Lecture 29: Nucleotides Flashcards
Basic nucleotide structure
Base + ribose (or deoxyribose) + 1 or more phosphates
Nucleoside = base + sugar
Classes of nucleotides
- Purines (2 heterocyclic rings, A, G, X, HX)
- Pyrimidines (C, U, T)
Regulation of de novo purine biosynthesis
Negative feedback by purine products and their derivatives (IMP, AMP, GMP, ADP, GDP, ATP, GTP)
Methods of purine synthesis
- De novo
- Salvage
Regulation of pyrimidine biosynthesis
Activation by ATP
Negative feedback by pyrimidine products (UMP, UDP, UTP, CTP)
Ribonucleotide reductase regulation
2 allosteric sites:
1. dATP binding site inhibiting overall activity
2. Control of substrate specificity for balanced deoxyribonucleotide supply; 2nd site
Substrate specificity control of ribonucleotide reductase
- dATP/ATP binding → ↑UDP, CDP reduction
- dTTP bind. → ↑GDP reduction, ↓UDP, CDP reduction
- dGTP bind. → ↑ADP reduction
Allopurinol
Xanthine oxidase inhibitor, used to lower uric acid levels and treat gout
Gout
Precipitation of uric acid crystals causing inflammation, esp. in joints. Caused by ↑formation or ↓excretion of uric acid e.g. w/ excess purine synthesis
Lesch-Nyhan Syndrome
Complete absence of HGPRT, results in gout + neuro symptoms
Adenine phosphoribosyltransferase deficiency
APRT deficiency; results in 2,8-dioxyadenine stones in urine.
Orotic acidurea
Pyrimidine synthesis deficiency
Adenosine deaminase deficiency
Results in Severe Combined Immunodeficiency (SCID) due to defective T and B cells
Purine nucleoside phosphorylase deficiency
Causes defective T cell immunity.
Nucleotides and cancer chemotherapy
Many chemotherapies interfere w/ nucleotide synthesis:
1. Agents blocking NT biosynth. e.g. thymidylate synthase inhib. (F-dUMP)
2. Agents killing proliferating cells e.g. folate antagonists, methotrexate
3. Nucleotide analogues blocking DNA replication e.g. araC
Antiviral nucleoside analogues
These require phosphorylation to become active, allowing cellular selectivity e.g. araA to treat viral encephalitis. Act as chain terminators in DNA synthesis and compete w/ natural substrates.
