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Questions and Answers
What are the two primary molecules that nucleic acids are derived from?
What are the two primary molecules that nucleic acids are derived from?
The numbering of bases in nucleic acids is primed.
The numbering of bases in nucleic acids is primed.
False
Nucleosides are formed by linking one or more phosphates with a nucleoside through esterification.
Nucleosides are formed by linking one or more phosphates with a nucleoside through esterification.
False
What are the three main types of phosphates involved in nucleotides?
What are the three main types of phosphates involved in nucleotides?
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Nucleotides are the monomers of nucleic acids.
Nucleotides are the monomers of nucleic acids.
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What are the three purine bases found in both deoxyribonucleotides and ribonucleotides?
What are the three purine bases found in both deoxyribonucleotides and ribonucleotides?
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What is the primary difference between ribonucleotides and deoxyribonucleotides?
What is the primary difference between ribonucleotides and deoxyribonucleotides?
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What are the three main components of purine nucleotides?
What are the three main components of purine nucleotides?
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What is the first purine derivative formed in the de novo synthesis pathway?
What is the first purine derivative formed in the de novo synthesis pathway?
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What is the purine base that is incorporated into IMP?
What is the purine base that is incorporated into IMP?
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AMP and GMP are formed directly from hypoxanthine.
AMP and GMP are formed directly from hypoxanthine.
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The purine de novo synthesis pathway involves the use of ATP in all steps.
The purine de novo synthesis pathway involves the use of ATP in all steps.
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What role does PRPP play in purine synthesis?
What role does PRPP play in purine synthesis?
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The hydrolysis of PP₁ in step 2 of the purine de novo synthesis pathway is reversible.
The hydrolysis of PP₁ in step 2 of the purine de novo synthesis pathway is reversible.
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ATP hydrolysis can only be used to drive endergonic reactions.
ATP hydrolysis can only be used to drive endergonic reactions.
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What are the two main functions of channeling in the purine biosynthetic pathway?
What are the two main functions of channeling in the purine biosynthetic pathway?
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What are the two main regulatory points for purine biosynthesis?
What are the two main regulatory points for purine biosynthesis?
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PRPP is not involved in the regulation of purine biosynthesis.
PRPP is not involved in the regulation of purine biosynthesis.
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The rate of AMP production is elevated when GTP levels are high.
The rate of AMP production is elevated when GTP levels are high.
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Purine biosynthesis is strictly regulated at only one level.
Purine biosynthesis is strictly regulated at only one level.
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What is the final product of purine degradation?
What is the final product of purine degradation?
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Uric acid can further degrade under normal conditions, leading to the production of urea.
Uric acid can further degrade under normal conditions, leading to the production of urea.
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Name two enzymes involved in the degradation of ingested nucleic acids.
Name two enzymes involved in the degradation of ingested nucleic acids.
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What are the two main steps involved in the degradation of nucleosides?
What are the two main steps involved in the degradation of nucleosides?
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What is the point of convergence for the metabolism of various purine bases?
What is the point of convergence for the metabolism of various purine bases?
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Xanthine oxidase catalyzes the conversion of xanthine to hypoxanthine.
Xanthine oxidase catalyzes the conversion of xanthine to hypoxanthine.
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The degradation pathway for purine ribonucleotides is identical to the pathway for purine deoxyribonucleotides.
The degradation pathway for purine ribonucleotides is identical to the pathway for purine deoxyribonucleotides.
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Purine salvage is a process that involves the resynthesis of purines de novo.
Purine salvage is a process that involves the resynthesis of purines de novo.
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What are the two main enzymes involved in purine salvage?
What are the two main enzymes involved in purine salvage?
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Purine salvage reactions are irreversible.
Purine salvage reactions are irreversible.
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What is the primary cause of gout?
What is the primary cause of gout?
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Uric acid crystals are a common cause of renal stones.
Uric acid crystals are a common cause of renal stones.
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Allopurinol is a substrate analog that inhibits the activity of xanthine oxidase.
Allopurinol is a substrate analog that inhibits the activity of xanthine oxidase.
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Lesch-Nyhan syndrome results from a deficiency in the activity of APRT.
Lesch-Nyhan syndrome results from a deficiency in the activity of APRT.
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Lesch-Nyhan syndrome only causes neurological symptoms.
Lesch-Nyhan syndrome only causes neurological symptoms.
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Individuals with Lesch-Nyhan syndrome also have elevated levels of PRPP.
Individuals with Lesch-Nyhan syndrome also have elevated levels of PRPP.
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The diagnosis of purine autism requires a single urine test.
The diagnosis of purine autism requires a single urine test.
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The synthesis of pyrimidine nucleotides begins with the formation of cytidine monophosphate (CMP).
The synthesis of pyrimidine nucleotides begins with the formation of cytidine monophosphate (CMP).
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The synthesis of pyrimidine nucleotides involves the attachment of the ribose-5-phosphate unit after the completion of the pyrimidine ring structure.
The synthesis of pyrimidine nucleotides involves the attachment of the ribose-5-phosphate unit after the completion of the pyrimidine ring structure.
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Carbamoyl-phosphate synthetase II is regulated at the same level in both animals and bacteria.
Carbamoyl-phosphate synthetase II is regulated at the same level in both animals and bacteria.
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Both UMP and CMP are known to inhibit OMP decarboxylase.
Both UMP and CMP are known to inhibit OMP decarboxylase.
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Purine synthesis is not affected by changes in PRPP levels.
Purine synthesis is not affected by changes in PRPP levels.
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CTP is formed directly from UTP.
CTP is formed directly from UTP.
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In animals, the amide group for CTP is provided by aspartate.
In animals, the amide group for CTP is provided by aspartate.
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Degradation of pyrimidines involves the production of uric acid.
Degradation of pyrimidines involves the production of uric acid.
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Degradation of pyrimidines primarily occurs in the liver.
Degradation of pyrimidines primarily occurs in the liver.
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The degradation of pyrimidines is the same for both ribonucleotides and deoxyribonucleotides.
The degradation of pyrimidines is the same for both ribonucleotides and deoxyribonucleotides.
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The biosynthesis of deoxyribonucleotides relies on the same pathways as the biosynthesis of ribonucleotides.
The biosynthesis of deoxyribonucleotides relies on the same pathways as the biosynthesis of ribonucleotides.
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Deoxyribonucleotides are directly synthesized from their corresponding ribonucleotides.
Deoxyribonucleotides are directly synthesized from their corresponding ribonucleotides.
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ADA deficiency affects the production of uric acid.
ADA deficiency affects the production of uric acid.
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ADA deficiency primarily affects B-cells.
ADA deficiency primarily affects B-cells.
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All known ADA mutants affect the active site of the enzyme.
All known ADA mutants affect the active site of the enzyme.
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Adenosine deaminase is a type of TIM barrel enzyme.
Adenosine deaminase is a type of TIM barrel enzyme.
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The active site of adenosine deaminase is found at the top of a funnel-shaped pocket.
The active site of adenosine deaminase is found at the top of a funnel-shaped pocket.
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Adenosine deaminase is found exclusively in glycolytic enzymes.
Adenosine deaminase is found exclusively in glycolytic enzymes.
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Adenosine deaminase is involved in the transport of metabolites.
Adenosine deaminase is involved in the transport of metabolites.
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Study Notes
Nucleic Acids - Chemistry, Function & Metabolism
- Learning Objectives: To discuss the structure of nitrogenous bases, the biological role of DNA and RNA, and associated disorders.
Topic Outcomes
- 30.1: Describe the structure, function, and biological role of nucleosides, nucleotides, and analogues.
- 30.2: Describe the structure, function, and types of nucleic acids (DNA and RNA).
- 30.3: Explain purine and pyrimidine biosynthetic pathways and their regulation.
- 30.4: Explain the role of ribonucleotide reductase.
- 30.5: Describe the disorders associated with purine and pyrimidine metabolism.
Nitrogenous Bases
- Planar, aromatic, and heterocyclic.
- Derived from purine or pyrimidine.
- Bases are numbered "unprimed".
- Includes adenine (A), guanine (G), thymine (T), cytosine (C), and uracil (U).
Sugars
- Pentoses (5-carbon sugars).
- Numbering of sugars is "primed".
- Includes D-ribose and 2'-deoxyribose.
- 2'-deoxyribose lacks a 2'-OH group.
Nucleosides
- Result from linking sugars with a purine or pyrimidine base via an N-glycosidic linkage.
- Purines bond to the C1' carbon at the N9 atom.
- Pyrimidines bond to the C1' carbon at the N1 atom.
- Examples include adenosine, guanosine, thymidine, cytidine, and uridine.
Nucleotides
- Result from linking one or more phosphates to a nucleoside via esterification at the 5' end.
- Phosphates can be bonded to either the C3 or C5 atoms of the sugar.
- Can be mono-, di-, or triphosphates.
- Examples include adenosine monophosphate (AMP), deoxythymidine monophosphate, and others.
Nucleotides (continued)
- Monomers for nucleic acid polymers.
- Nucleoside triphosphates (NTPs) are important energy carriers (e.g., ATP, GTP).
- Important components of coenzymes (e.g., FAD, NAD+ and Coenzyme A).
- RNA (ribonucleic acid) is a polymer of ribonucleotides.
- DNA (deoxyribonucleic acid) is a polymer of deoxyribonucleotides.
- Ribonucleotides contain uracil; deoxyribonucleotides contain thymine.
Naming Conventions
-
Nucleosides: Purine nucleosides end in "-sine", Pyrimidine nucleosides end in "-dine". -
Examples: adenosine, guanosine, uridine, thymidine. -
Nucleotides: Add "mono-," "di-," or "triphosphate" to the nucleoside name.
Nucleotide Metabolism
- Purine Nucleotides: Formed de novo (i.e., not initially synthesized as free bases).
- First purine derivative formed is Inosine Monophosphate (IMP).
- Purine base is hypoxanthine.
- AMP and GMP are formed from IMP.
- Purine ring components come from aspartate, formate, glutamine, glycine, and bicarbonate.
Purine Biosynthetic Pathway
- Channeling organizes and controls substrate processing in each step to increase the overall rate of the pathway and protect it from degradation.
- Pathway increases overall rate and protects intermediates from degradation.
- In animals, IMP synthesis has channeling at reactions 3, 4, 6, 7, 8, 10, and 11.
IMP Conversion to AMP
- Aspartate and GTP are involved in converting IMP to AMP.
IMP Conversion to GMP
- NAD+, glutamine, and ATP are involved in converting IMP to GMP.
Regulatory Control of Purine Nucleotide Synthesis
- GTP is involved in AMP synthesis; ATP is involved in GMP synthesis (reciprocal control.)
- PRPP is a biosynthetically central molecule.
- ADP/GDP levels provide negative feedback on Ribose Phosphate Pyrophosphokinase.
- Allopurinol is a xanthine oxidase inhibitor.
Purine Catabolism and Salvage
- Ingested nucleic acids are broken down by pancreatic nucleases and intestinal phosphodiesterases; nucleotides are degraded into nucleosides.
- Nucleosides can be directly absorbed or further degraded.
- Intracellular purine catabolism involves enzymes such as 5'-nucleotidase and purine nucleoside phosphorylase (PNP).
- Xanthine is a point of convergence for the metabolism of purine bases; Xanthine oxidation catalyzes two reactions.
- Purine ribonucleotide degradation pathways are the same for purine deoxyribonucleotides.
Adenosine Degradation
- Adenosine deaminase (ADA) converts adenosine to inosine.
- Inosine is a product of adenosine deamination.
Xanthine Degradation
- Ribose sugar is converted back to Ribose-1-Phosphate(R-5-P)
- Hypoxanthine is converted to xanthine by Xanthine Oxidase.
- Guanine is converted to Xanthine by Guanine Deaminase.
- Xanthine gets converted to uric acid via Xanthine Oxidase.
Xanthine Oxidase
- Is a homodimeric protein.
- Contains electron transfer proteins.
- Mo-pterin complex is in a +4 or +6 state.
- Has two 2Fe-2S clusters.
- Transfers electrons to O2.
- H2O2 is toxic; disproportionated via catalase.
The Purine Nucleotide Cycle
- Combining reactions 1 and 2, aspartate gets deaminated to fumarate.
- The overall reaction converts aspartate to fumarate at the cost of GTP.
Uric Acid Excretion
- Humans excrete uric acid as insoluble crystals.
- Birds, reptiles, etc. excrete uric acid as insoluble crystals in paste form.
- Excess amino Nitrogen converts into uric acid (conserves water.)
- Other organisms modify uric acid further.
Purine Salvage
- Adenine phosphoribosyl transferase (APRT) converts adenine + PRPP into AMP + PP₁.
- Hypoxanthine-Guanine phosphoribosyl transferase (HGPRT) converts hypoxanthine+ PRPP into IMP + PP₁ and Guanine + PRPP into GMP + PP₁.
Gout
- Impaired excretion or overproduction of uric acid.
- Uric acid precipitates in joints, kidneys, and ureters.
- Impairs uric acid excretion, potentially causing lead poisoning.
- Xanthine oxidase inhibitors inhibit uric acid production, treating gout.
- Allopurinol is a treatment — a hypoxanthine analog that binds to xanthine oxidase to reduce uric acid production.
Lesch-Nyhan Syndrome
- A defect in HGPRT production/activity.
- Leads to increased hypoxanthine and guanine, increasing their degradation, producing uric acid.
- PRPP accumulates.
- Stimulates purine nucleotide production, increasing their degradation.
- Causes gout-like symptoms and neurological symptoms like spasticity, aggression, and self-mutilation.
- First neuropsychiatric abnormality attributed to a single enzyme
Purine Autism
- 25% of autistic patients may overproduce purines.
- Diagnosis requires 24-hour urine testing.
- Biochemical findings often disappear in adolescence.
- Pink urine due to uric acid crystals can occur in diapers.
Pyrimidine Ribonucleotide Synthesis
• Uridine Monophosphate (UMP) is synthesized first, followed by Cytidine triphosphate from UMP, and finally Thymidine from dihydroorotate. • Pyrimidine ring synthesis occurs first, then attached to ribose-5-phosphate. • Nitrogen atoms come from aspartate, bicarbonate, and glutamine.
Pyrimidine Synthesis
- Two ATPs are needed for the first step of the pathway where one is used in phosphate transfer, and the other is hydrolyzed to 2ADP and Pi
- Two condensation reactions occur in the pyrimidine synthesis to form carbamoyl aspartate and dihydroorotate.
UMP Synthesis Overview
- Two ATPs are needed for the first step.
- Condensation reactions form carbamoyl aspartate and dihydroorotate.
- Dihydroorotate dehydrogenase is an intramitochondrial enzyme, oxidizing power comes from quinone reduction.
- OPRT adds the base to the ribose ring.
- PRPP provides ribose-5-P.
- PPi is split off by PRPP.
- Enzymes 1, 2, and 3 are on the same chain; 5 and 6 are on the same chain.
OMP Decarboxylase
- Final reaction in Pyrimidine pathway.
- No high-energy intermediate needed.
- No cofactors needed.
- Binding energy between OMP and active site stabilizes the transition state (preferential transition state binding.)
UTP and CTP
- Nucleoside monophosphate kinase transfers phosphate to UMP, forming UDP.
- Nucleoside diphosphate kinase transfers the phosphate from ATP to UDP to form UTP.
- CTP is formed from UTP via CTP synthetase—driven by ATP hydrolysis.
- Glutamine provides amide nitrogen for animal C4.
Regulatory Control of Pyrimidine Synthesis
- Differs between bacteria and animals.
- Bacterial regulation at ATCase reaction where animal regulation is at carbamoyl phosphate synthetase II.
- UDP/UTP inhibits enzymes; ATP/PRPP activates it.
- UMP and CMP competitively inhibit OMP Decarboxylase.
- Purine synthesis is inhibited by GDP and ADP at ribose phosphate pyrophosphokinase, controlling the level of PRPP. Regulation of pyrimidines is also included.
Degradation of Pyrimidines
- CMP and UMP degrade to bases similar to purines; the steps are dephosphorylation, deamination, and glycosidic bond cleavage.
- Uracil is reduced in the liver, forming beta-alanine; converted to malonyl-CoA for fatty acid synthesis.
Deoxyribonucleotide Formation
- Purine/Pyrimidine degradation is the same, regardless of whether the nucleotide is a ribonucleotide or deoxyribonucleotide
- Biosynthetic pathways are only for ribonucleotide production.
- Deoxyribonucleotides are synthesized from corresponding ribonucleotides.
Adenosine Deaminase Deficiency
- Purine degradation uses adenosine deaminase (ADA); Adenosine converts to Inosine.
- ADA deficiency causes severe combined immunodeficiency (SCID).
- Selectively kills lymphocytes (both B and T cells).
- Mediates much of the immune response.
- All known ADA mutants structurally perturb the active site.
Adenosine Deaminase
- Catalyzes deamination of adenosine to inosine using the a/b barrel domain structure (TIM barrel).
- The active site is located at the bottom of a funnel-shaped pocket, and the enzyme is found in all glycolytic enzymes and proteins that bind and transport metabolites.
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