Ribonucleotide reductase catalytic cycle

When induced in macrophages, iNOS produces large amounts of NO which represents a major cytotoxic principle of those cells. Due to its affinity to protein-bound iron, NO can inhibit a number of key enzymes that contain iron in their catalytic centers. These include ribonucleotide reductase (rate-limiting in DNA replication), iron-sulfur cluster-dependent enzymes (complex I and II) involved in mitochondrial electron transport and cis-aconitase in the citric acid cycle. In addition, higher concentrations of NO,... 

Bollinger, J. M., Krehs, C., Vicol, A., Chen, S. X., Ley, B. A., Edmondson, D. E., and Huynh, B. H., 1998, Engineering the diiron site of Escherichia coli ribonucleotide reductase protein R2 to accumulate an intermediate similar to H-peroxo, the putative peroxodiiron(III) complex from the methane monooxygenase catalytic cycle. J. Am. Chem. Soc. 120 1094nl095. 

Cisplatin reacts with nucleosides and nucleic acids and can cross-link cellular DNA. The effects on cross-linking with DNA appear to differ among cell type however, the effects on cross-linking are most pronounced during the S-phase of the cell cycle. In addition, cisplatin inhibits a number of enzymes that contain a catalytically active sulfydryl group. Ribonucleotide reductase is extremely sensitive to the effects of cisplatin, with greater than 90% inhibition observed in vitro in the presence of a two-molar excess of cisplatin. The inhibition was nearly instantaneous and was irreversible. 

Biomimetic studies are currently focused on generating diiron complexes that can serve as structural and/or electronic models for oxidation states higher than Fe " that are proposed to partake in the catalytic cycles of diiron proteins such as methane monooxygenase and ribonucleotide reductase. Mossbauer spectroscopy has played a leading role in the eharacterization... 

Figure 23. Proposed catalytic cycle for ribonucleotide reductase from Chlamydia trachomatis. High-valent iron oxygen intermediate X is shown in step III. Reprinted with permission from [306]. Copyright 2006, National Academy of Sciences, USA.

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