nucleotide metabolism - indiana university...
TRANSCRIPT
![Page 1: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/1.jpg)
Nucleotide Metabolism
C483 Spring 2013
![Page 2: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/2.jpg)
1. A ribose sugar is added to ________ rings after their synthesis and to ________ rings during their synthesis.A) purine; pyrimidineB) pyrimidine; purineC) purine; purineD) pyrimidine; pyrimidine 2. The first nucleotide product in the de novo biosynthetic pathway of purines is A) AMP.B) GMP.C) IMP.D) XMP.
3. Which of the following statements is false concerning purine synthesis?A) N7 is from glycineB) C2 is from carbon dioxide (bicarbonate)C) N3 is from glutamineD) C8 is from 10-formylTHF.
![Page 3: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/3.jpg)
4. Which is a precursor in the de novo synthesize CTP? A) CMP.B) GMP.C) TMP.D) UMP.
5. Which of the following is not a role of a catalytic sulfur atom in ribonucleotide reductase?
A) Proton donorB) Radical stabilizationC) Redox reactionD) Covalent catalysis
6. Dihydrofolate reductase and thymidylate synthetase are major targets for anticancer drugs because A) these enzymes are unique in cancer cells. B) cancer cells lack sufficient amounts of these enzymes.C) cancer cells grow rapidly and are very dependent upon the activities of these enzymes. D) they donate one-carbon groups.E) All of the above.
![Page 4: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/4.jpg)
Terminology of Nucleic Acids
• Nucleotide• Nucleoside• Nucleobase• AMP• ADP• ATP• dAMP
![Page 5: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/5.jpg)
Some Examples of Nucleotides
ATP
GTP
S-AM
FADNAD+
UDP-Glucose
CoA
![Page 6: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/6.jpg)
De Novo Synthesis
![Page 7: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/7.jpg)
De Novo Synthesis of Purines
• Form activated ribose
• Form 5-phospho ribosylamine
• Build IMP from precursors
• Synthesis of AMP and GMP
![Page 8: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/8.jpg)
PRPP
• Pentose phosphate pathway
• 2 ATP equivalents• Over production of
PRPP is one cause of gout because PRPP stimulates the next step…
![Page 9: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/9.jpg)
5-phosphoribosylamine
• First step of purine biosynthesis
• Glutamine is N donor• Regulated– Activation by PPRP– Increased purine levels– Degradation of purines
leads to compound which can cause gout
![Page 10: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/10.jpg)
Purine Pathway
• Don’t need to know details, order
• Know precursors– N from Asp, Gln– C from THF, Gly, CO2
• Cost– 2 ATP eq for PRPP– 5 more ATP steps Know this figure!
![Page 11: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/11.jpg)
![Page 12: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/12.jpg)
Purines
• Two distinct strategies for amination– Mechanisms
• Regulation– Feedback to 5-phospho
ribosylamine– Branchpoint regulation
![Page 13: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/13.jpg)
Compare/Contrast• Purine biosynthesis– Salvage is a major
pathway– Base synthesized while
attached to ribose– IMP is common
intermediate for AMP and GMP, but itself is not a typical nucleotide
• Pyrimidine biosynthesis– De novo is a major
pathway– Base is synthesized, then
attached to ribose– UMP, a typical nucleic
acid, is converted into other pyrimidines
![Page 14: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/14.jpg)
De novo Pyrimidine Synthesis
• First step regulated (compare to urea cycle)
• Asp is different than purine—whole molecule is incorporated
![Page 15: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/15.jpg)
Further Modifications
• Interconversion of nucleotides (mono, di, tri phosphates)
• Reduction to form deoxynucleotides• Methylation to form dTMP
![Page 16: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/16.jpg)
Nucleotide Interconversions
• Fast, reversible, driven by high [ATP]• NMPNDP catalyzed by specific nucleoside
monophosphate kinase• NDPNTP catalyzed by nonspecific kinase• AMP + ATP ADP + ADP important in energy
balance
NMP NDP NTP
ATP ADP ATP ADP
![Page 17: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/17.jpg)
Deoxyribonucleotides• Deoxygenation occurs on diphosphates• One enzyme affects all transformations
[dUDP]
![Page 18: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/18.jpg)
Ribonucleotide Reductase
• Sulfur does amazing chemistry!– Stable radical– Proton donor– Redox reagent
• NADPH is ultimate source of reducing
![Page 19: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/19.jpg)
![Page 20: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/20.jpg)
Regulation of Reductase
• One enzyme balances needs of cell via regulation of activity and selectivity
• Be able to explain why this table makes sense
![Page 21: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/21.jpg)
Methylation• dTMP is made from dUMP• Key step in replicating cells• Therapeutic target for anti-cancer drugs• Two key enzymes
![Page 22: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/22.jpg)
Thymidylate Synthase
• Methylene-THF acts as a “methyl” donor– Donates methylene– And hydride
• Fascinating chemistry!– Sulfur is covalent
catalyst– Internal 1,3-hydride
shift• THF is left as DHF
![Page 23: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/23.jpg)
5-Fluorouracil• Incorporated into
monophosphate nucleotide in body
• Mechanism based inhibitor (Trojan Horse)
• Forms covalent link to enzyme like normal
• No elimination possible because proton replaced with fluorine
NH
O
ONO
OHOH
HH
HH
OP-O
O-
O
NH
O
ONO
OHOH
HH
HH
OP-O
O-
O
F
![Page 24: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/24.jpg)
DHF reductase
• DHF must be reduced back to THF to be a viable cofactor
• Second chemotherapy target
• Competitive inhibitor that is structurally similar to THF would end methylation process
![Page 25: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/25.jpg)
![Page 26: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/26.jpg)
Review of Purines• Knowing blue in figure will help with chapter summary
![Page 27: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/27.jpg)
Review of Pyrimidines• Knowing blue in figure will help with chapter summary
![Page 28: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/28.jpg)
Catabolism
• Less important than other catabolic processes– not a major energy source– Lots of salvage– Serves to clear excess
• In humans, purines uric acid (excreted)• In humans, pyrimidines acetyl CoA, succinyl
CoA for some energy gain
![Page 29: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/29.jpg)
Severe Combined Immunodeficiency Syndrome (SCIDS)
• Deficiency of adenosine deaminase
• First step in catabolism• High levels of dATP
lead to low levels of dNTP
• No DNA kills fast growing T-cells
*
![Page 30: Nucleotide Metabolism - Indiana University Bloomingtoncourses.chem.indiana.edu/c483/documents/Lecture29.pptx · PPT file · Web view2013-03-22 · The first nucleotide product in](https://reader036.vdocuments.us/reader036/viewer/2022062911/5c79e45509d3f2065e8b5a72/html5/thumbnails/30.jpg)
Answers
1. B2. C3. B4. D5. D6. C