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Metabolism of Nucleotides and Nucleic acids - Coggle Diagram
Metabolism of Nucleotides and Nucleic acids
Ribonucleotides Are Precursors to Deoxyribonucleotides
2'C-OH bond is directly reduced to 2'-H bond... without activating the carbon!
Two H atoms are donated by NADPH and carried by proteins thioredoxin or glutaredoxin.
dTMP Is Made from dUTP
Roundabout pathway
dUTP is made.
dUTP to dUMP by dUTPase
d UMP dTMP by thymidylate synthase
adds a methyl group from tetrahydrofolate
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Thymidylate synthase is a target for some anticancer drugs.
Conversion of dUMP to dTMP by Thymidylate Synthase
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Regulation of Ribonucleotide Reductase by dNTPs
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Ribonucleotide Reductase Has Two Types of Regulatory Sites
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Nucleotide Biosynthesis
• Nucleotides can be synthesized de novo ("from the beginning") from amino acids,ribose-5-phosphate,CO2 and NH3
• Nucleotides can be salvaged from RNA, DNA, and cofactor degradation.
• Many parasites (e.g., malaria) lack de novo biosynthesis pathways and rely exclusively on salvage.
Compounds that inhibit salvage pathways are promising antiparasite drugs.
De Novo Biosynthesis of Purines Begins with PRPP
Adenine and guanine are synthesized as AMP and GMP.
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Synthesis begins with reaction of 5-phosphoribosyl 1- pyrophosphate (PRPP) with Glu.
Purine ring builds up following the addition of three carbons from glycine.
The first intermediate with a full purine ring is inosinate (IMP).
2-5
Regulation
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De Novo Synthesis of Pyrimidine Nucleotides
pyrimidine synthesis proceeds by first making the pyrimidine ring (in the form of orotate) and then attaching it to ribose 5-phosphate.
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After addition of ribose-5-phosphate via PRPP, the resulting (orotidylate) nucleotide is decarborylated to form uridylate (UMP), the first possible pyrimidine.
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UMP is phosphorylated to UTP.
After formation of UTP, amination can convert UTP to CTP.
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Regulation of Pyrimidine Biosynthesis Is Also via Feedback Inhibition
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Ribonucleotide Reductase
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De Novo Biosynthesis of Nucleotides
Bases synthesized while attached to ribose
1
Glu provides most amino groups.
Gly is precursor for purines
Asp is precursor for pyrimidines
Nucleotide pools are kept low, so cells must continually synthesize them.
This synthesis may actually limit rates of transcription and replication.
Catabolism of Pyrimidines
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Antibiotics Also Target Nucleotide Biosynthesis
Allopurinol, and so on
studied against African sleeping sickness (trypanosomiasis)
because the trypanosomes lack enzymes for de novo nucleotide synthesis
Trimethoprim
inhibits bacterial dihydrofolate reductase but binds human enzyme several orders of magnitude less strongly
Many Chemotherapeutic Agents Target Nucleotide Biosynthesis
Glutamine analogs: azaserine, acivicin
inhibit glutamine amidotransferases
Fluorouracil
converted by salvage pathway into FdUMP, which inhibits thymidylate synthase
Methotrexate and aminopterin
inhibit dihydrofolate reductase (competitive inhibitors)
Folic Acid Deficiency Leads to Reduced Thymidylate Synthesis
• Folic acid deficiency is widespread, especially in nutritionally poor populations.
• Reduced thymidylate synthesis causes uracil to be incorporated into DNA.
• Repair mechanisms remove the uracil by creating strand breaks that affect the structure and function of DNA.
Conversion of Uric Acid to Allantoin, Allantoate, and Urea
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Purine and Pyrimidine Bases Are Recycled by Salvage Pathways
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Excess Uric Acid Seen in Gout
Painful joints (often in toes) due to deposits of sodium urate crystals
Primarily affects males
May involve genetic under-excretion of urate and/or may involve overconsumption of fructose
Treated with avoidance of purine-rich foods (seafood, liver) or avoidance of fructose
Also treated with xanthine oxidase inhibitor allopurinol
Catabolism of Purines
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