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Post-Midterm Biochem
Purine Metabolism
| Question | Answer |
|---|---|
| What are the functions of nucleotides? | 1) building blocks for DNA/RNA, 2) Carriers for activated intermediates (ie – UDP-glucose), 3) Structural components of reaction coenzymes/cofactors |
| Which 4 Cofactors/Coenzymes are nucleotides a structural component of? | 1) CoA, 2) FAD, 3) NAD+, and 4) NADP+ |
| What are the components of a nucleotide? | 1) Nitrogenous base, 2) Pentose Monosaccharide (Sugar), 3) 1-3 phosphate groups |
| Describe the amount of nucleotides that must be present for DNA synthesis to occur. | All 4 nucleotides (A, C, T, G) must be present in relatively equal amounts for DNA synthesis to occur. |
| Name the 2 Purines found in DNA and RNA. | Adenine and Guanine |
| Name the 2 Pyrimidines found in DNA. | Cytosine and Thymine |
| Name the 2 Pyrimidines found in RNA. | Cytosine and Uracil |
| How many rings does the structure of a Purine contain? | 2 rings |
| How many rings does the structure of a pyrimidine contain? | 1 ring |
| What are the 2 additional bases (aside from A, C, T, G, and U) that are involved in Purine synthesis and degradation? | Hypoxanthine (from Inositol Monophosphate (IMP)) and Xanthine (from Xanthine Monophosphate) |
| In addition to the usual bases, there are a number of unusual bases in the body – What are they usually a component of and what type of derivatives are they? | The unusual bases are typically found in tRNA and viral DNA, they are *methyl* derivatives of normal bases |
| What is a nucleoside? | A pentose monosaccharide (sugar) and a nitrogenous base (NO phosphate group) ie – Adenosine, Cytidine, Guanosine, Uridine, and Thymidine |
| Describe the 3 types of nucleotides. | nucleoside monophosphate (1P), nucleoside diphosphate (2P), and nucleoside triphosphate (3P) |
| What component of the nucleotide is responsible for the negative charges associated with DNA and RNA? | The phosphate groups (PO4-) |
| Describe the proper nomenclature for ribose and deoxyribose nucleotides. | ribose sugar = adenosine triphosphate (ATP) or deoxyribose sugar = deoxy-adenosine triphosphate (dATP) |
| Name the 2 pathways available for Purine synthesis. | De novo (from scratch) or Salvage |
| Describe the general process of De Novo Purine Synthesis. | It is accomplished by first constructing a purine ring through a series of reactions that add the carbon and nitrogen to a preformed ribose-5-phosphate molecule. Sugar is made first, then the base. |
| Where does the Ribose-5-Phosphate for De Novo Purine Synthesis come from? | Hexose Monophosphate Pathway (Pentose Phosphate Pathway) |
| Where are the enzymes for De Novo Purine synthesis found within the cell? | Cytoplasm |
| Where are the Carbons that contribute to the ring structure donated from in De Novo Purine synthesis? | CO2, N-Formyl-THF, Glycine |
| Where are the Nitogens that contribute to the ring structure donated from in De Novo Purine synthesis? | Aspartate, Glycine, Glutamine |
| Overall, which components donate the Nitrogens and Carbons to the ring structure in De Novo Purine Synthesis? | Glycine, Aspartate, Glutamine, CO2, and F-THF |
| What structure is formed before purine synthesis can take place? | 5-phosphoribosyl-1-pyrophosphate (PRPP) must be produced from ribose-5-phosphate and ATP |
| What enzyme is responsible for producing PRPP from R-5-P and ATP? | Ribose Phosphate Pyrophosphokinase |
| What reactions is PRPP involved in? | 1) De Novo Synthesis of Purines and Pyrimidines, 2) Salvage of Purines and Pyrimidines, 3) Synthesis of NAD+, 4) Synthesis of Histidine, 5) Conversion of Guanine to GMP |
| What activates Ribose Phosphate Pyrophosphokinase? | Phosphate ions (Pi) and abundance of Ribose-5-Phosphate |
| What inhibits Ribose Phosphate Pyrophosphokinase? | Purine Ribonucleotides (PRPP) |
| What is the first step of De Novo Purine Synthesis? | PRPP -> 5’-phosphoribosylamine via the enzyme Glutamine:Phosphoribosyl Pyrophosphate Amidotransferase |
| Is the first step of De Novo Purine Synthesis rate limiting and commited? | Yes, it is both rate-limiting and commited |
| Which compounds control the rate of action of Glutamine:Phosphoribosyl Pyrophosphate Amidotransferase? | Glutamine and PRPP |
| Which compounds inhibit the action of Glutamine:Phosphoribosyl Pyrophosphate Amidotransferase? | AMP, GMP, and IMP |
| How much ATP is required to perform De Novo Purine Synthesis? | 4 ATP |
| What cofactor does Glutamine:Phosphoribosyl Pyrophosphate Amidotransferase require? | Mg2+ |
| What is PABA and what do its structural analogs do? | PABA is an intermediate in bacterial Folate synthesis. PABA analogs (sulfonamides) competitively inhibit the synthesis of Folate in bacteria which slows down purine synthesis and thus cell division which requires Folate (THF). |
| Why don’t Sulfonamides affect humans? | Humans cannot synthesize folate and must rely of external (dietary) sources, therefore PABA analogs like sulfonamides to not inhibit human purine synthesis. (However, Folate analogs will). |
| Describe Methotrexate and its action. | Methotrexate is a Folate analog that inhibits the reduction of DTF to THF by dihydrofolate reductase. By limiting the amount of THF available for purine synthesis, they slow down DNA synthesis in dividing mammalian cells. |
| What type of disorder is Methrotrexate used to treat? | Rapidly diving cancer cells (though it is toxic to all dividing cells), specifically *leukemia* |
| What are the side effects of treatment with Methotrexate in normal cells? | Since they effect any rapidly diving cells, not just cancer, patients often experience Scaly skin, Anemia, GI tract disturbances, Respiratory tract disturbances, and Baldness. |
| What enzyme does Methotrexate inhibit? | Dihydrofolate reductase |
| What compound has the same effect as Methotrexate in bacteria? | Trimethoprim (it is also inhibits the synthesis of THF) |
| What is the most common vitamin deficiency in the world? | Folate deficiency |
| How do folate deficiencies typically present themselves (symptoms)? | Megalobastic anemia with low [Hb] and large number of large, immature Megaloblastic erythrocytes |
| How do Cancer Cells become resistant to Methotrexate? | Amplification of the gene for dihydrofolate reductase (make more enzyme to overcome inhibitory effects) |
| What is the obligate precursor of AMP and GMP? | IMP |
| Using flow, describe the pathway of IMP to ATP. | IMP -> AMP -> ADP -> ATP |
| Using flow, describe the pathway of IMP to GTP. | IMP -> GMP -> GDP -> GTP |
| Are the pathways to create AMP and GMP from IMP different? | Yes, they are separate athways |
| What compound does synthesis of AMP require and what enzyme is involved? | GTP and Adenylsuccinate synthetase (as well as adenosuccinase in the following step) |
| What compound does synthesis of GMP require and what enzyme is involved? | ATP and GMP synthetase (as well as IMP dehydrogenase, and NAD+ in the previous step) |
| How are nucleotide monophosphates turned into diphosphates and triphosphate, respectively? | By nucleoside monophosphate kinases (base specific) and nucleoside diphosphate kinases. |
| What is the function of Mycophenolic acid? | It inhibits the enzyme IMP dehydrogenase which is the enzyme that produces Xanthine monophosphate which is turned into GMP by GMP synthetase. So, it is a GMP synthesis inhibitor. |
| When is Mycophenolic acid used? | Because it deprives rapidly proliferating B and T cells of key components of nucleic acids is is given to prevent graft rejection |
| What type of inhibitor is Mycophenolic Acid? | Reversible Non-competitive inhibitor |
| Which Purines can be salvaged? | Purines that result from normal turnover of cellular nucleic acids or that are obtained from the diet and not degraded can be salvaged |
| Which two enzymes are involved in Purine Salvage? | 1) Hypoxanthine-guanine phosphoribosyltransferase and 2) Adenine phosphoribosyltransferase |
| Describe Lesch-Nyhan Syndrome. | *X-linked* Complete deficiency of Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) that causes an inability to salvage Hypoxanthine or Guanine |
| What is another name for Lesch-Nyhan syndrome? | HGPRT deficiency |
| Production of what compounds is inhibited in Lesch-Nyhan syndrome? | Inability to produce IMP, GMP because the enzyme to do so is virtually absent |
| What accumulates in Lesch-Nyhan Syndrome? | PRPP, Guanine, Hypoxanthine accumulate because the enzyme to convert them is virtually absent |
| What happens to the De Novo Purine Synthesis Pathway when Salvage isn’t functioning? | Increased activity due to accumulation of PRPP |
| What happens to the compounds that accumulate in Lesch-Nyhan syndrome? | Theyre degregaded to Uric acid which accumulates causing manifestations including gout, mental retardation, self-mutilation (lip biting), involuntary movements, and increased uric acid in the urine (creating orange crystals in the affect infant’s diaper) |
| Are purines and pyrimidines essential in the diet? | No, we can synthesize them or salvage them |
| What happens to most Purines from dietary intake? | They are degraded to Uric acid |
| What happens to most Pyrimidines from dietary intake? | They are absorbed in the intestinal mucosa and returned to circulation |
| When purines are degraded, what happens to the released ribose and deoxyribose? | They are absorbed by the intestinal mucosa and returned to circulation |
| Are dietary purines and pyrimidines used to large extent for synthesis of tissue nucleic acids? | No |
| Describe Adenosine Deaminase Deficiency (SCIDS). | Prevents the degradation of Adenosine to Inosine resulting in immunodeficiency |
| Why does Adenosine Deaminase cause immunodeficiency? | Because DNA synthesis in quickly proliferating cells (like B and T cells) is inhibited (due to high dATP levels). This immunodeficiency results in death before the age of 2 years due to severe infection. |
| Why would high dATP levels inhibit DNA synthesis? | Ribonucleotide Reductase converts ribonucleotides (ADP, GDP, UDP, CDP) to deoxyribonucleotides (dADP, etc.) which are then phosphorylated to dNTP form (dATP, etc.). Excess dATP prevents the reduction of ALL ribonucleotides, thus preventing DNA synthesis. |
| Why does dATP buildup in Adenosine Deaminase Deficiency? | Because ADA deficiency causes a buildup of Adenosine, which kinases freely converted into its nucleotide form (dATP) |
| What does SCIDS stand for? | Severe Combined Immunodeficiency Syndrome |
| What are the best substrates for Purine Nucleotide Phosphorylase (PNP)? | Guanosine and Inosine (Adenosine is a poor substrate which is why it is converted to Inosine for degradation) |
| Using a flow, describe the degradation of AMP. | AMP -> Inosine -> Hypoxanthine -> Xanthine -> Uric Acid |
| Using a flow, describe the degradation of GMP. | GMP -> Guanosine -> Guanine -> Xanthine -> Uric Acid |
| Describe Purine Nucleoside Phosphorylase (PNP) Deficiency. | Deficiency of this enzyme causes impairment of the T-cell function, decreased uric acid production, and increased purine nucleosides/nucleotides, not as bad as Adenosine Deaminase deficiency because B-cells are still functional |
| In most cases, is Gout a result of overproduction of Uric Acid or an accumulation of Uric Acid? | Accumulation (underexcretion) is far more common than overproduction. Overproduction only occurs when there is an inborn error of metabolism that creates an excess of Purines. |
| What are the symptoms and results of Gout? | Inflammation and Arthritic due to accumulation of sodium urate crystals |
| How does Allopurinol treat Gout? | It competitively inhibits xanthine oxidase so uric acid isn’t formed and the degradation of Purines stops at Xanthine (from GMP) and Hypoxanthine (from AMP) which are excreted more easily due to their increased solubility (as compared to uric acid) |
| Aside from Allopurinol, what is another treatment for Gout? | Colchicine, a microtubule inhibitor, it does NOT descrease serum uric acid levels like Allopurinol does but it helps the clinical symptoms by inhibiting migration of WBC to joint joints where sodium urate crystals accumulate. |
| What is the different between Primary and Secondary Gout? | Primary = genetic, affects males over the age of 30, Secondary = brought on by disorders, affects males and females of any age |
| What are some causes of Secondary Gout? | Leukemia, Polycythemia, Lesch-Nyhan (HGPRT) Syndrome, cancer treatment with anti-metabolites, and chronic renal insufficiency |
| Deficiency in which 3 enzymes can cause *overproduction of uric acid* which results in Gout? | 1) Glucose-6-Phosphatase (Von Gierke type 1), 2) Aldolase B (Fructose Intolerance), and 3) Galactose-1-phosphate-uridyltransferase aka GALT (classical galactosemia)… all of these result in trapping of phosphate in sugars which prevents AMP -> ADP, ATP |
| How can Alcoholism lead to Gout? | Alcoholism increases NDH:NAD+ which shunts pyruvate into lactate metabolism, excess lactate overrides uric acid transport (because they share a common transporter) so uric acid accumulates causing Gout. |
| What molecule receives the carbons and nitrogens donated by CO2, Amino acids, and THF? | Ribose phosphate |
| What does PRPP donate in Purine synthesis? | Ribose sugar and phosphate |
| True or False: Purines are built on an activated ribose (sugar) first, then the base is formed? | True |
| True or False: Folic Acid is required for BOTH purine and pyrimidine synthesis? | True |
| True or False: PRPP is one of the substrates used to form IMP? | True (Hypoxanthine + PRPP -> (via HGPRT) IMP + PPi |
| True or False: Ribonucleotide Reductase requires NADPH and thiredoxin to convert nucleosides into deoxynucleosides | True |
| True or False: HGPRT salvages hypoxanthine and converts it xanthine? | False - Hypoxanthine is degraded to Xanthine, it is recovered to IMP |
| True or False: A defect in Purine salvage results in a defect of purine degradation? | False (Purine salvage defects will cause increased de-novo synthesis of purines) |
| True or False: Uric acid accumulates to cause gout as a result of a block of an enzyme that converts uric acid into more soluble metabolites? | False |
| True or False: AMP and GMP are both eventually degraded to Hypoxanthine then uric acid? | False, both are degraded to Xanthine (first) then Hypoxanthine |
| True or False: There are NO diseases associated with pyrimidine degradation? | True (only Orotic Aciduria, and thats a defect in synthesis, not degradation) |
| True or False: Orate is formed before PRPP is added in pyrimidine synthesis? | True - Base first, then sugar |
| True or False: dCTP and dTTP are both formed from UMP? | True (if you go back far enough) |
| True or False: UDP forms UTP via methyl-THF | False |
| True or False: Pyrimidines are salavaged by taking a free pyrimidine , converting it to a nucleoside, then converting it to a nucleotide? | True |
| True or False: In Lesch Nyhan syndrome, PRPP is low, IMP is high, GMP is high, and uric acid cannot be formed? | False, all of these are backwards (IMP and GMP are low, PRPP is high, and uric acid is still formed) |
| In Severe Combines Immune Disease: a) there is an increase in dATP, b) there is a decrease in the activity of ribonucleotide reductase, c) Lymphocytes are effected, d) theres a defect in purine degradation but salvage is fine? | All of the above (are characterized by SCIDS aka 'bubble boy' disease) |
| Which compounds are used in the formation of the carbon/nitrogen rings in BOTH purines and pyrimidine? Which is the only one used in Purine synthesis and not in pyrimidine synthesis? | CO2, Glutamine, Aspartate, and THF (Glycine used only in Purine synthesis) |
| What is the difference between the THF's used in purine vs. pyrimidine synthesis? | Formyl-THF for purine, Methylene-THF for pyrimidine |
| What compound is NOT DIRECTLY formed by ribonucleotide redutase? | dTDP (dTMP is formed from dUMP in the thymidilate synthase reaction then phosphorylated to dFDP then dFTP respectively) |
| Describe the structure of a molecule of ribonucleotide reductase. | 2 active sites (bind dATP for inactivity, ATP for activity) and 2 substrate sites (to convert NDP -> dNDP) |
Created by:
sprater16