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Questions and Answers
What is the objective of this lecture?
What is the objective of this lecture?
To discuss the structure of nitrogenous bases, the biological role of DNA and RNA, and disorders associated with them.
From what are nitrogenous bases derived?
From what are nitrogenous bases derived?
What is the name of the sugar that is linked to a purine or pyrimidine base in a nucleoside?
What is the name of the sugar that is linked to a purine or pyrimidine base in a nucleoside?
How are nucleotides formed?
How are nucleotides formed?
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What is the name of the compound that is formed when purines are degraded?
What is the name of the compound that is formed when purines are degraded?
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The purine ring components come from different sources.
The purine ring components come from different sources.
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Which of the following is an example of a purine nucleoside?
Which of the following is an example of a purine nucleoside?
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What enzyme is responsible for the degradation of adenosine to inosine?
What enzyme is responsible for the degradation of adenosine to inosine?
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What is the name of the disorder that involves the accumulation of uric acid in the body?
What is the name of the disorder that involves the accumulation of uric acid in the body?
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Which of the following is an analog used to inhibit xanthine oxidase?
Which of the following is an analog used to inhibit xanthine oxidase?
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What are the two major categories of nucleic acid polymers?
What are the two major categories of nucleic acid polymers?
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What is a nucleoside triphosphate?
What is a nucleoside triphosphate?
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The purine biosynthetic pathway is regulated in different ways in bacteria and animals?
The purine biosynthetic pathway is regulated in different ways in bacteria and animals?
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The degradation of purines and pyrimidines is the same for ribonucleotides and deoxyribonucleotides.
The degradation of purines and pyrimidines is the same for ribonucleotides and deoxyribonucleotides.
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What is the name of the enzyme that catalyzes the transfer of a phosphate group from ATP to UDP?
What is the name of the enzyme that catalyzes the transfer of a phosphate group from ATP to UDP?
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The synthesis of deoxyribonucleotides is carried out through the same pathways as ribonucleotides.
The synthesis of deoxyribonucleotides is carried out through the same pathways as ribonucleotides.
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Which of the following is true about the purine nucleotide cycle?
Which of the following is true about the purine nucleotide cycle?
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What is the name of the enzyme that catalyzes the conversion of xanthine to uric acid?
What is the name of the enzyme that catalyzes the conversion of xanthine to uric acid?
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What is the name of the genetic disorder that results from a deficiency in HGPRT?
What is the name of the genetic disorder that results from a deficiency in HGPRT?
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Deoxyribonucleotides are synthesized from corresponding ribonucleotides.
Deoxyribonucleotides are synthesized from corresponding ribonucleotides.
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Which of the following is a characteristic of both DNA and RNA?
Which of the following is a characteristic of both DNA and RNA?
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What is the name of the enzyme that catalyzes the conversion of UTP to CTP?
What is the name of the enzyme that catalyzes the conversion of UTP to CTP?
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ADP and GDP inhibit PRPP synthesis.
ADP and GDP inhibit PRPP synthesis.
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What is the name of the enzyme that is responsible for the degradation of both CMP and UMP?
What is the name of the enzyme that is responsible for the degradation of both CMP and UMP?
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What is the name of the process that converts a ribonucleotide to a deoxyribonucleotide?
What is the name of the process that converts a ribonucleotide to a deoxyribonucleotide?
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The regulation of pyrimidine synthesis is the same in bacteria and animals.
The regulation of pyrimidine synthesis is the same in bacteria and animals.
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Which of the following is a product of purine catabolism?
Which of the following is a product of purine catabolism?
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The deficiency of adenosine deaminase (ADA) can lead to severe combined immunodeficiency (SCID).
The deficiency of adenosine deaminase (ADA) can lead to severe combined immunodeficiency (SCID).
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In the purine nucleotide cycle, the amino group from aspartate is transferred to fumarate.
In the purine nucleotide cycle, the amino group from aspartate is transferred to fumarate.
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Study Notes
Course Information
- Course: Molecular and Cellular Basis of Medicine 1
- Subject: Introduction to Basic Sciences
- Topic: L30 Nucleic Acids – Chemistry, Function & Metabolism
- Lecturer: Prof. Dr. Abd. Rahman Md. Said
- Date: Wednesday, 23.10.24
- Time: 10:00am
- Location: LR1
- Course code: MBBS L30 Nucleic acids
Learning Objectives
- Discuss the structure of nitrogenous bases
- Discuss the biological role of DNA and RNA and associated disorders
Topic Outcomes
- Describe the structure, function, and biological role of nucleosides, nucleotides, and analogues.
- Describe the structure, function, and types of nucleic acids (DNA and RNA).
- Explain purine and pyrimidine biosynthetic pathways and its regulation.
- Explain the role of ribonucleotide reductase.
- Describe the disorders associated with purine and pyrimidine metabolism.
Nitrogenous Bases
- Planar, aromatic, and heterocyclic
- Derived from purine or pyrimidine
- Numbering of bases is "unprimed"
- Include Adenine (A), Guanine (G), Cytosine (C), Thymine (T), Uracil (U)
Sugars
- Pentoses (5-carbon sugars)
- Numbering of sugars is "primed"
- Include D-Ribose and 2'-Deoxyribose
- 2'-Deoxyribose lacks a 2'-OH group
Nucleosides
- Result from linking one of the sugars with a purine or pyrimidine base through an N-glycosidic linkage.
- Purines bond to the C1' carbon of the sugar at their N9 atoms.
- Pyrimidines bond to the C1' carbon of the sugar at their N1 atoms.
Nucleotides
- Result from linking one or more phosphates with a nucleoside onto the 5' end of the molecule through esterification
- Phosphates can be bonded to either C3 or C5 atoms of the sugar
- Include mono-, di- or triphosphates: Adenosine Monophosphate (AMP); 2'-Deoxythymidine Monophosphate
- Monomers for nucleic acid polymers
- Important energy carriers (ATP, GTP)
- Important components of coenzymes (FAD, NAD+, Coenzyme A)
Nucleic Acid Polymers
- RNA (ribonucleic acid) is a polymer of ribonucleotides
- DNA (deoxyribonucleic acid) is a polymer of deoxyribonucleotides.
- Contain: Adenine, Guanine, Cytosine, and Uracil (RNA); and Adenine, Guanine, Cytosine, and Thymine (DNA)
Naming Conventions
- Nucleosides: Purines (end in "-sine"), Pyrimidines (end in "-dine")
- Nucleotides: Add "mono-," "di-," or "triphosphate" to nucleoside name.
Nucleotide Metabolism
- Purine ribonucleotides are formed de novo (not from free bases)
- First purine derivative formed is Inosine Monophosphate (IMP)
- The purine base is hypoxanthine
- AMP and GMP are formed from IMP
- Purine ring components come from: Aspartate amine; Formate; Glutamine; Glycine; Bicarbonate ion
Purine Nucleotide Synthesis
- ATP is involved in 6 steps
- PRPP is a precursor for synthesis of other molecules
- In step 2, the C1 notation changes from α to β.
- Hydrolyzing a phosphate from ATP is relatively easy
- ∆G°'= -30.5 kJ/mol
- Part of the ATP can be transferred to an acceptor (Pi, PPi, adenyl, or adenosinyl group)
- ATP hydrolysis drives other unfavorable reactions
Purine Biosynthetic Pathway
- Channeling of some reactions organizes substrate processing.
- Increases the overall rate of the pathway and protects intermediates from degradation
- Shows channeling at reactions 3, 4, 6; 7, 8; and 10, 11
IMP Conversion
- IMP converts to AMP and GMP
IMP Conversion to GMP
- Conversion of IMP to GMP, using NAD, Gln, and ATP
Regulatory Control of Purine Nucleotide Biosynthesis
- GTP is involved in AMP synthesis and ATP is involved in GMP synthesis (reciprocal control)
- PRPP is a central molecule
- ADP/GDP levels, negative feedback on Ribose Phosphate Pyrophosphokinase
- Amidophosphoribosyl transferase is activated by PRPP levels
- ATP, ADP, AMP and GTP, GDP, GMP binding is at separate sites.
- Rate of AMP production increases with increasing concentrations of GTP and for GMP with increasing concentrations of ATP
Regulatory Control of Purine Biosynthesis
- Above the level of IMP production: Independent control, Synergistic control, Feedforward activation
- Below level of IMP production: Reciprocal control
- Total amounts of purine nucleotides controlled
- Relative amounts of ATP, GTP controlled
Purine Catabolism and Salvage
- All purine degradation leads to uric acid.
- Ingested nucleic acids are degraded to nucleotides by pancreatic nucleases and intestinal phosphodiesterases
- Group-specific nucleotidases and non-specific phosphatases degrade nucleotides into nucleosides.
- Direct absorption of nucleosides.
- Nucleosides hydrolyse into base + ribose-1-phosphate (nucleoside phosphorylase)
- Base + ribose-1-phosphate (n. phosphorylase) yields base + ribose-5-phosphate
Intracellular Purine Catabolism
- Nucleotides are broken down to nucleosides by 5'-nucleotidase.
- Purine nucleoside phosphorylase (PNP): inosine --> hypoxanthine, xanthosine --> xanthine, guanosine --> guanine.
- Ribose-1-phosphate splits off (can be isomerized to ribose-5-phosphate).
- Adenosine is deaminated to inosine (by ADA)
- Xanthine is a point of convergence for the metabolism of the purine bases
- Xanthine oxidase catalyzes two reactions (to uric acid).
- Purine ribonucleotide degradaton pathway for purine deoxyribonucleotides
Adenosine Degradation
- Inosine is a product from adenosine degradation.
- Adenine deaminase converts AMP to IMP.
Xanthine Degradation
- Ribose sugar is recycled (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 by Xanthine Oxidase
Xanthine Oxidase
- A homodimeric protein
- Contains electron transfer proteins -FAD
- Mo-pterin complex in +4 or +6 state
- Two 2Fe-2S clusters
- Transfers electrons to O2
- H2O2 is toxic
- Disproportionated to H2O and O2 by catalase
The Purine Nucleotide Cycle
- AMP + H2O --> IMP + NH4+ (AMP deaminase)
- IMP + Aspartate + GTP --> AMP + Fumarate + GDP + Pi (Adenylosuccinate synthetase)
Uric Acid Excretion
- Humans excrete uric acid into urine, which forms crystals
- Birds, reptiles, and some insects excrete uric acid as crystals in paste form.
- Excess amino nitrogen converted to uric acid (conserves water)
- Others further modify it to urea, allantoic acid, or ammonia.
Purine Salvage
- Adenine phosphoribosyl transferase (APRT) catalyzes Adenine + PRPP --> AMP + PPi
- Hypoxanthine-Guanine phosphoribosyl transferase (HGPRT) catalyzes Hypoxanthine + PRPP --> IMP + PPi and Guanine + PRPP --> GMP + PPi.
- These are reversible reactions.
- AMP, IMP, and GMP do not need to be resynthesized de novo.
Gout
- Impaired excretion or overproduction of uric acid leads to uric acid crystals precipitating into joints (Gouty Arthritis) and kidneys/ureters (stones).
- Lead impairs uric acid excretion.
- Fall of Roman Empire?
- Xanthine oxidase inhibitors inhibit uric acid production, treating gout
- Allopurinol treatment- hypoxanthine analog which binds to Xanthine Oxidase to decrease uric acid production
Allopurinol
- A xanthine oxidase inhibitor
- A substrate analog which converts to an inhibitor, a suicide inhibitor
Lesch-Nyhan Syndrome
- A defect in the production or activity of HGPRT.
- Causes increased levels of hypoxanthine and guanine.
- Also, PRPP accumulates.
- Stimulates production of purine nucleotides, increasing their degradation.
- Causes gout-like symptoms, but also neurological symptoms (spasticity, aggressiveness, self-mutilation).
- First neuropsychiatric abnormality that was attributed to a single enzyme.
Purine Autism
- 25% of autistic patients may overproduce purines.
- Diagnose by testing urine over 24 hours.
- Biochemical findings disappear in adolescence.
- Urine specimen needed in infancy (difficult).
- Pink urine due to uric acid crystals may be seen in diapers
Pyrimidine Ribonucleotide Synthesis
- Uridine monophosphate (UMP) is synthesized first, followed by CTP
Pyrimidine Synthesis
- Multi-step process, uses 2 ATP, HCO3, Glutamine, and H2O for synthesis
- Forms UMP
UMP Synthesis Overview
- 2 ATP needed (one transferred, one hydrolyzed to ADP and Pi)
- 2 condensation reactions (Carbamoyl aspartate and dihydroorotate form)
- Dihydroorotate dehydrogenase is an intra-mitochondrial enzyme that uses oxidizing power
- Attachment of base to ribose ring catalyzed by OPRT, PRPP provides ribose-5-P
- PP, splits off PRPP (irreversible)
- Enzymes 1, 2, and 3 on one chain and 5 and 6 on the other chain.
OMP Decarboxylase
- Final reaction in pyrimidine pathway
- No high-energy carbocation intermediate needed
- No cofactors needed
- Binding energy stabilizes transition state
UTP and CTP
- Nucleoside monophosphate kinase transfers P to UMP --> UDP
- Nucleoside diphosphate kinase transfers P from ATP to UDP --> UTP
- CTP formed from UTP via CTP synthetase (driven by ATP hydrolysis)
- Glutamine provides amide nitrogen for C4 in animals.
Regulatory Control of Pyrimidine Synthesis
- Differs between bacteria and animals
- Bacteria regulation at ATCase reaction
- Animals regulation at carbamoyl phosphate synthetase II
- UDP and UTP inhibit the enzyme, while ATP and PRPP activate it
- UMP and CMP competitively inhibit OMP decarboxylase.
- Purine synthesis inhibited by ADP and GDP, controlling PRPP levels, also regulating pyrimidines
Degradation of Pyrimidines
- CMP and UMP degraded to bases similarly to purines.
- Dephosphorylation, Deamination, and Glycosidic bond cleavage
- Uracil reduced in liver, forming β-alanine
- Converted to malonyl-CoA for fatty acid synthesis (energy metabolism)
Deoxyribonucleotide Formation
- Purine/pyrimidine degradation pathway same for ribonucleotides and deoxyribonucleotides
- Biosynthetic pathways only for ribonucleotide production
- Deoxyribonucleotides are synthesized from corresponding ribonucleotides
Adenosine Deaminase Deficiency
- In purine degradation, adenosine --> inosine (enzyme is ADA)
- ADA deficiency results in 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
- Enzyme catalyzing deamination of Adenosine to Inosine
- α/β barrel domain structure
- “TIM Barrel”– central barrel structure with 8 twisted parallel β-strands connected by 8 α-helical loops.
- Active site is at the bottom of a funnel-shaped pocket formed by loops.
- Found in all glycolytic enzymes and proteins that bind and transport metabolites.
References
- The references list various textbooks and websites.
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Description
This quiz covers the chemistry, function, and metabolism of nucleic acids as part of the 'Molecular and Cellular Basis of Medicine 1' course. Focus on the structure and biological roles of DNA, RNA, and associated disorders. Test your understanding of nitrogenous bases and their biosynthetic pathways.
