Lecture 29: Nucleotides

Question 1

Basic nucleotide structure

Answer 1

Base + ribose (or deoxyribose) + 1 or more phosphates
Nucleoside = base + sugar

Question 2

Classes of nucleotides

Answer 2

1. Purines (2 heterocyclic rings, A, G, X, HX)
2. Pyrimidines (C, U, T)

Question 3

Regulation of de novo purine biosynthesis

Answer 3

Negative feedback by purine products and their derivatives (IMP, AMP, GMP, ADP, GDP, ATP, GTP)

Question 4

Methods of purine synthesis

Answer 4

1. De novo
2. Salvage

Question 5

Regulation of pyrimidine biosynthesis

Answer 5

Activation by ATP
Negative feedback by pyrimidine products (UMP, UDP, UTP, CTP)

Question 6

Ribonucleotide reductase regulation

Answer 6

2 allosteric sites:
1. dATP binding site inhibiting overall activity
2. Control of substrate specificity for balanced deoxyribonucleotide supply; 2nd site

Question 7

Substrate specificity control of ribonucleotide reductase

Answer 7

• dATP/ATP binding → ↑UDP, CDP reduction
• dTTP bind. → ↑GDP reduction, ↓UDP, CDP reduction
• dGTP bind. → ↑ADP reduction

Question 8

Allopurinol

Answer 8

Xanthine oxidase inhibitor, used to lower uric acid levels and treat gout

Question 9

Gout

Answer 9

Precipitation of uric acid crystals causing inflammation, esp. in joints. Caused by ↑formation or ↓excretion of uric acid e.g. w/ excess purine synthesis

Question 10

Lesch-Nyhan Syndrome

Answer 10

Complete absence of HGPRT, results in gout + neuro symptoms

Question 11

Adenine phosphoribosyltransferase deficiency

Answer 11

APRT deficiency; results in 2,8-dioxyadenine stones in urine.

Question 12

Orotic acidurea

Answer 12

Pyrimidine synthesis deficiency

Question 13

Adenosine deaminase deficiency

Answer 13

Results in Severe Combined Immunodeficiency (SCID) due to defective T and B cells

Question 14

Purine nucleoside phosphorylase deficiency

Answer 14

Causes defective T cell immunity.

Question 15

Nucleotides and cancer chemotherapy

Answer 15

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

Question 16

Antiviral nucleoside analogues

Answer 16

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.