Ribonucleotide Reductase

Ribonucleotide reductase is the enzyme that catalyzes synthesis of deoxyribonucleoside diphophosphates (dNDPs) from ribonucleoside diphosphates (rNDPs). Ribonucleotide reductase reduces the hydroxyl at carbon 2 of the ribose sugar in the rNDP to a hydrogen, forming a deoxyribose sugar and a corresponding dNDP. A free-radical mechanism is involved in the reaction. Three classes of ribonucleotide reductases are known.

> Class I Ribonucleotide Reductases - The most widely distributed form of ribonucleotide reductase. It acts upon ribonucleoside diphosphates. The enzyme generates a free radical on a tyrosine residue, with the aid of a diferric oxygen bridge.

> Class II Ribonucleotide Reductases - Found in cyanobacteria, some bacteria, and Euglena. The enzyme acts on ribonucleoside triphosphate substrates. It uses adenosylcobalamin, a B 12 coenzyme to generate a free radical.

> Class III Ribonucleotide Reductases - Found only in facultative or obligate anaerobes. The enzyme acts on ribonucleoside triphosphate substrates. It uses S-adenosylmethionine and an iron-sulfur center to generate the catalytically essential radical on a glycine residue.

The most common form of ribonucleotide reductase (Class I) is an 2 2 dimer. The structure of the E. coli enzyme is shown in Figure 22.13. The two subunits form the large subunit of the protein called R1. It contains the active site. The two subunits make up the small subunit of the protein called R2, which contains the free radical. A clue to the mechanism of action of the enzyme (tyrosine free radical) is shown in Figure 22.14. Hydroxyurea, an inhibitor of ribonucleotide reductase, destroys the free radical.

A proposed mechanism of action of ribonucleotide reductase is shown in Figure 22.15. Reduction of the ribonucleotides requires electrons. These ultimately come from NADPH and are delivered to ribonucleotide reductase by either thioredoxin or glutaredoxin, as shown in Figure 22.16. Evidence exists for a possible third electron carrier in E. coli. Some of the interesting biological activities of thioredoxin are listed in Table 22.1.

See also: Regulation of Ribonucleotide Reductase, Ribonucleotide Reductase and Deoxyribonucleotide Biosynthesis

INTERNET LINK: Ribonucleotide Reductase R2 Structure