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Questions and Answers
What is the primary effect of increasing PRPP levels in purine metabolism?
What is the primary effect of increasing PRPP levels in purine metabolism?
Which outcome is most likely if there is a decrease in purine reutilization?
Which outcome is most likely if there is a decrease in purine reutilization?
What effect does increased purine synthesis have on the degradation of purines?
What effect does increased purine synthesis have on the degradation of purines?
Which of the following processes directly leads to an increase in uric acid?
Which of the following processes directly leads to an increase in uric acid?
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How does the de novo pathway influence overall purine metabolism?
How does the de novo pathway influence overall purine metabolism?
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What enzyme is involved in the synthesis of 5-phosphoribosyl-1-pyrophosphate (PRPP)?
What enzyme is involved in the synthesis of 5-phosphoribosyl-1-pyrophosphate (PRPP)?
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In which organ does most de novo synthesis occur?
In which organ does most de novo synthesis occur?
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What are the substrates used in the synthesis of PRPP?
What are the substrates used in the synthesis of PRPP?
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What does low PRPP concentration indicate in the pathway?
What does low PRPP concentration indicate in the pathway?
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What is the role of the pentose phosphate pathway in the context of PRPP synthesis?
What is the role of the pentose phosphate pathway in the context of PRPP synthesis?
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What is the primary structure that forms the foundation for purine ring synthesis?
What is the primary structure that forms the foundation for purine ring synthesis?
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Where are the enzymes necessary for purine ring synthesis located in human cells?
Where are the enzymes necessary for purine ring synthesis located in human cells?
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Which of the following statements correctly describes the role of the purine ring in drug metabolism?
Which of the following statements correctly describes the role of the purine ring in drug metabolism?
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Which of the following components is directly added to the ribose 5-phosphate during the purine ring synthesis process?
Which of the following components is directly added to the ribose 5-phosphate during the purine ring synthesis process?
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What is the main purpose of the enzymes found in the cytoplasm related to purine ring synthesis?
What is the main purpose of the enzymes found in the cytoplasm related to purine ring synthesis?
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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
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Nucleotide synthesis
-
Purine synthesis
- Purine salvage pathway
- Purines degradation
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Pyrimidine synthesis
- Salvage of pyrimidine
- Pyrimidine degradation
- Synthesis of deoxyribonucleotides (necessary for DNA synthesis)
- Thymine nucleotide synthesis
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Purine 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
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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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