Hydroxyurea in the treatment of Leukemia

Case details

A physician evaluates a 32-year-old patient for fatigue. The patient is found to have an elevated white blood cell count and an enlarged spleen. A referral to an oncologist results in a diagnosis of chronic myelogenous leukemia. Treatment with hydroxyurea, a ribonucleotide reductase inhibitor is begun. The normal functioning of this enzyme is to do which of the following?

A. Converts xanthine to uric acid

B. Converts ribonucleotides to deoxyribonucleotides

C. Degrades guanine to xanthine

D. Degrades AMP to IMP

E. Converts PRPP to phosphoribosylamine

 

The correct answer is- B- Converts ribonucleotides to deoxyribonucleotides.

Either hydroxyurea or Busulfan as single agents can provide hematological control in the majority of patients (> 75%) with chronic phase CML. Hydroxyurea is also approved for use in the treatment of melanoma and recurrent, metastatic, or inoperable carcinoma of the ovary. It is also recommended as a treatment for sickle-cell disease.

Hydroxyurea is a ribonucleotide reductase inhibitor. Ribonucleotide reductase is essential for deoxyribonucleic acid (DNA) synthesis, and its inhibition by hydroxyurea results in S-phase cell cycle arrest. Other mechanisms may be responsible for the fact that this drug acts as a radiation sensitizer, inhibiting the repair of damaged DNA.

The efficacy of hydroxyurea in the treatment of sickle-cell disease is generally attributed to its ability to boost the levels of fetal hemoglobin (Hb F, α2γ2). This lowers the concentration of Hb S within a cell resulting in less polymerization of the abnormal hemoglobin.

Ribonucleotide reductase

The reduction of the 2′-hydroxyl of purine and pyrimidine ribonucleotides to deoxyribonucleoside diphosphates (dNDPs) is catalyzed by ribonucleotide reductase enzyme complex. This is the rate-limiting step of DNA biosynthesis.

Ribonucleotide reductase is a multi subunit enzyme having each of two identical B1 and B2 subunits (figure-1).

Ribonucleotide reductase Structure

Figure-1- Ribonucleotide reductase enzyme; the activity and substrate sites are for the regulation of enzyme activity

ADP, GDP, CDP and UDP are converted to dADP, d GDP, d CDP and dUDP (their deoxy forms) respectively as a result of its action.

Reaction catalyzed can be represented as follows:

Ribonucleotide reductase

Figure-2- The reaction catalyzed by Ribonucleotide reductase; he enzyme complex requires reduced Thioredoxin for its action.

The immediate donors of the hydrogen atoms needed for the reduction of the 2′- hydroxyl are two sulfhydryl groups on the enzyme itself, which, during the reaction form a disulphide bond.

In order for the enzyme to continue its action, the disulphide bond created during the process of catalysis must be reduced back. The process of reduction is carried out by Thioredoxin, a peptide coenzyme of Ribonucleotide reductase. Thioredoxin contains two cysteine residues separated by two amino acids in the peptide chain. These two sulfhydryl groups of Thioredoxin donate their hydrogen atoms to ribonucleotide reductase, in the process forming a disulfide bond. The reduction of Thioredoxin itself is carried out by Thioredoxin reductase. The necessary reducing equivalents are provided by NADPH+H+ (Figure-2).

Regulation of Ribonucleotide reductase

Reduction of Ribonucleoside diphosphates (NDPs) to deoxyribonucleoside diphosphates (dNDPs) is subjected to complex regulatory controls that achieve balanced production of deoxyribonucleotides for synthesis of DNA. The enzyme has an active site and additionally possesses two allosteric sites. The regulation at these sites can be explained as follows:

  1. Activity site- The binding of ATP increases the net rate, whereas d ATP binding to this allosteric site inhibits the overall catalytic activity of the enzyme, thus the reduction of all the ribonucleotides is inhibited. This effectively prevents DNA synthesis.

Clinical significance– In “Adenosine deaminase” deficiency, DNA synthesis is inhibited due to inhibition of Ribonucleotide reductase by excess dATP. The impact is mainly observed in the rapidly dividing cells; especially the proliferation of B and T lymphocytes is inhibited; which is one of the reasons for reduced immunity in the affected patients.

  1. Substrate specific site- The binding of specific nucleoside triphosphates to substrate specific site regulates substrates specificity causing an increase in the conversion of specific ribonucleotides to deoxy ribonucleotides as required for DNA synthesis.

As regards other options

A. Converts xanthine to uric acid- This is incorrect; this conversion is carried out by Xanthine oxidase.

C. Degrades guanine to xanthine- The degradation of guanine to xanthine is carried out by Guanase.

D. Degrades AMP to IMP- this specific reaction is carried out by AMP deaminase.

E. Converts PRPP to phosphoribosylamine- This is also an incorrect answer, since the reaction is catalyzed by Amido transferase, the second step of de novo synthesis of purine nucleotides.

Thus B- Conversion of Ribonucleotides to deoxyribonucleotide carried out by Ribonucleotide reductase is the correct answer.

 

 

 

 

 

 

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