Molecular Biology, Nucleotide Metabolism, & Pharmacogenomics
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| True/False: Promoters have similar structure and resemble a consensus sequence at the 5' end. | True
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| What happens to cyclic AMP levels when glucose levels are high? | Decreases
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| What happens to cyclic AMP levels when glucose levels are low? | Increases
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| Under low lactose conditions the operator in the lac operon is bound by: | Repressor
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| Under high lactose conditions the operator in the lac operon is bound by: | RNA Polymerase (CRP-cAMP activation)
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| Under high glucose conditions the operator in the lac operon is bound by: | Nothing
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| True/False: The leader peptide plays an indirect role in causing RNA polymerase to attenuate with no involvement of the mRNA. | True
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| True/False: Trp codons in the leader peptide mRNA allow the system to respond to tryptophan levels in the cell. | True
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| True/False: When tryptophan levels are low, mRNA synthesis at the trp operon is attenuated. | False
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| The 2-3 mRNA structure promotes: | Transcription
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| The 3-4 mRNA structure promotes: | Attenuation
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| What two components are involved in steroid hormone action? | Hormone-receptor complexes & Receptor-DNA interactions
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| True/False: UMP is the precursor for the pyrmidines. | True
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| True/False: Deoxynucleoside triphosphates are used for DNA replication during the S phase of the cell cycle. | True
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| True/False: Bases are always synthesized while attached to ribose or deoxyribose. | True
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| How is PRPP synthesized? | ATP and ribose 5'-phosphate
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| True/False: PRPP is required for both purine and pyrimidine de novo synthesis. | True
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| What molecule does PRPP combine with in the first step of purine synthesis? | Glutamine
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| What is the immediate precursor to dTMP? | dUMP
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| What enzyme does tetrahydrofolic acid supply? | Thymidylate synthase
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| True/False: dNTPs are used only for DNA synthesis. | True
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| What antifolate drugs target dihydrofolate reductase? | Trimethoprim & Methotrexate
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| What prodrug directly inhibits thymidylate synthase and results in decreased levels of dTMP? | 5-fluoro-dUMP
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| What enzyme is found in the degradation pathway of AMP, what is the end product of the pathway, and what drug inhibits the enzyme causing the end product? | Xanthine oxidase; uric acid; Allopurinol
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| What three purines can be directly salvaged? | Guanine, adenine, & hypoxanthine
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| What is hypoxanthine-guanine phosphoribosyltransferase responsible for? | Salvaging hypoxanthine and guanine to IMP and GMP, respectively.
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| What enzyme is responsible for salvaging adenine to AMP? | Adenine phosphoribosyl transferase
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| Describe recombinant erythropoietin (Epogen). | Glycoprotein produced in kidney that binds EPO receptor and stimulates red blood cell production (erythropoiesis).
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| Describe Bevacizumab (Avastin). | Inactivated VEGF and blocks blood vessel growth. Used for colorectal and breast cancer.
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| Describe Trastuzumab (Herceptin). | Signals HER2 which induces intracellular signaling that controls growth.
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| What is the antibiotic selection in E. coli? | Ampicillin
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| What is the antibiotic selection in mammalian cells? | Hygromycin
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| What reaction requires dNTPs, template DNA, thermostable DNA polymerase (Taq), two primers, and a thermal cycling machine? | Polymerase chain reaction (PCR)
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| Somatic mutation | Not passed on to progeny; external environmental factors
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| Germ line mutation | Passed on to progeny
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| Explain why allopurinol is sometimes used by patients who are taking a chemotherapeutic agent. | Chemotherapy causes cell death, which increases the concentration of purines. The degradation of AMP by xanthine oxidase to uric acid is inhibited by allopurinol.
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| If there is a decrease in 6-thio-IMP then AMP and GMP: | Increase
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| How does allopurinol affect the metabolism of 6-mercaptopurine? | It inhibits hypoxanthine-guanine phosphoribosyl transferase, the enzyme needed to convert 6-mercaptopurine to 6-thio-IMP.
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| What is the role of hypoxanthine-guanine phosphoribosyl transferase (HGPRT) in the metabolism of 6-mercaptopurine and 6-thioguanine? | 6-Mercaptopurine is converted to 6-thio-IMP by Hypoxanthine-guanine phosphoribosyl transferase, and 6-thio-IMP is converted to 6-thioguanine by the same enzyme (HGPRT).
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| What are vinca alkaloids? | Mitotic inhibitors that stop microtubule polymerization
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| What are taxanes? | Mitotic inhibitors that stop microtubule depolymerization
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| What are two topoisomerase inhibitors? | Irinotecan & etoposide
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| What three features does a vector generally have? | (1) No more than one recognition site for a specific restriction enzyme, (2) replication origin(s), and (3) antibiotic resistance gene(s)
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| What four features are required to make recombinant DNA? | (1) Restriction endonuclease(s), (2) vector, (3) host cell, and (4) ligase.
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| True/False regarding PCR: The boundaries of the amplified DNA are determined by the synthetic oligonucleotides used as primers. | True
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| Are the primers of a polymerase chain reaction incorporated into the final DNA product? | Yes
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| True/False: During the S phase of the cell cycle there is a high rate of dNTP synthesis. | True
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| What is the significance of 5-FU? | 5-fluorouracil is converted to 5-dUMP which inhibits thymidylate synthase.
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| What is the relationship of 5-FdUMP to thymidylate synthase and methylene tetrahydrofolate (MTHF)? | Folinic acid can increase MTHF and potentiate action of 5-dUMP.
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| Which part of the cell cycle involves antimetabolites (antipurines, antipyrimidines, and antifolates)? | S phase
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| Define haplotype. | Set of polymorphisms that are inherited together
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| Define polymorphism. | Variation in DNA sequence
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| What are two broad categories of genes that have polymorphisms that can affect an individual's response to a drug? | Pharmacokinetics & pharmacodynamics
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| Synonymous single nucleotide polymorphism: | Nucleotide change without a change in amino acid (silent)
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| Nonsynonymous single nucleotide polymorphism: | Nucleotide change with a change in amino acid (missense)
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| Describe the P450 nomenclature system. | First letters/numbers identify gene; number-letter after gene indicates nucleotide location; first number-letter represents wild type; second number-letter represents polymorphism.
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| What does UGT1A1*28 specifically refer to and how is this related to the metabolism of SN-38? | UGT1A1*28 has 7 TA repeats and reduces metabolism
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| What are examples of CYP alleles related to drug metabolism? | CYP2C9*1 NL enzyme activity, CYP2C9*2 decreased enzyme activity, CYP2C9*3 decreased enzyme activity; CYP2C19*1 NL enzyme activity, CYP2C19*2 no enzyme activity, CYP2C19*3 no activity
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| How can a poor metabolizer be at risk for drug-induced side effects for one drug and have lack of a therapeutic effect for another drug? | Diminished drug elimination or lack of therapeutic effect resulting from failure to generate the active form of the drug.
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| What is abacavir's indication and mechanism of action? | Indication: HIV/AIDS; Mechanism of action: Nucleoside analog reverse transcriptase inhibitor
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| What is the relationship between the HLA-B*57001 allele and abacavir? | HLA-B*5701 confers high risk of abacavir-induced hypersensitivity
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| How can HER2 be measured? | Immunohistochemistry (IHC) & gene amplification by fluorescent in situ hybridization (FISH)
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| What is Azathioprine's mechanism of action? | Perturbs de novo purine synthesis with TPMT by inactivating 6-mercaptopurine
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| Describe TPMT*3A allele and how it affects azathioprine dosing. | Intermediate TPMT increases risk of myelotoxicity; low/absent TPMT increases risk of severe life-threatening myelotoxicity
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| What are the genetic variants to warfarin? | Variants in CYP2C9 decrease warfarin metabolism; variants in VKORC1 decrease levels of warfarin target
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| What is the potential role of UGT1A1 alleles in irinotecan metabolism? | High expression of UGT1A1 results in increased SN-38 glucuronide (inactive metabolite)
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| Describe the potential role of CYP2C19 alleles in Clopidogrel metabolism. | CYP2C19 metabolizes drug to active form; CYP2C19*1 functional; CYP2C19*2 nonfunctional (splicing); CYP2C19*3 nonfunctional (premature stop codon)
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| The polymorphic gene VKORC1 belongs to what drug? | Warfarin
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| The polymorphic gene CYP2C9 belongs to what drug? | Warfarin
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| The polymorphic gene HLA-B belongs to what drug? | Abacavir
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| The polymorphic gene CYP2C19 belongs to what drug? | Clopidogrel
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| The polymorphic gene UGT1A1 belongs to what drug? | Irinotecan
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| The polymorphic gene TPMT belongs to what drug? | Azathioprine
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| The polymorphic gene HER2 belongs to what drug? | Trastuzumab
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| What genes have a polymorphism in their promoter? | VKORC1 (-1639G>A) & UGT1A1 (6 TA repeats)
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| True/False: Individuals with the TPMT*3A/*3A genotype are more likely to experience toxicity with a conventional dose of azathioprine as compared to individuals that are homozygous wild type for TPMT. | True
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| True/False: CYP2C9 polymorphisms are the principle polymorphisms responsible for individual differences in response to azathioprine. | False - TPMT polymorphisms are
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| Which polymorphisms result in changes in the amino acid sequence of the corresponding enzyme? | CYP2C9*3, CYP2C19*2 (splicing), and CYP2C19*3 (stop codon)
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| What polymorphisms affect pharmacokinetics? | CYP2C9, CYP2C19, UGT1A1, TPMT
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| What polymorphisms affect pharmacodynamics? | VKORC1, HLA-B, HER2
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| True/False: Polymorphisms in pharmacokinetic and pharmacodynamics parameters can explain the variability in warfarin toxicity. | True
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| What enzyme is defective in hereditary fructose intolerance? | Aldolase B
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| What enzyme is deficient in essential fructosuria? | Fructokinase
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| For what purpose is fructose made in humans? | Fuel for spermatazoa
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| In which tissue is fructose made for spermatozoa fuel? | Seminal vesicles
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| What does the lacY gene do? | Promotes cellular uptake of lactose
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| What does the lacA gene do? | Modifies toxic products for excretion from bacteria
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| What does the lacZ gene do? |
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