. |
|
Definition
| bone marrow transplants; enzyme replacement therapy; somatic-cell gene therapy |
|
|
Term
| Protocol for gene therapy is: ADA ___ is packaged into a retroviral vector; then isolate peripheral blood ___ and ___ from patient, and finally infect patient’s cells in culture with ___, reinject back into patient over 2-year period. |
|
Definition
| cDNA; T-cells, bone marrow stem cells; retroviral gene construct |
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|
Term
|
Definition
|
|
Term
| What are the two substrates for thymidylate synthase? What are the reaction products? |
|
Definition
| dUMP, N5-N10-methyl THF; dTMP->->dTTP |
|
|
Term
| Where might the dUMP for this reaction come from? From dUTP by ___, from dUDP by ___, or from dCMP by ___. |
|
Definition
| dUTPase; UMP kinase; deoxycytidylate deaminase. |
|
|
Term
| TMP is formed by ___ of dUMP. |
|
Definition
|
|
Term
| When in the cell cycle might thymidylate synthetase activity be highest? Why then? |
|
Definition
| dNTP levels are highest during S-phase of the cell cycle, when DNA replicates. |
|
|
Term
| deoxyribose units for DNA are formed by modification of ___ or by salvage reactions; ribonucleotides are/are not directly formed from deoxynucleotides. |
|
Definition
|
|
Term
| In the thymidylate synthase rx. dUMP receives a methyl group from N5, N10-mTHF, converting the latter to ___. To sustain dTMP formation (for ongoing DNA replication), ___ must be reduced to THF by ___; then, THF is remethylated to form N5, N10-mTHF. Fola |
|
Definition
| dihydrofolate (DHF); DHF; dihydrofolate reductase (DHFR) |
|
|
Term
| The thymidylate synthase reaction is inhibited directly by ___ or inhibited indirectly by ___ or ___ . |
|
Definition
| 5-flurouracil 5-FU; methotrexate or aminopterin |
|
|
Term
5-FU is a structural analog of ___ and of ___ after 5-FU is metabolically activated to ___. Florouracil locks THF and enzyme thymidylate synthase.
This activation involves base salvage, kinasing and Ribo R’tase reduction and dephosphorylation. |
|
Definition
|
|
Term
| -Second half of this rxn-since you need n-5,n-10 mTHF we can inhibit generation of this methyl donor by inhibitng ___ with ___ and ___. |
|
Definition
| dihydrofolate reductase (DHFR); aminopterin; methotrexate (MTX). |
|
|
Term
| Methotrexate: Why would you use a ‘high-dose’ type of therapy? Why would this include supplementation with leucovorin? |
|
Definition
| a low dose over time selects for cancer cells that developed resistance to MTX. It is better to treat with a high dose of MTX for a short time to kill all cancer cells. This high dose also arrests the cell cycle progression of more slowly dividing normal cells, but these cells subsequently can be rescued by supplementation with N5-formyl-THF-Ca+2 (leucovorin). |
|
|
Term
| Do cancer cells ever become resistant to chemotherapeutic drugs? Any thoughts on how? |
|
Definition
| Some MTX-resistant cells may develop deficiencies in the MTX uptake transport protein or MTX metabolic activation enzymes. Alternatively, the resistant cells may be overproducing MDR1 (multiple drug resistance protein; P-glycoprotein), a membrane efflux protein which pumps MTX out of the cell |
|
|
Term
| A deficiency in Vit. B12 prevents return of ___ to the THF pool, decreasing the THF available for N5, N10-mTHF formation; eventually all the ___ may become trapped in the N5-mTHF form. The only available THF is derived from ___. |
|
Definition
| N5-mTHF; folate; dietary folates |
|
|
Term
| Salvage of bases O and U to the NMP form requires ___+___, a normal biosynthetic enzyme |
|
Definition
| PRPP + orotate phosphoribosyl transferase |
|
|
Term
| In contrast, thymidine phosphorylase, a deoxyribose-specific enzyme salvages ___ only to the ___ form. ___ is never salvaged to a ribonucleoside or ribonucleotide form. |
|
Definition
|
|
Term
| EXCEPTION: ___ is specific for A, but it is/is not sugar-specific; can/can not phosphorylate rA and dA. |
|
Definition
| Adenosine kinase; is not; can |
|
|
Term
| Adenine phosphoribosyl transferase (APRTase) and hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) salvage free ___ bases directly to the ___ forms in a reaction using PRPP as the ribose-phosphate donor |
|
Definition
|
|
Term
| SAVINGS: ___ ~P/base needed for salvage to its (d)NTP. ___ ~P/nucleoside need for salvage to its (d)NTP. |
|
Definition
|
|
Term
| ___ and ___ can be transported into cells; ___ can not. |
|
Definition
| Bases; nucleosides; nucleotides |
|
|
Term
| Are salvage reactions useful therapeutically? If so, how? What drugs follow this path? |
|
Definition
| drugs are administered as bases or nucleosides, then metabolically activated intracellularly. Metabolic activation of chemotherapeutic drugs 5-fluorouracil and 5-fluorouridine. Since nucleotides are the active form of most base analog drugs, they must be similarly activated via normal salvage pathways. 5-florouracil, 5-florouridine |
|
|
Term
| Pyrimidines that are not salvaged or those from the diet are degraded to___ and ___, which are highly soluble and may be execreted or reutilized. Thus, there are/are not metabolic problems associated with normal degradation of pyrimidines. |
|
Definition
| β-alanine and β-aminoisobutyrate; are not |
|
|
Term
| enzyme deficiencies may lead to drug toxicity in a patient undergoing cancer chemotherapy. For example, ___ (catalyzes the reduction of T, U to dihydrouracil, dihydrothymine). |
|
Definition
| dihydropyrimidine dehydrogenase (DPD) |
|
|
Term
| Also, note that β-aminoisobutyrate is a breakdown product only of ___. Thus, its presence in urine reflects turnover of ___, not ___. |
|
Definition
|
|
Term
| The enzymes for conversion of AMP or adenosine to hypoxanthine include the ___ and ___. Enzymes for converting GMP, guanosine and guanine to xanthine also include ___. Deficiencies in ADA or purine nucleoside phosphorylase cause immune system problems of |
|
Definition
| adenosine deaminase (ADA); purine nucleoside phosphorylase; purine nucleoside phosphorylase; SCID; T-cell deficiency |
|
|
Term
| Hypoxanthine conversion to xanthine and xanthine to uric acid are catalyzed by___. |
|
Definition
|
|
Term
| Since the solubilities of uric acid, hypoxanthine or xanthine increase/decrease at higher pH temporary mild alkalinization of urine PLUS forcing fluids will: |
|
Definition
| increase; increase the excretion of urate, xanthine and hypoxanthine; decrease urate crystal formation and precipitation, resulting in more rapid decrease in tissue urate levels. (if pt. has gout, raise her pH) |
|
|
Term
| Allopurinol (Allop) is a therapeutic analog of ___ and is used to reduce body urate levels. |
|
Definition
| hypoxanthine. Allopurinol forms a 'suicide-inhibitor' omplex. |
|
|
Term
| ___ degrades urate to allantoin, which is 5-10 times more soluble that urate. Produced as a recombinant protein in yeast cells from an Aspergillus flavus cDNA. Sold as ___, it is an approved intravenous protein drug for temporary relief of high plasma ura |
|
Definition
|
|
Term
| A mutation in an enzyme that normally catabolizes purine bases and that is under-active can lead to toxic levels of some administered drugs. For example, ___ is important in the catabolic inactivation of thiopurine and leads to toxic levels of the drugs _ |
|
Definition
| thiopurine S-methyltransferase (TPMT); mercaptopurine, azathioprine |
|
|
Term
| Likewise, mutations to the pyrimidine catabolic enzyme ___ can generate toxic levels of 5-FU activation products |
|
Definition
|
|
Term
|
Definition
|
|
Term
| Metabolic activation of Capecitabine (CAP): This oral ___ pro-drug is designed for a multi-step, multi-tissue metabolic activation. Step 1.___ cleavage in liver Step 2. ___ rxn in most tissues, including tumor cells. Step 3. ___rxn in all tissues but at h |
|
Definition
| 5-FU; Carboxylesterase; Cytidine deaminase; Thymidine phosphorylase |
|
|
Term
| Can you list and discuss various genetic polymorphisms that might be important to consider/test for? |
|
Definition
| Mutations in gene for ADA (on chromosome 20); mutations to the pyrimidine catabolic enzyme DPD can generate toxic levels of 5-FU activation products |
|
|
