Nucleotide Structure

SugarsSugar + base = nucleoside

Bases

Sugar + base + phosphate(s) = nucleotide

Nucleotide Structure

De Novo Purine Nucleotide Synthesis

• Begin with ribose 5-phosphate• Base constructed by series of reactions that contribute

carbon and nitrogen atoms

Synthesis Of PRPP

• PRPP synthetase adds pyrophosphate to ribose 5-phosphate• PRPP involved in pyrimidine synthesis and salvage pathways• Inhibited by AMP, GMP, IMP

• IMP is “parent” purine• Committed step:

– glutamine:PRPP amidotransferase

– Inhibited by AMP, GMP, IMP

• Inhibitors of IMP synthesis

– Folic acid analogs– Sulfonamides

Synthesis Of IMP

IMP To AMP And GMP

• Each conversion by a different two step pathway• End product of each pathway inhibits first reaction• AMP synthesis requires GTP; GMP synthesis requires ATP

NMPs To NDPs And NTPs

• NMPs → NDPs by different base-specific kinases (adenylate kinase, guanylate kinase, etc.)

• NDPs → NTPs by nucleoside diphosphate kinase• ATP is source of transferred phosphate

•Purines reconverted to nucleotides•Base added to PPRP by APRT or by HGPRT

Salvage Pathway For Purines

Degradation Of Purine Nucleotides

• Guanosine- remove sugar, deaminate, oxidize to uric acid• Adenosine- deaminate, remove sugar, oxidize to xanthine then uric acid

Gout

• Hyperuricemia can cause uric acid crystals to form in joints

• Contributing factors– certain inherited metabolic disorders– diet rich in meat and seafood– chronic kidney disease– cancers that cause abnormal cell turnover– chemotherapy treatments that cause rapid cell death

• Treatment with allopurinol

Adenosine Deaminase Deficiency

• Severe combined immunodeficiency involving T and B cells

• Buildup of deoxyadenosine, which leads to buildup of dATP

• dATP inhibits ribonucleotide reductase, DNA synthesis

Pyrimidine Synthesis

• Base made first and then added to sugar• Base constructed by reactions that

contribute carbon and nitrogen atoms

Synthesis Of OMP & UMP

• Committed step- CPS II, inhibited by UTP, activated by ATP & PPRP• Synthesis of orate “parent” pyrimidine & addition to PRPP

UTP To CTP

• Amination of UTP

NDPs To dNDPs

• Reduction of nucleoside diphosphates to deoxy forms• Catalyzed by ribonucleotide reductase; dNTPs inhibit• Thioredoxin coenzyme serves as hydrogen donor

dUMP To dTMP

• Thymidylate synthase catalyzes methylation of dUMP• N5,N10-methylene THF contributes methyl group