Nucleotide Synthesis and Thymidylate Synthase
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Questions and Answers

What is the role of thymidylate synthase in nucleotide synthesis?

  • It converts dUMP to dTMP. (correct)
  • It synthesizes orotic acid.
  • It phosphorylates uridine.
  • It inhibits ribonucleotide reduction.

    • Orotic aciduria results from high activities of orotate phosphoribosyl transferase and orotidylate decarboxylase.

    False

    What nitrogen donor is used in the synthesis of cytidine from uridine?

    glutamine

    5-Fluorouracil is a thymine analogue and irreversibly inhibits thymidylate synthase by binding to it and causing _______.

    <p>covalent modification</p> Signup and view all the answers

    Match the following inhibitors with their effects:

    <p>5-Fluorouracil = Irreversible inhibitor of thymidylate synthase Methotrexate = Inhibits reduction of Dihydrofolate to Tetrahydrofolate Orotate = Causes abnormal growth when accumulated CTP synthase = Converts UTP to CTP</p> Signup and view all the answers

    What are the building units of DNA and RNA?

    <p>Nucleotides</p> Signup and view all the answers

    ATP and GTP are both sources of energy in biological systems.

    <p>True</p> Signup and view all the answers

    What is the role of cAMP and cGMP in the cell?

    <p>They serve as second messengers in signal transduction pathways.</p> Signup and view all the answers

    Nucleotides are essential for the _________ of the genome.

    <p>replication</p> Signup and view all the answers

    Match the following components of nucleotides with their correct descriptions:

    <p>Nitrogenous Base = Purines or pyrimidines Pentose Sugar = Ribose or deoxyribose Phosphate = 1P, 2P, or 3P</p> Signup and view all the answers

    Which of the following is NOT a function of nucleotides?

    <p>Directly coding for proteins</p> Signup and view all the answers

    Hyperuricemia is a condition related to the degradation of pyrimidines.

    <p>False</p> Signup and view all the answers

    Name one clinical manifestation of Lesch-Nyhan syndrome.

    <p>Gout</p> Signup and view all the answers

    What percentage of nucleotide synthesis can come from salvage pathways?

    <p>90%</p> Signup and view all the answers

    The pyrimidine ring is completely broken down into CO2 and NH4+ during nucleotide biosynthesis.

    <p>True</p> Signup and view all the answers

    What is urate, and why might it contribute to increased lifespan in humans?

    <p>Urate is a degradation product of purine bases and acts as a powerful antioxidant, which may aid in increasing lifespan.</p> Signup and view all the answers

    Deoxyribonucleotides are synthesized from ribonucleotides by __________.

    <p>reduction</p> Signup and view all the answers

    Match the following disorders to their causes:

    <p>Gout = Precipitation of urate crystals Lesch-Nyhan syndrome = Inactive salvage pathway enzyme High urate levels = Frequent disease occurrence Spasticity = Defect in urate clearance</p> Signup and view all the answers

    What is the main precursor used in the biosynthesis of nucleotides?

    <p>Phosphoribosyl pyrophosphate (PRPP)</p> Signup and view all the answers

    The salvage pathway requires more energy compared to the de novo pathway.

    <p>False</p> Signup and view all the answers

    Which of the following purine nucleotides is formed from the addition of aspartate?

    <p>AMP</p> Signup and view all the answers

    What is the first step in pyrimidine biosynthesis?

    <p>Synthesis of carbamoyl phosphate</p> Signup and view all the answers

    The salvage pathway accounts for 90% of purine nucleotides formation.

    <p>True</p> Signup and view all the answers

    The enzyme used in the first step of pyrimidine biosynthesis is ________.

    <p>CPS II</p> Signup and view all the answers

    What regulates the overall rate of purine biosynthesis?

    <p>Feedback inhibition</p> Signup and view all the answers

    Adenine phosphoribosyltransferase catalyzes the formation of __________.

    <p>adenylate</p> Signup and view all the answers

    Match the following pathways with their descriptions:

    <p>De Novo Pathway = Synthesis from simpler materials using energy Salvage Pathway = Synthesis from preformed bases with minimal energy CPS II = Enzyme for carbamoyl phosphate synthesis Transcarbomylase = Catalyzes ring closure in pyrimidine biosynthesis</p> Signup and view all the answers

    Match the following terms with their descriptions:

    <p>IMP = Precursor of AMP and GMP HGPRT = Enzyme that catalyzes the formation of guanylate Adenylosuccinate = Intermediate in AMP synthesis Fumarate = Released during AMP formation process</p> Signup and view all the answers

    Which of the following statements about nucleotide biosynthesis is correct?

    <p>Salvage pathways can account for up to 90% of nucleotide synthesis.</p> Signup and view all the answers

    The reaction catalyzed by transcarbomylase involves the conversion of carbamoyl phosphate and aspartate.

    <p>True</p> Signup and view all the answers

    Which compound is a precursor of GMP?

    <p>Inosine Monophosphate</p> Signup and view all the answers

    What is the main component that activates the reaction in the biosynthesis of nucleotides?

    <p>Phosphoribosyl pyrophosphate (PRPP)</p> Signup and view all the answers

    Hydrolysis of glutamine contributes an amino group to the synthesis of GMP.

    <p>True</p> Signup and view all the answers

    Nucleotide biosynthesis is controlled by __________ regulation.

    <p>feedback</p> Signup and view all the answers

    What is the final product of purine degradation in humans?

    <p>Urate</p> Signup and view all the answers

    Urate has no antioxidant properties in humans.

    <p>False</p> Signup and view all the answers

    What illness is characterized by self-destructive behavior and is linked to a deficiency in HGPRT?

    <p>Lesch-Nyhan syndrome</p> Signup and view all the answers

    Elevated levels of urate can lead to _____ in the kidneys.

    <p>kidney stones</p> Signup and view all the answers

    Match the following diseases or conditions with their associated enzymes or effects:

    <p>Gout = Xanthine oxidase inhibitor Lesch-Nyhan syndrome = HGPRT deficiency ADA Deficiency = Adenosine deaminase deficiency Allopurinol = Reduces uric acid levels</p> Signup and view all the answers

    What medication is used to treat gout by inhibiting xanthine oxidase?

    <p>Allopurinol</p> Signup and view all the answers

    High levels of urate are beneficial as they can lead to a longer lifespan.

    <p>True</p> Signup and view all the answers

    What is the primary consequence of the mutation of nucleotide biosynthetic enzymes?

    <p>Accumulation of intermediates</p> Signup and view all the answers

    Study Notes

    PHBC 522 - Biochemistry I, Winter 2024, Lecture 7 - Nucleotide Metabolism

    • Learning Outcomes: Students should be able to draw purine and pyrimidine structures, identify purine and pyrimidine biosynthesis pathways, describe nucleotide biosynthesis regulations and feedback inhibition, identify clinical disorders of purine degradation, describe Leshnyhan syndrome and gout, describe nucleotide digestion, and outline the treatment for hyperuricemia and gout.

    Importance of Nucleotides

    • Nucleotides are the building blocks of DNA and RNA.
    • They are crucial for genome replication, transcription of genetic information.
    • Act as carriers for activated intermediates in carbohydrate, lipid, and protein synthesis, like UDP-glucose for glycogen formation.
    • Form coenzymes (e.g., Coenzyme A, FAD, NAD+, NADH+).
    • ATP is the primary energy currency, with GTP also serving as an energy source.
    • ATP acts as a phosphoryl donor, transferred by protein kinase.
    • cAMP and cGMP act as secondary messengers in signal transduction pathways.
    • Nucleotide biosynthesis is vital for drug development, as many anticancer drugs target steps in DNA synthesis.

    Nucleotide Structure

    • A nucleotide consists of a nitrogenous base, a pentose sugar (ribose or deoxyribose), and a phosphate group.
    • Nitrogenous bases are either purines (adenine, guanine) or pyrimidines (cytosine, thymine, uracil).
    • The phosphate group can have 1, 2, or 3 phosphates.

    Nucleic Acids - Bases

    • Nucleic acid information is encoded in base sequences.
    • Bases are derived from purine (adenine, guanine) and pyrimidine (cytosine, thymine, uracil) heterocycles.
    • Uracil replaces thymine in RNA.

    Unusual Bases

    • Some DNA and RNA contain unusual bases.
    • Base modifications (e.g., methylation, glycosylation, amination, acetylation, and reduction) can occur.
    • Unusual bases aid in nucleotide recognition by specific enzymes or protect against degradation.

    Pentoses in Nucleic Acids

    • Ribose is the pentose sugar in RNA.
    • Deoxyribose is the pentose sugar in DNA.

    Nucleotides as Phosphate Esters

    • Nucleotides are mono-, di-, or triphosphate esters of nucleosides.
    • The first phosphate group is attached to the 5' carbon of the pentose sugar.
    • The phosphate groups carry negative charges, making DNA and RNA acidic.

    Nomenclature of Bases, Nucleosides, and Nucleotides

    • Tables detailing the nomenclature of bases, nucleosides, and nucleotides in RNA and DNA are provided, referencing the base, ribonucleoside vs deoxyribonucleoside, and ribonucleotide vs deoxyribonucleotide.

    Biosynthesis of Nucleotides - Two Pathways

    • De novo pathways: Synthesize nucleotides from simpler precursors (PRPP, amino acids, ATP, CO2, etc.).
    • Salvage pathways: Synthesize nucleotides from pre-formed bases.

    Biosynthesis of Pyrimidine Nucleotides

    • The first step is the synthesis of carbamoyl phosphate; this occurs in the cytosol.
    • The synthesis is a phosphate transfer reaction without net oxidation or reduction.
    • Step 2: Carbamoyl phosphate is coupled to aspartate to form carbamoylaspartate, then orotate.
    • Step 3: Oroate is coupled to PRPP to form orotate, then uridylate.

    Biosynthesis of Purine Nucleotides

    • Committed step: Glutamine is used to produce 5-phosphoribosyl-1-amine.
    • Multiple steps to form IMP (inosine monophosphate).
    • IMP is a precursor to AMP (adenine monophosphate) and GMP (guanine monophosphate).

    Regulation of Pyrimidine Biosynthesis

    • Feedback inhibition by UTP, activated by ATP and PRPP.
    • Feedback inhibition of aspartate transcarbamoylase (inhibited by CTP and stimulated by ATP.)

    Salvage Pathway of Pyrimidines

    • Only 30% of pyrimidine nucleotides are formed via salvage pathways.
    • Salvage pathway involves uptake of pyrimidine nucleosides (not free bases.).

    Degradation of Nucleotides

    • Pyrimidines degrade to CO2 and NH4.
    • Purine bases are degraded to uric acid and related compounds (hypoxanthine, xanthine).
    • Xanthine oxidase is crucial for purine degradation and generating uric acid.

    Diseases Associated with Purine Degradation

    • Lesch-Nyhan syndrome: Inherited disorder with HGPRT deficiency, resulting in excessive uric acid accumulation, self-mutilation, and neurological problems.
    • Adenine Defficiency syndrome (ADA) : ADA enzyme deficiency leads to a severe immune deficiency.
    • Gout: Uric acid crystal deposition in joints, often associated with excessive uric acid production or excretion problems.

    Degradation of Dietary Nucleic Acids in the Small Intestine

    • Ribonucleases and deoxyribonucleases break down DNA and RNA into oligonucleotides.
    • Phosphodiesterases further break down oligonucleotides into nucleotides.
    • Nucleosidases remove phosphate from nucleotides, leaving nucleosides.
    • Nucleosides can be absorbed or converted into bases.

    Urate Benefits and Diseases:

    • Urate is a byproduct of purine metabolism.
    • Uric acid is an antioxidant, potentially contributing to human longevity.
    • High uric acid (hyperuricemia) can cause gout and kidney problems.
    • Genetic mutations can affect nucleotide synthesis & degradation, leading to diseases.

    Summary

    • Two main nucleotide synthesis pathways (de novo and salvage).
    • Pyrimidine synthesis involves constructing the pyrimidine ring, and then attaching it to PRPP.
    • Purine synthesis involves constructing the purine ring on a sugar template.
    • Nucleotide biosynthesis regulated.
    • Degradation pathways for both purines (uric acid production) and pyrimidines.
    • Diseases can arise from issues in either nucleotide synthesis or degradation.

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    PHBC 522 Biochemistry I Lecture 7 - Nucleotide Metabolism (Winter 2024) PDF

    Description

    This quiz focuses on the roles of key enzymes, such as thymidylate synthase, in nucleotide synthesis, along with the functions of nucleotides in biological systems. It also covers conditions related to nucleotide metabolism, including orotic aciduria and hyperuricemia. Test your knowledge on the essential components and pathways involved in DNA and RNA synthesis.

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