General Iron-Sulfur Reactions:
                           How the metal cluster interfaces with the SAM molecule

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Cheek, J. & Broderick, J. B. (2001). J Biol Inorg Chem. 6, 209

 

Iron-Sulfur Clusters and Electron Transfer:

To form the catalytically important 5’deoxyadenosyl radical, SAM must be reduced by one electron which is supplied by the [4Fe-4S]+ cluster in radical SAM enzymes. However, the addition of an electron to the sulfonium group of group of SAM yields a mechanistic problem and a large energy barrier due to the ideal gas configuration of sulfur.

                                                                      

 

Text Box: This large energy difference must be lowered. The mechanism of electron transfer and reductive cleavage lowers this energetic barrier.                  
                   Duschene, Veneziano, Silver & Broderick. (2009). Current Opinion of Chemical Biology. 13(1), 74.

 

The Sulfonium sulfur of SAM has orbital overlap with the cluster. This orbital overlap has been proposed to occur via a bridging sulfide of the cluster and provides a likely pathway for inner sphere electron transfer from the cluster to SAM to initiate radical cleavage.

 
The Site Differentiated Iron Cluster:

 

 

Amino Nitrogen and carboxylate oxygen chelated coordination serves as an anchor to position the SAM for reaction

 
           
Layer, G., Heinz, D. W., Jahn, D. & Schubert, W. (2004). Current Opinion in Chemical Biology, 8, 468.

The Fe-S cluster – SAM Mechanism:


*Depends on the direct ligation of SAM to the 4Fe-4S cluster through the carboxylate and the amino group and on inner sphere electron transfer from the [4Fe-4S]+  cluster to the sulfonium group concomitant with the homolytic cleavage of the adenosyl-C5’-S bond*

                                           
                                Duschene, Veneziano, Silver & Broderick. (2009). Current Opinion of Chemical Biology. 13(1), 74.

To Summarize the Mechanism:

                                                     

                                       
                                                        Adapted from: Roje, S. (2006). Phytochemistry, 67, 1686

The reductive cleavage of SAM, facilitated by the 4Fe-4S cluster, generates a catalytically essential 5’deoxyadenosyl radical intermediate, which is then used to abstract a hydrogen atom from an appropriately near-by substrate. This is what ultimately drives the radical SAM mechanism, and also what allows the class of enzymes to catalyze such a variety of reactions.

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