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Fe/Mn Swap in Dioxygenase Active Sites

Recent research from the group of Professor Lawrence Que.

In work that appears in the May 27, 2008 issue of Proceedings of the National Academy of Sciences USA (Proc. Natl. Acad. Sci. USA 2008, 105, 7347-7352), postdoctoral associates Joseph Emerson and Elena Kovaleva, together with graduate student Erik Farquhar, in the groups of Profs. Larry Que and John Lipscomb report the surprising observation that the metal centers of a pair of iron- and manganese-dependent dioxygenases, namely Fe-HPCD and Mn-MndD, can be swapped without affecting the catalytic parameters of these enzymes. Both enzymes catalyze the activation of dioxygen to cleave the C2-C3 bond of 3,4-dihydroxyphenylacetate.

Fe-HPCD and Mn-MndD are respectively found in Brevibacterium fuscum and Arthrobacter globiformis CM-2 and have been cloned and over-expressed in E. coli. The two enzymes share >80% sequence identity and have crystal structures that show nearly superimposable active sites. Growth of the E. coli cells with the desired metal ion present in excess allowed the isolation of Fe-MndD and Mn-HPCD, enzymes with the non-native metal ion in the respective active sites. Interestingly, all four enzyme preparations exhibited very similar KM and Vmax values, representing the first pair of structurally characterized metalloenzymes that activate O2 and remain fully active even after a metal swap. The near-superimposability of the two active sites suggests that the protein environment does not tune the dramatically different redox properties of Fe and Mn to achieve a common redox potential to carry out oxygen activation. This remarkable observation leads us to conclude that an integral redox change at the metal, specifically M(II) to M(III), is not an essential feature of the catalytic mechanism, making this pair of enzymes an exception to the widely accepted paradigm for oxygen activation at transition metal centers.

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