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What are the two main aspects of nucleic acid metabolism?
What are the two main aspects of nucleic acid metabolism?
Purine metabolism is one aspect of nucleic acid metabolism.
Purine metabolism is one aspect of nucleic acid metabolism.
True
What processes are involved in the central dogma of molecular biology?
What processes are involved in the central dogma of molecular biology?
Replication, transcription, and translation
Nucleoside analogs are used to treat __________ infections.
Nucleoside analogs are used to treat __________ infections.
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Match the following terms to their descriptions:
Match the following terms to their descriptions:
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Which enzyme is negatively feedback inhibited by GDP?
Which enzyme is negatively feedback inhibited by GDP?
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Adenylosuccinate synthetase is inhibited by GMP.
Adenylosuccinate synthetase is inhibited by GMP.
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What is the final product of GMP catabolism after its breakdown by nucleotidase?
What is the final product of GMP catabolism after its breakdown by nucleotidase?
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What is the primary role of Glutamine phosphoribosyl amidotransferase?
What is the primary role of Glutamine phosphoribosyl amidotransferase?
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Uric acid is excreted in the urine by all species without exception.
Uric acid is excreted in the urine by all species without exception.
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IMP dehydrogenase converts IMP into __________.
IMP dehydrogenase converts IMP into __________.
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What enzyme deaminates Guanine to form xanthine?
What enzyme deaminates Guanine to form xanthine?
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Which of the following enzymes is activated by PRPP?
Which of the following enzymes is activated by PRPP?
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The salvage pathway of purine synthesis is mainly important in __________ and __________ tissues.
The salvage pathway of purine synthesis is mainly important in __________ and __________ tissues.
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The enzyme _____ catalyzes the breakdown of xanthine to uric acid.
The enzyme _____ catalyzes the breakdown of xanthine to uric acid.
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Match the following organisms with their uric acid processing:
Match the following organisms with their uric acid processing:
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Which of the following is a common feedback inhibitor for Glutamine phosphoribosyl amidotransferase?
Which of the following is a common feedback inhibitor for Glutamine phosphoribosyl amidotransferase?
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Which of the following is a step in the de novo synthesis of pyrimidines?
Which of the following is a step in the de novo synthesis of pyrimidines?
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Match the following enzymes with their corresponding feedback regulators:
Match the following enzymes with their corresponding feedback regulators:
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Marine invertebrates can break down uric acid all the way to ammonia.
Marine invertebrates can break down uric acid all the way to ammonia.
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The pyrimidine bases include cytosine, thymine, and _____.
The pyrimidine bases include cytosine, thymine, and _____.
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What does Adenine phosphoribosyl transferase (APRT) catalyze the formation of?
What does Adenine phosphoribosyl transferase (APRT) catalyze the formation of?
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A deficiency of HGPRT leads to the accumulation of PRPP and activation of Amido phosphoribosyltransferase.
A deficiency of HGPRT leads to the accumulation of PRPP and activation of Amido phosphoribosyltransferase.
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What syndrome is characterized by gout, kidney stones, and severe self-mutilation due to HGPRT deficiency?
What syndrome is characterized by gout, kidney stones, and severe self-mutilation due to HGPRT deficiency?
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The end product of purine metabolism in humans is _____ acid.
The end product of purine metabolism in humans is _____ acid.
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What enzyme catalyzes the conversion of AMP to IMP?
What enzyme catalyzes the conversion of AMP to IMP?
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Match the following compounds with their corresponding enzymes:
Match the following compounds with their corresponding enzymes:
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Inosine is converted to hypoxanthine & ribose-1-phosphate by _____ phosphorylase.
Inosine is converted to hypoxanthine & ribose-1-phosphate by _____ phosphorylase.
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Most bases in purine metabolism are reused to form nucleotides rather than degraded to uric acid.
Most bases in purine metabolism are reused to form nucleotides rather than degraded to uric acid.
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What is a primary cause of gout?
What is a primary cause of gout?
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Allopurinol is an enzyme that degrades purines to uric acid.
Allopurinol is an enzyme that degrades purines to uric acid.
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What condition is characterized by cognitive deficits, aggressive behavior, and self-mutilation in males?
What condition is characterized by cognitive deficits, aggressive behavior, and self-mutilation in males?
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Purine-rich foods such as __________ and __________ may exacerbate gout.
Purine-rich foods such as __________ and __________ may exacerbate gout.
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Which of the following treatments for gout inhibits the enzyme xanthine oxidase?
Which of the following treatments for gout inhibits the enzyme xanthine oxidase?
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Hypoxanthine and xanthine can accumulate to harmful concentrations in the body when allopurinol is used.
Hypoxanthine and xanthine can accumulate to harmful concentrations in the body when allopurinol is used.
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Match the following treatments with their respective effects on gout:
Match the following treatments with their respective effects on gout:
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What is the name of the genetic disorder caused by a deficiency of HGPRT?
What is the name of the genetic disorder caused by a deficiency of HGPRT?
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What is the role of Carbamoyl phosphate in pyrimidine biosynthesis?
What is the role of Carbamoyl phosphate in pyrimidine biosynthesis?
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Dihydroorotate is formed by the removal of water from N-carbamoyl aspartate.
Dihydroorotate is formed by the removal of water from N-carbamoyl aspartate.
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What is the enzyme that catalyzes the conversion of dihydroorotate to orotate?
What is the enzyme that catalyzes the conversion of dihydroorotate to orotate?
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The reaction between orotate and PRPP produces __________.
The reaction between orotate and PRPP produces __________.
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Match the enzymes with their corresponding reactions in pyrimidine biosynthesis:
Match the enzymes with their corresponding reactions in pyrimidine biosynthesis:
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Which of the following is a target for novel antimalarial drug development?
Which of the following is a target for novel antimalarial drug development?
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The first three enzymes in pyrimidine biosynthesis operate independently in mammals.
The first three enzymes in pyrimidine biosynthesis operate independently in mammals.
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What are the two final products formed from orotidylate during pyrimidine biosynthesis?
What are the two final products formed from orotidylate during pyrimidine biosynthesis?
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Study Notes
Nucleic Acids Metabolism
- Nucleic acid metabolism encompasses two key aspects: biosynthesis (anabolism) and degradation (catabolism).
- The focus of metabolism includes purine and pyrimidine metabolism, as well as associated abnormalities.
- This metabolism is paramount to cellular functions, such as replication, transcription, and translation, which are vital to gene expression and cellular function.
Modern Relevance to Medicine
- Cancer therapy relies on targeting nucleic acid metabolism pathways to develop chemotherapeutic agents inhibiting DNA synthesis/repair.
- Understanding nucleic acid metabolism aids in diagnosing and treating numerous genetic conditions, facilitating gene therapy.
- Nucleoside analogs are used in antiviral treatments to combat viral infections by interfering with viral nucleic acid synthesis.
- Personalized medicine benefits from advances in genomics and RNA sequencing for tailoring treatments based on individual genetic profiles.
What Nucleic Acids Do
- Dictate the amino acid sequence in proteins.
- Carry genetic information passed from parent to offspring via chromosomes.
- Act as the fourth type of macromolecules.
- Link generations chemically.
- Are the source of genetic information within chromosomes.
Central Dogma of Molecular Biology
- DNA replication leads to identical copies of DNA.
- Transcription converts DNA's instructions to RNA.
- RNA translation interprets RNA's instructions to create proteins.
- This series of processes plays a crucial role in molecular biology.
- The processes involved in HIV replication that targets specific actions within the body.
Inhibitors of Nucleic Acid Synthesis
- 6-Mercaptopurine inhibits IMP conversion to AMP and GMP.
- Sulfonamides are analogs of PABA inhibiting folic acid synthesis.
- Acyclovir is converted to triphosphate, inhibiting viral DNA polymerase.
- Methotrexate inhibits dihydrofolate reductase & thymidylate synthase, crucial for DNA/RNA synthesis.
- Azaserine is a glutamine antagonist inhibiting purine and pyrimidine synthesis.
- Mycophenolic acid is a reversible, uncompetitive inhibitor of IMP dehydrogenase.
- 6-Thioguanine & 8-aza-guanine are anticancer agents inhibiting glutamine PRPP amidotransferase and the conversion of IMP to GMP.
- Fluorouracil is an anticancer drug converted to FdUMP, inhibiting thymidylate synthase.
- Zidovudine is an HIV/AIDS drug that terminates nucleotide formation.
Synthesis of Purine Ribonucleotides
- IMP is synthesized through the assembly of a purine base on ribose-5-phosphate.
- Kinases convert IMP-derived AMP and GMP to ATP and GTP.
- Purine nucleotide synthesis is regulated by feedback inhibition and feedforward activation.
- Salvage reactions convert purines to their nucleotide forms.
De Novo Biosynthesis of IMP
- The process starts with the synthesis of ribose-phosphate.
- A critical regulatory step is converting PRPP to 5-Phosphoribosyl-1-amine.
- Amidophosphoribosyl transferase is a key regulatory enzyme.
- Various amino acids play crucial roles.
- Several steps are involved in the process, utilizing molecules such as glycine, 5,10-methenyl-THF, glutamine, and aspartate.
Conversion of IMP to AMP & GMP:
- Shows feedback inhibition.
- Myofenolic acid is a reversible & uncompetitive inhibitor of IMP dehydrogenase.
- The drug prevents the rapid proliferation of T/B cells, critical for nucleic acid synthesis preventing graft rejection.
Conversion of Hypoxanthine to Adenine/Guanine
- Adenine/Guanine conversion involves changing a carbonyl oxygen to an amino group.
- The mechanism is common to both A and G conversions.
Formation of Di & Tri-phosphates
- Nucleoside monophosphates are converted to their di & triphosphate counterparts.
- Phosphate transfer from ATP (phosphorylation) catalyzed by specific nucleoside monophosphate kinases.
- Nucleoside diphosphate kinases are less specific for the process.
Formation of Deoxyribonucleotides from Ribonucleotides
- Deoxyribonucleotides are derived form corresponding nucleotides by reducing the 2'-C of ribose.
- This enzymatic conversion is catalyzed by ribonucleotide reductase.
- NADPH donates a pair of H-atoms.
- Ribonucleoside diphosphate/triphosphates work as substrates.
Regulatory Control of Purine Nucleotide Biosynthesis
- Purine biosynthesis is precisely regulated by feedback inhibition.
- Four key enzymes are involved in feedback regulation: PRPP synthetase, glutamine phosphoribosyl amidotransferase, adenylosuccinate synthetase, and IMP dehydrogenase.
- The step where PRPP synthetase converts ribose-5-phosphate to Phosphoribosyl pyrophosphate is regulated.
- Glutamine phosphoribosyl amidotransferase is activated by PRPP and competitively inhibited by AMP, GMP, and IMP.
- Adenylosuccinate synthetase is competitively inhibited by AMP without affecting GMP synthesis.
- IMP dehydrogenase is competitively inhibited by GMP without affecting AMP synthesis.
Purine Salvage Pathways
- Free purines released during nucleic acid degradation are converted into nucleotides through salvage pathways.
- Adenine phosphoribosyltransferase and hypoxanthine/guanine phosphoribosyltransferase are crucial enzymes in these pathways.
Digestion & Degradation of Nucleic Acids/Purine Nucleotides in the Gastrointestinal Tract (GI tract)
- Ingested nucleic acids are degraded into nucleotides by pancreatic nucleases and intestinal phosphodiesterases.
- Nucleotides are converted to nucleosides, and nucleosides are further degraded or absorbed.
- Bases are reused in salvage pathways.
- Most bases are degraded into uric acid and excreted in urine.
Degradation of Purines in Humans
- Purines in humans are degraded to urate.
- Many enzymes are involved in the process, including nucleotidases, nucleoside phosphorylases, deaminases, and xanthine oxidases.
- Urate is the final product and excreted.
AMP Degradation/Catabolism
- AMP is degraded to IMP by AMP deaminase.
- Nucleotidase hydrolyzes AMP to adenosine and IMP to inosine.
- Adenosine is deaminated to inosine and inosine is converted to hypoxanthine.
- Xanthine oxidase oxidizes hypoxanthine to xanthine, and then xanthine to uric acid.
- Uric acid is the end product and excreted in urine.
GMP Degradation/Catabolism
- GMP is degraded to GMP by nucleotidase.
- GMP is converted to guanosine.
- Guanosine is converted to guanine, and guanine is deaminated to xanthine.
- Xanthine oxidase converts xanthine to uric acid.
The Fate of Uric Acid
- In primates, uric acid is the final product and excreted.
- In other mammals, uric acid is oxidized to allantoin, which is then hydrolyzed to allantoic acid.
- Some organisms convert uric acid to glyoxylic acid.
Degradation of Uric Acid
- Excretion or degradation, depending on species
- Breakdown by marine invertebrates down to ammonia.
Pyrimidine Metabolism
- Pyrimidine biosynthesis involves de novo pathways and salvage pathways.
- Pyrimidine catabolism focuses on the breakdown of pyrimidine nucleotide bases.
De Novo Synthesis of Pyrimidine Nucleotides
- Pyrimidine ring synthesis occurs before the ribose-5-phosphate attachment.
- Specific atoms of the pyrimidine ring are derived from bicarbonate, ammonia, and aspartate.
De Novo Biosynthesis of Pyrimidines: Step-by-Step
- Step 1: Synthesis of carbamoyl phosphate from bicarbonate, ammonia, and ATP.
- Step 2: Carbamoyl phosphate reacts with aspartate to form N-carbamoyl aspartate, a committed step.
- Step 3: Dihydroorotase acts on N-carbamoyl aspartate to form dihydroorotate. This step removes water.
- Step 4: Dihydroorotate is oxidized to orotate via dihydroorotate dehydrogenase.
- Step 5: Orotate reacts with PRPP to create orotidine 5'-monophosphate (OMP).
- Step 6: OMP is decarboxylated to form UMP by orotidylate decarboxylase.
Overview of De Novo Synthesis of Pyrimidines
- Shows the key steps and enzymes involved in the synthesis of pyrimidines from carbamoyl phosphate, aspartate.
- Diagram the process from bicarbonate, ammonia and glutamine to finally synthesizing UMP.
De Novo Biosynthesis of Pyrimidines: Step 7 (Continuation)
- Uridylate (UMP) is converted to UTP through steps using ATP and kinases.
- Specific UMP kinase & less specific UDP kinase play critical roles.
Synthesis of Cytidine Triphosphate (CTP) from UTP
- Forming CTP involves replacing a carbonyl with an amino group on UTP using ATP with the action of CTP synthetase.
- Glutamine acts as the nitrogen donor in animals, while ammonia serves the same role in bacteria.
Overview of Thymidylate Biosynthesis
- Thymidylate synthesis processes converting dUMP to dTMP.
- This conversion is crucial for DNA synthesis and involves specific enzymes.
- Glycine, serine, and 10-formyl-THF play key roles in the process.
- 5-Fluorouracil is a crucial inhibitor of this synthesis in cancer treatment.
Salvage Pathway Synthesis of Pyrimidines
- Free pyrimidines released during nucleotide breakdown are salvaged and recycled for pyrimidine nucleotide synthesis.
- Pyrimidine phosphoribosyltransferase enzyme is key in this process, using PRPP as the source of ribose-5-phosphate.
Feedback Regulatory Control of Pyrimidine Synthesis
- Regulation in bacteria occurs at aspartate transcarbamoylase (ATCase).
- In animals, regulation is at carbamoyl phosphate synthetase II (CPS II).
- UDP & UTP inhibits CPS II.
- ATP & PRPP activate CPS II.
- OMP decarboxylase is competitively inhibited by UMP & CMP.
- Inhibition of PRPP synthetase in purine synthesis also regulates pyrimidine synthesis.
Overview of Pyrimidine Biosynthesis Regulation
- Diagrams show the key regulatory steps and enzymes involved in the feedback regulation of pyrimidine biosynthesis.
- Highlights enzyme regulation by substrate and end product inhibition.
Catabolism/Degradation of Pyrimidine Nucleotides
- CMP and UMP are dephosphorylated by nucleotidase to form nucleosides.
- Nucleosides are cleaved to produce ribose-1-phosphate and free pyrimidine bases (cytosine, uracil, thymine) via nucleosidase or phosphorylase.
- Cytosine is converted to uracil, which is further degraded.
- Thymine is broken down to CO2, NH4, and β-aminoisobutyrate.
- Products are excreted in urine or converted to CO2, H20, and NH4+.
Abnormalities in Nucleic Acid Metabolism
- Gout is a painful arthritis associated with increased uric acid formation.
- Treatment involves inhibiting xanthine oxidase (e.g., allopurinol).
- Lesch-Nyhan syndrome results from HGPRT deficiency leading to excess purines.
- Treatment involves managing behavioral issues.
- Von Gierke's Disease (Type 1 glycogen storage disease) is caused by glucose-6-phosphatase deficiency, leading to hypoglycemia and purine overproduction.
- Xanthine oxidase deficiency causes hyperuricemia (high uric acid).
- Enzyme replacement therapy can prove beneficial.
Orotic Aciduria
- A genetic deficiency of either orotate phosphoribosyltransferase or orotidylate decarboxylase leads to orotic aciduria.
- This results in the excretion of orotic acid and leads to megaloblastic anemia.
- The treatment involves using uridine to bypass the missing enzymes.
Some Clinical Relevance of Nucleotide Synthesis
- Thymidylate synthesis is crucial for cell proliferation, making enzymes involved valuable drug targets.
- Chemotherapeutic agents like 5-fluorouracil, raltitrexed, methotrexate, and trimethoprim target involved enzymes in various cancers to inhibit.
- In 2002, research found that some organisms lack thymidine kinase yet survive on a thymidine deficient media.
- This observation led to the discovery of flavin-dependent thymidylate synthase.
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Description
Test your knowledge on nucleic acid metabolism, including purine metabolism and the central dogma of molecular biology. This quiz covers key enzymes, their functions, and metabolic pathways related to nucleotides. Answer questions about processes, feedback inhibition, and catabolism of guanine derivatives.
