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Questions and Answers
What is the first step in the biosynthesis of purine nucleotides?
What is the first step in the biosynthesis of purine nucleotides?
Which enzyme is primarily responsible for the conversion of adenosine to inosine?
Which enzyme is primarily responsible for the conversion of adenosine to inosine?
How is GMP synthesized from IMP?
How is GMP synthesized from IMP?
What causes the crystallization of Na-Urate in soft tissues, leading to gout?
What causes the crystallization of Na-Urate in soft tissues, leading to gout?
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Which drug is used to inhibit xanthine oxidase to reduce uric acid levels?
Which drug is used to inhibit xanthine oxidase to reduce uric acid levels?
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What role does ribonucleotide reductase (RR) play in the synthesis of nucleotides?
What role does ribonucleotide reductase (RR) play in the synthesis of nucleotides?
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What condition can lead to hyperuricemia?
What condition can lead to hyperuricemia?
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What effect does hydroxyurea have on ribonucleotide reductase (RR)?
What effect does hydroxyurea have on ribonucleotide reductase (RR)?
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What is the primary function of carbamoyl phosphate synthetase II in the cytosol?
What is the primary function of carbamoyl phosphate synthetase II in the cytosol?
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What compound is formed from dUMP by thymidylate synthase?
What compound is formed from dUMP by thymidylate synthase?
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Which condition is primarily caused by a deficiency of UMP synthase?
Which condition is primarily caused by a deficiency of UMP synthase?
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Which statement correctly distinguishes between OTC deficiency and UMP synthase deficiency?
Which statement correctly distinguishes between OTC deficiency and UMP synthase deficiency?
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What is the final product of the dehydration and dehydrogenation of orotate?
What is the final product of the dehydration and dehydrogenation of orotate?
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What is the primary treatment for acute gout attacks aimed at reducing inflammation?
What is the primary treatment for acute gout attacks aimed at reducing inflammation?
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How does 5-Fluorouracil function in cancer therapy?
How does 5-Fluorouracil function in cancer therapy?
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In cases of hyperuricemia due to under excretion of uric acid, which drug is typically prescribed?
In cases of hyperuricemia due to under excretion of uric acid, which drug is typically prescribed?
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What is the primary route for pyrimidine salvage in humans?
What is the primary route for pyrimidine salvage in humans?
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What adverse effect results from low activity of UMP synthase?
What adverse effect results from low activity of UMP synthase?
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What major complication arises from a deficiency in hypoxanthine-guanine phosphoribosyltransferase (HGPRT)?
What major complication arises from a deficiency in hypoxanthine-guanine phosphoribosyltransferase (HGPRT)?
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How does adenosine deaminase (ADA) deficiency affect dATP levels in the body?
How does adenosine deaminase (ADA) deficiency affect dATP levels in the body?
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What is the primary consequence of elevated dATP levels due to ADA deficiency?
What is the primary consequence of elevated dATP levels due to ADA deficiency?
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What is the first step in the salvage pathway for purine metabolism?
What is the first step in the salvage pathway for purine metabolism?
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What is a common characteristic of lymphocytes concerning nucleotide synthesis?
What is a common characteristic of lymphocytes concerning nucleotide synthesis?
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Which of the following is true regarding the synthesis of pyrimidines?
Which of the following is true regarding the synthesis of pyrimidines?
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What is the main difference between de novo purine and pyrimidine biosynthesis?
What is the main difference between de novo purine and pyrimidine biosynthesis?
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Which enzyme deficiency is associated with Lesch-Nyhan syndrome?
Which enzyme deficiency is associated with Lesch-Nyhan syndrome?
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What is the role of FH4 (tetrahydrofolate) in nucleotide biosynthesis?
What is the role of FH4 (tetrahydrofolate) in nucleotide biosynthesis?
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How is orotic aciduria differentiated in terms of underlying causes?
How is orotic aciduria differentiated in terms of underlying causes?
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What outcomes are associated with a deficiency in adenosine deaminase (ADA)?
What outcomes are associated with a deficiency in adenosine deaminase (ADA)?
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What metabolic condition results in the accumulation of orotic acid specifically through UMP synthase deficiency?
What metabolic condition results in the accumulation of orotic acid specifically through UMP synthase deficiency?
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Which of the following accurately describes the role of nucleotides in cellular processes?
Which of the following accurately describes the role of nucleotides in cellular processes?
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Which compound serves as the primary source for nucleotides in non-hepatic tissues?
Which compound serves as the primary source for nucleotides in non-hepatic tissues?
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What role do nucleotides play in cells aside from serving as energy currency?
What role do nucleotides play in cells aside from serving as energy currency?
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Which of the following nucleotides is produced from ribose and includes a phosphate group?
Which of the following nucleotides is produced from ribose and includes a phosphate group?
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What is the primary difference between de novo synthesis and salvage pathways in nucleotide metabolism?
What is the primary difference between de novo synthesis and salvage pathways in nucleotide metabolism?
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In which metabolic condition is uric acid accumulation most prominently observed?
In which metabolic condition is uric acid accumulation most prominently observed?
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Which enzyme deficiency is directly linked to the symptoms of Lesch-Nyhan syndrome?
Which enzyme deficiency is directly linked to the symptoms of Lesch-Nyhan syndrome?
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How do purines differ from pyrimidines?
How do purines differ from pyrimidines?
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What condition results from UMP synthase deficiency?
What condition results from UMP synthase deficiency?
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What accurately describes the function of tetrahydrofolate (FH4) in nucleotide biosynthesis?
What accurately describes the function of tetrahydrofolate (FH4) in nucleotide biosynthesis?
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What does carbamoyl phosphate synthetase II (CPS-II) synthesize from CO2 and glutamine?
What does carbamoyl phosphate synthetase II (CPS-II) synthesize from CO2 and glutamine?
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What is the initial pyrimidine nucleotide formed after the action of UMP synthase?
What is the initial pyrimidine nucleotide formed after the action of UMP synthase?
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Which condition can result from a deficiency of UMP synthase?
Which condition can result from a deficiency of UMP synthase?
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What laboratory test is useful to differentiate between OTC deficiency and UMP synthase deficiency?
What laboratory test is useful to differentiate between OTC deficiency and UMP synthase deficiency?
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What effect does the antimetabolite 5-Fluorouracil have in cancer treatment?
What effect does the antimetabolite 5-Fluorouracil have in cancer treatment?
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Which enzyme converts dUMP to dTMP?
Which enzyme converts dUMP to dTMP?
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What is a consequence of low UMP synthase activity?
What is a consequence of low UMP synthase activity?
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What pathway is primarily responsible for the salvage of pyrimidines in humans?
What pathway is primarily responsible for the salvage of pyrimidines in humans?
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What is the primary enzyme involved in the purine salvage pathway?
What is the primary enzyme involved in the purine salvage pathway?
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What condition is commonly associated with HGPRT deficiency?
What condition is commonly associated with HGPRT deficiency?
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Which of the following mutations would likely lead to severe combined immunodeficiency disease (SCID)?
Which of the following mutations would likely lead to severe combined immunodeficiency disease (SCID)?
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What is the effect of elevated dATP levels due to adenosine deaminase deficiency?
What is the effect of elevated dATP levels due to adenosine deaminase deficiency?
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How is hyperuricemia due to overproduction of uric acid commonly treated?
How is hyperuricemia due to overproduction of uric acid commonly treated?
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What occurs to PRPP levels in Lesch-Nyhan Syndrome?
What occurs to PRPP levels in Lesch-Nyhan Syndrome?
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What type of drug is probenecid?
What type of drug is probenecid?
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What is the first step in the biosynthesis of pyrimidines?
What is the first step in the biosynthesis of pyrimidines?
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What is the final product of purine catabolism in humans?
What is the final product of purine catabolism in humans?
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Which mechanism leads to the formation of AMP from IMP?
Which mechanism leads to the formation of AMP from IMP?
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What causes hyperuricemia in humans?
What causes hyperuricemia in humans?
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What role does xanthine oxidase play in purine metabolism?
What role does xanthine oxidase play in purine metabolism?
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Which condition is characterized by the crystallization of uric acid in tissues?
Which condition is characterized by the crystallization of uric acid in tissues?
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Which drug acts as an inhibitor of xanthine oxidase?
Which drug acts as an inhibitor of xanthine oxidase?
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What is the starting compound for the synthesis of purine nucleotides?
What is the starting compound for the synthesis of purine nucleotides?
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What is the primary action of ribonucleotide reductase (RR)?
What is the primary action of ribonucleotide reductase (RR)?
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Study Notes
Purine and Pyrimidine Metabolism
- Purine and pyrimidine metabolism are covered in Marks' Basic Medical Biochemistry, 6th Ed chapter 39 (pages 867-884), Biochemistry, Cell and Molecular Biology, and Genetics, Part V Chapter 37 (pages 313-323).
- Zeynep Gromley, Ph.D. ([email protected]) provides the lecture material for MANS 429.
Learning Objectives
- Outline differences between de novo and salvage pathways for purine and pyrimidine biosynthesis.
- Describe the role of folate coenzyme (FH4) in purine and pyrimidine biosynthesis.
- Explain the metabolic basis, signs, and symptoms of gout and uric acid accumulation.
- Explain HGPRT enzyme deficiency and Lesch-Nyhan syndrome.
- Describe SCID due to ADA deficiency.
- Describe metabolic conditions (like UMP synthase and OTC deficiency) leading to orotic acid accumulation in urine.
- Differentiate orotic aciduria from B12/folate deficiency megaloblastic anemia.
Functions of Nucleotides
- Nucleotides synthesize DNA and RNA.
- They are the energy currency (e.g., ATP, GTP).
- They act as carriers of active intermediates in metabolic pathways (e.g., UDP-glucose in glycogen synthesis, SAM).
- They are components of coenzymes (e.g., CoA, FAD, NAD, NADP).
- They act as second messengers (e.g., cAMP, cGMP).
- They regulate metabolic pathways allosterically (e.g., ATP inhibits PFK-1).
Nucleotide Structure
- Ribose sugar (ribose, deoxyribose)
- Nitrogenous bases (purines, pyrimidines)
- Nucleoside (base + ribose)
- Nucleotide (base + ribose + phosphate)
- Examples of nucleotides: AMP, GMP, CMP, UMP, dAMP, dGMP, dCMP, dTMP
Nucleotide Synthesis
- Nucleotides are made via two processes:
- Salvage pathway (reusing nucleotides from degradation or diet, important for non-hepatic tissues).
- De novo synthesis (building from scratch, important for most tissues)
De Novo Purine Synthesis
- A multi-step process including:
- Ribose-5-phosphate activation.
- Conversion of PRPP to PRA
- Constructing the IMP ring
- Converting IMP to AMP and GMP.
- Details of these steps are outlined in diagrams on pages 6 and 7 of the slides. Specific enzymes and intermediates are given in detail in diagrams.
AMP and GMP Synthesis
- IMP serves as a precursor for both AMP and GMP synthesis.
- Aspartate is used for AMP synthesis, and glutamine is used for GMP synthesis.
Ribonucleotide Reductase (RR)
- RR is a target for cancer treatment.
- A key enzyme for converting ribonucleotides to deoxyribonucleotides.
- Inhibitor hydroxyurea is used for treatment of CML.
Human Purine Catabolism
- Adenosine converts to inosine through adenosine deaminase.
- Inosine and guanosine convert to hypoxanthine and guanine through purine nucleotide phosphorylase.
- Hypoathine and guanine convert to xanthine through guanine deaminase and xanthine oxidase converts xanthine to uric acid.
- Uric acid is the end product and is excreted in the urine.
Uric Acid and Gout
- Uric acid being poorly soluble can lead to its accumulation and crystal formation in tissues/joints.
- This leads to inflammation (gouty arthritis).
- Hyperuricemia can result either from decreased excretion or increased production of uric acid. Specific examples of causes of hyperuricemia (e.g., underexcretion from drugs, overproduction due to tissue turnover) are mentioned, and their mechanisms are briefly described.
Purine Salvage Pathway
- Free purines during nucleotide catabolism can be salvaged by attaching the bases to PRPP to regenerate nucleotides.
- Salvage pathway plays major role in certain cell types, like lymphocytes. The specific enzymes involved in the purine salvage pathway (e.g., hypoxanthine-guanine phosphoribosyltransferase (HGPRT), Adenine phosphoribosyltransferase) are introduced.
HGPRT Deficiency (Lesch-Nyhan Syndrome)
- X-linked recessive genetic disorder.
- Causes decreased or abolished HGPRT activity leading to increased PRPP, excess purine synthesis and high plasma/urine uric acid.
- Affected children suffer from intellectual disability and self-mutilation.
ADA Deficiency
- Deficiency of Adenosine Deaminase (ADA) leads to accumulation of adenosine, which is converted to AMP, and then to ADP.
- This causes a buildup of dATP, an inhibitor of ribonucleotide reductase.
- This inhibits nucleotide synthesis and DNA/cell division which is critical for immune cell function and leads to Severe Combined Immunodeficiency (SCID). The specifics of dATP inhibition of ribonucleotide reductase are included in the discussion.
Pyrimidine Synthesis
- Pyrimidine ring form first, then combines with PRPP to form the initial nucleotide UMP.
- Carbamoyl phosphate synthetase II (CPS-II) creates carbamoyl phosphate from CO2 and glutamine.
- Aspartate transcarbamoylase forms N-carbamoyl aspartate.
- Dehydration and dehydrogenation create orotate.
- Orotate combines with PRPP, catalyzed by UMP synthase—producing UMP, the initial pyrimidine nucleotide.
UMP, UDP, and dTMP
- UMP is changed to UDP via Ribonucleotide reductase.
- Thymidylate synthase methylates dUMP to create dTMP.
Antimetabolites
- Antimetabolites like 5-fluorouracil inhibit thymidylate synthetase, which is crucial for dTMP production, halting DNA synthesis in cancer cells.
- Dihydrofolate reductase inhibitors (e.g., methotrexate) impede de novo purine synthesis.
UMP Synthase Deficiency
- Low UMP synthase activity causes orotic aciduria and megaloblastic anemia due to impaired pyrimidine nucleotide synthesis.
- Uridine administration can treat this condition by supplying a pyrimidine precursor, enabling nucleotide production.
OTC Deficiency
- Distinguish OTC deficiencies from UMP Synthase deficiencies via blood ammonia levels.
Pyrimidine Catabolism
- Pyrimidine ring cleavage produces highly soluble end products.
- Pyrimidine nucleosides are salvaged by nucleoside kinases.
Salvage of Pyrimidines
- The salvage pathway for pyrimidines is a minor pathway in humans, with the pyrimidine nucleosides being salvaged by nucleoside kinases. The reaction is nucleoside + ATP → nucleotide + ADP.
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Description
Test your knowledge on purine and pyrimidine metabolism with this quiz based on Marks' Basic Medical Biochemistry and related resources. Explore key topics such as biosynthesis pathways, the role of folate, and metabolic disorders like gout and SCID. Perfect for students in biochemistry or medical courses.
