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Questions and Answers

What is the primary effect of increasing PRPP levels in purine metabolism?

  • Decreases purine synthesis
  • Stimulates the de novo pathway (correct)
  • Enhances purine reutilization
  • Increases purine degradation

Which outcome is most likely if there is a decrease in purine reutilization?

  • Increased availability of purines
  • Enhanced purine degradation
  • Elevated uric acid levels (correct)
  • Decreased uric acid levels

What effect does increased purine synthesis have on the degradation of purines?

  • It has no significant effect
  • It enhances purine reutilization
  • It increases purine degradation rates (correct)
  • It decreases purine degradation rates

Which of the following processes directly leads to an increase in uric acid?

<p>Increase in purine degradation (B)</p> Signup and view all the answers

How does the de novo pathway influence overall purine metabolism?

<p>It is stimulated by increased PRPP levels (C)</p> Signup and view all the answers

What enzyme is involved in the synthesis of 5-phosphoribosyl-1-pyrophosphate (PRPP)?

<p>PRPP synthetase (D)</p> Signup and view all the answers

In which organ does most de novo synthesis occur?

<p>Liver (A)</p> Signup and view all the answers

What are the substrates used in the synthesis of PRPP?

<p>Ribose-5-phosphate and ATP (B)</p> Signup and view all the answers

What does low PRPP concentration indicate in the pathway?

<p>End product inhibition (D)</p> Signup and view all the answers

What is the role of the pentose phosphate pathway in the context of PRPP synthesis?

<p>It provides ribose-5-phosphate for PRPP production (D)</p> Signup and view all the answers

What is the primary structure that forms the foundation for purine ring synthesis?

<p>Ribose 5-phosphate (C)</p> Signup and view all the answers

Where are the enzymes necessary for purine ring synthesis located in human cells?

<p>Cytoplasm (C)</p> Signup and view all the answers

Which of the following statements correctly describes the role of the purine ring in drug metabolism?

<p>It serves as a nucleotide precursor. (B)</p> Signup and view all the answers

Which of the following components is directly added to the ribose 5-phosphate during the purine ring synthesis process?

<p>Nitrogen from ammonia (B)</p> Signup and view all the answers

What is the main purpose of the enzymes found in the cytoplasm related to purine ring synthesis?

<p>To catalyze reactions that build the purine ring (D)</p> Signup and view all the answers

Flashcards

De novo synthesis

The process of building a molecule from scratch, using smaller precursor molecules.

PRPP

5-phosphoribosyl-1-pyrophosphate, a key molecule in purine and pyrimidine biosynthesis.

PRPP synthesis

The process of converting ribose-5-phosphate into PRPP, using ATP as an energy source.

Phosphoribosyl phosphate synthetase (PRPP synthetase)

The enzyme responsible for catalyzing the conversion of ribose-5-phosphate to PRPP.

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Salvage pathway

A pathway that recycles pre-existing purine and pyrimidine bases to form nucleotides, bypassing de novo synthesis.

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Purine Synthesis

The process by which purine bases, like adenine and guanine, are created from simpler molecules.

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Ribose 5-phosphate

A five-carbon sugar molecule that serves as the starting point for purine synthesis.

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Donated Carbons and Nitrogens

These are the building blocks used to create the purine ring. They are provided by various amino acids and other molecules.

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Cytoplasm

The jelly-like substance inside a cell where many important processes, like purine synthesis, occur.

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Enzymes

Special proteins that facilitate and speed up chemical reactions, like purine synthesis.

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PRPP levels

PRPP (phosphoribosyl pyrophosphate) is a molecule involved in the synthesis of purines. Increased PRPP levels stimulate the de novo pathway, meaning purines are made from scratch.

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De novo pathway

The de novo pathway is a metabolic process that creates purines (building blocks of DNA and RNA) from scratch using simple molecules.

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Purine reutilization

Purine reutilization is the process of recycling existing purines instead of making new ones. It helps save energy and resources.

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Purine degradation

Purine degradation is the breakdown of purines into simpler molecules, including uric acid.

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Increased uric acid

Uric acid is a waste product of purine breakdown. Increased purine degradation leads to higher uric acid levels.

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Study Notes

Nucleotide Metabolism

  • Nucleotides are the building blocks of nucleic acids (DNA & RNA).
  • They are non-essential nutrients, as they can be synthesized within the body.
  • Nucleotides are crucial components of ATP, the primary energy source in cells.
  • They are integral parts of coenzymes like NAD, NADP, and FAD.
  • Nucleotides also form cAMP and cGMP, secondary messengers for hormones.
  • Nucleotides act as regulatory molecules in metabolic pathways, either inhibiting or activating key enzymes.
  • Purines and pyrimidines, components of nucleotides, can be synthesized de novo or obtained via salvage pathways.

Nucleotide Synthesis Outline

  • Nucleotide synthesis
    • Purine synthesis
      • Purine salvage pathway
      • Purines degradation
    • Pyrimidine synthesis
      • Salvage of pyrimidine
      • Pyrimidine degradation
      • Synthesis of deoxyribonucleotides (necessary for DNA synthesis)
      • Thymine nucleotide synthesis

Introduction

  • Nucleotides are the building blocks of nucleic acids (DNA & RNA).
  • Nucleotides can be synthesized within the body, making them a non-essential nutrient.
  • Nucleotides are integral components of ATP, the cell's primary energy source.
  • Nucleotides are also parts of coenzymes (NAD, NADP, and FAD), and secondary messengers (cAMP and cGMP).
  • Nucleotides play crucial roles as regulatory molecules in metabolic pathways, influencing the activity of enzymes.
  • Purines and pyrimidines (found in nucleotides) can be synthesized de novo or through salvage pathways.

Nucleic Acids and Nucleotide Structures

  • Nucleic acids are linear polymers specialized for storing and transmitting genetic information for cell growth and reproduction.
  • Purine bases: adenine and guanine
  • Pyrimidine bases: cytosine, uracil, and thymine
  • T and U differ only in the presence of a methyl group on thymine.

Unusual Bases

  • Some species have unusual (modified) bases in their DNA and RNA.
  • Examples include tRNAs and some viral DNA.
  • Base modifications include methylation, acetylation, and reduction.

Nucleosides

  • Adding a pentose sugar (ribose or deoxyribose) to a base (purine or pyrimidine) forms a nucleoside.
  • This linkage is through an N-glycosidic bond.

Nucleotides

  • Adding one or more phosphate groups to a nucleoside forms a nucleotide.
  • Nucleotides consist of a base, a pentose sugar (ribose or deoxyribose), and one or more phosphate groups bonded to the pentose sugar's 5'-OH.

Two Important Points

  • Phosphate groups are responsible for the negative charge associated with DNA and RNA.
  • One phosphate group: nucleoside monophosphate (example: AMP)
  • Two or three phosphate groups: nucleoside diphosphate (example: ADP) or nucleoside triphosphate (example: ATP).

Naming Nucleotides

  • Nucleosides and nucleotides (RNA): Adenosine/Guanosine/Cytidine/Uridine, AMP/GMP/CMP/UMP
  • Nucleosides and nucleotides (DNA): Deoxyadenosine/Deoxyguanosine/Deoxycytidine/Deoxythymidine, dAMP/dGMP/dCMP/dTMP

Nucleotide Biosynthesis

  • Three major pathways lead to nucleotide synthesis:
    • De novo synthesis
    • Salvage pathways
    • Conversion of ribonucleotides to deoxyribonucleotides.

Purine Biosynthesis

  • Purine ring atoms are derived from various compounds.
  • Purine ring is assembled by adding carbon and nitrogen atoms to a preformed ribose-5-phosphate.
  • All necessary enzymes are located in the cytoplasm.
  • Most de novo purine synthesis occurs in the liver.

Step 1: 5-phosphoribosyl-1-pyrophosphate (PRPP) synthesis

  • This step involves the production of PRPP from ribose-5-phosphate using ATP.
  • The enzyme is phosphoribosyl phosphate synthetase (PRPP synthetase).
  • The committed step is not the first step in purine synthesis.

Step 2: Synthesis of 5'-phosphoribosylamine

  • This step, a committed step in purine synthesis, involves the addition of an amide group from glutamine to PRPP.
  • The enzyme is glutamine phosphoribosyl amidotransferase (GPAT).
  • This step is highly regulated.

Step 3: Synthesis of Glycinamide Ribosyl-5'-Phosphate (GAR)

  • Here, the glycine molecule is attached to the growing precursor.
  • Glycine provides the carbons for part of the purine ring.
  • Energy is needed, provided by ATP.

Step 4-11: Further Purine Ring Closure -IMP Production

  • Further steps are involved in closing the purine ring to form IMP.
  • Key components and energy (ATP) are essential for these latter stages

Adenosine / Guanine Monophosphate Synthesis

  • These nucleotides can be derived from IMP through specific enzymatic steps.
  • The process involves a series of enzymatic reactions & cross-regulation.

Mycophenolic Acid

  • An inhibitor of inosine monophosphate dehydrogenase
  • The drug decreases the production of key components needed to make DNA in dividing cells
  • Used as an immunosuppressant to avoid graft rejection

Purine Salvage Pathway

  • This pathway recycles preformed purine bases and nucleosides.
  • Two critical enzymes, HGPRT and APRT, are involved.
  • This pathway utilizes PRPP as a source of ribose-5-phosphate and releases pyrophosphate, making the reaction irreversible.
  • Lack of HGPRT causes Lesch-Nyhan Syndrome.

Lesch-Nyhan Syndrome

  • Caused by a deficiency of HGPRT.
  • Leads to increased levels of uric acid.
  • Characterized by self-mutilation and other behavioral, neurological symptoms.

Deoxyribonucleotide Synthesis

  • 2'-deoxyribonucleotides are critical for DNA synthesis.
  • They are made specifically from ribonucleoside diphosphates by ribonucleotide reductase.
  • Hydrogen atoms for the conversion are provided by enzymes through thioredoxin regeneration.

Regulation of Deoxyribonucleotide Synthesis

  • Ribonucleotide reductase, involved in maintaining deoxyribonucleotides, is regulated.
  • The enzyme is complex and includes allosteric (activator/inhibitor) sites reacting with NTPs, specifically ATP activating and dATP inhibiting the enzyme.

Degradation of Purine Nucleotides

  • Dietary RNA and DNA are broken down into smaller components in the small intestine.
  • Nucleases, phosphodiesterases, and nucleosidases sequentially degrade them to free purine bases.
  • Inside cells, purine bases are converted to uric acid and excreted.

Formation of Uric Acid

  • An amino group is removed from AMP and adenosine to make IMP and inosine, respectively.
  • IMP and GMP are converted to nucleotide forms, inosine, and guanosine through 5′ nucleotidase action.
  • Inosine and guanosine are converted to purine bases through purine nucleoside phosphorylase.
  • The bases are converted to uric acid by the enzyme xanthine oxidase.

Gout

  • A disorder caused by high levels of uric acid (hyperuricemia).
  • Can be caused by overproduction or underexcretion of uric acid.
  • Crystals of monosodium urate are deposited in joints, causing inflammation and pain.

Diagnosis of Gout

  • Definitive diagnosis requires fluid aspiration from affected joints and microscopic examination of the fluid for needle-shaped crystals.

Treatment of Gout

  • Management involves drugs to reduce inflammation and relieve pain during acute attacks.
  • Drugs that inhibit uric acid production also help control the condition.

Adenosine Deaminase Deficiency

  • A deficiency in the ADA enzyme leads to an accumulation of adenosine and its metabolites.
  • This can inhibit ribonucleotide reductase, hindering DNA and thus cell production, resulting in severe combined immunodeficiency (SCID).

Pyrimidine Synthesis Outline

  • Pyrimidine synthesis
    • De novo synthesis
    • Salvage pathway
  • Pyrimidine degradation

Sources of Pyrimidine Atoms

  • Amide nitrogen of glutamine
  • Aspartate

First Step in De Novo Pyrimidine Synthesis

  • Carbamoyl phosphate synthesis: conversion of glutamine, CO2 and ATP into carbamoyl phosphate
  • This reaction mirrors the first step in the urea cycle

Differences Between CPSI and CPSII

  • CPSI = Urea Cycle enzyme; CPSII is for Pyrimidine Synthesis
  • Located in different cellular compartments (mitochondria vs cytosol).
  • Source of nitrogen (ammonia vs amide group of glutamine).
  • Regulators (N-acetyl glutamate activates CPSI vs PRPP ,UTP activates CPSII).

Regulation of De Novo Pyrimidine Synthesis

  • CPSII is inhibited by UTP and activated by PRPP.
  • Regulated by the cell cycle—more activity in S phase, less inhibition.

Pyrimidine Nucleotide Synthesis: Cytidine Triphosphate (CTP)

  • CTP is produced from UTP by amination (adding an amino group).
  • CTP synthetase is the enzyme involved.

Deoxythymidine Monophosphate (dTMP) Synthesis

  • dUMP is converted to dTMP by thymidylate synthase.
  • Inhibitors of thymidylate synthase (e.g., 5-fluorouracil) and inhibitors of dihydrofolate reductase (e.g., methotrexate) affect DNA synthesis and are commonly used in anticancer therapies.

Salvage of Pyrimidine Bases

  • Two-step process: non-specific pyrimidine nucleoside phosphorylase to convert a pyrimidine base to its corresponding nucleoside and then specific nucleoside kinases.

Degradation of Pyrimidine

  • Pyrimidine nucleotides are dephosphorylated to nucleosides.
  • Nucleosides are cleaved into free pyrimidines and ribose-1-phosphate.
  • Further degradation of the pyrimidine bases leads to the production of various compounds, including CO2, NH4+, beta-alanine, and beta-aminoisobutyrate, which are ultimately excreted.

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