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Pyrimidine Metabolism and Cancer Therapy. LEARNING OBJECTIVES. Nomenclature of pyrimidines* Key features of biosynthetic pathway and origin of atoms in pyrimidine ring Basis of chemotherapy using nucleotide analogs. *Key words are highlighted in yellow. Pyrimidine Synthesis. - PowerPoint PPT Presentation
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Pyrimidine Metabolism and Cancer Therapy
LEARNING OBJECTIVES
1. Nomenclature of pyrimidines*
2. Key features of biosynthetic pathway and origin of atoms in pyrimidine ring
3. Basis of chemotherapy using nucleotide analogs
*Key words are highlighted in yellow
Pyrimidine Synthesis
• The pyrimidine ring is completely synthesized, then attached to a ribose-5-phosphate donated by PRPP
• Source of carbons and nitrogens less diverse than with purines.
(Carbamoyl-P)
Pyrimidine SynthesisUrea Synthesis
Miles et al. J. Biol. Chem. 274, 12193-12199 (1999)
Carbamoyl Phosphate Synthase and Carbamoyl Phosphate Synthase and Channeling of IntermediatesChanneling of Intermediates
Enzymatic functions from one large protein (215,000 Mr)
Enzymatic functions from one large protein
What to Know
1. Compare and contrast CPS I and CPS II
2. CPSII, aspartate transcarbamoylase, and dihydroorotase are three enzymatic functions in one protein.
3. Oratate phosphoribosyltransferase and OMP decarboxylase are two enzymatic functions in one protein. Deficiency leads to Orotic Aciduria. Know symptoms and how to treat.
4. Orotate is made and then attached to a PRPP.
UMP UDP UTPUridine monophosphate kinase Uridine diphosphate kinase
Nitrogen Donor(again!)
Uridine
Cytidine
5-fluorouracil
Methotrexate alsoinhibits this reaction
Thymidylate synthase is a major target for anti-cancer therapy.
See Figs 26.25-26.27 in reading for more details
Regulation of Pyrimidine Synthesis
Pyrimidine Breakdown
De novo purine synthesis
IMP
AMP
GMP
ADP ATP
GDP GTP
Adenosinemonophosphate
kinase
Adenosinediphosphate
kinase
Guanosinemonophosphate
kinase
Guanosinediphosphate
kinase
De novo pyrimidine synthesis
UMP UDPUridine monophosphate kinase
UTPUridine
diphosphatekinase
CTPdUDPdUMP
dTMP
Thymidylate synthase
dTDP dTTPThymidine monophosphate kinase
Thymidinediphosphate
kinase
Ribonucleotides to Deoxyribonucleotides
Very Important!
Ribonucleotides to Deoxyribonucleotides
Logic For Deoxynucleotide Synthesis (Fig 26.24) in reading
•High [ATP], plenty of energy, ok to make DNA
•High [ATP] means the ribonucleotide reductase is active (ON)
•ATP in specificity site S favors CDP or UDP in catalytic site C [dCDP] and
[dUDP] ↑
•dCDP and dUDP become metabolized to dTTP (thus justifying the synthesis of
dUMP even though it does not get incorporated into DNA)
•As [dTTP]↑, it will begin to occupy specificity site favoring GDP in catalytic site,
thus leading to [dGP]↑ [dGTP]↑
•As [dGTP]↑ it begins to occupy specificity site and thus favor ADP in catalytic
site, leading to [dADP]↑ which will replace ATP in activity site and turn
enzyme off
Uracil Analogues in Cancer Therapy
Uracil
5-fluorouracil β-D-arabinofuranosylcytosine (Ara-C)
dUMP dTMPThymidylateSynthase
Cancer Therapy with 5-fluorouracil
•5-FU is typically given with thymidine to boost its effectiveness
•5-FU is converted to dFUMP
•dFUMP inhibits Thymidylate synthase
•In cancer cells, 5-FU is also incorporated into RNA
•5-FU in RNA is detrimental to cancer cells
•Inhibition of Thymidylate synthase is detrimental to both cancer and normal cells
•So, administration of thymidine protects both normal and cancer cells, but 5-FU in cancer cells kill them
O
FHN
O N
O
HO
2-O3POH2C dFUMP
Thymine Analogues in Cancer Therapy
Thymidine
Bromodeoxyuridine Trifluorothymidine
Purine Analogues in Cancer Therapy
Hypoxanthine
6-mercaptopurine 6-thioguanine
Purines are used as free bases or nucleosides, as nucleotides are poorly transported across the membrane.