Biosynthesis of DNA precursors in anaerobic organisms : iron, S-adenosylmethionine and free radicals

The importance of oxygen for class I ribonucleotide reductase, and therefore for DNA synthesis, led us in 1988 to address the never-before-studied question of deoxyribonucleotide biosynthesis in living organisms growing in strictly anaerobic conditions. This work led to the isolation of a new ribonucleotide reductase (known as class III), which has been almost completely characterized. Its structural and chemical properties are unique and were presented during this lesson. The ribonucleotide reductase itself is a dimer containing an extremely oxygen-sensitive glycinyl radical, essential for enzymatic activity as it enables radical activation of the ribose moiety of the substrate. This radical character brings it into line with class I RNR. Like Class I RNR, it is subject to complex allosteric regulation, involving deoxyribonucleotides and ATP. A second subunit, also essential because its role is to catalyze the formation of the glycinyl radical, comprises a [4Fe-4s] cluster chelated by 3 cysteines, in a CXXXCXXC sequence, and with an iron atom complexed by S-adenosylmethionine (SAM). It is now well established that this association leads, in the presence of an electron source, to the decomposition of SAM into methionine, on the one hand, and the 5'-deoxyadenosyl radical, on the other, which uses its powerful oxidizing power to strip a hydrogen atom from the glycine of the RNR to form the glycinyl radical.