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A human diiron enzyme that controls cell growth

Recent research from the research group of Professor Lawrence Que.

Deoxyhypusine hydroxylase (DOHH) is an iron-requiring enzyme that catalyzes the hydroxylation of a deoxyhypusine residue in the final step of the maturation of eukaryotic translation initiation factor 5A (eIF5A). This transformation plays an essential role in the regulation of eukaryotic cell proliferation, making DOHH an attractive target for anti-tumor and anti-HIV therapies. However, little is known of the details of its iron active site and reaction mechanism.

In a paper that has just appeared in Proceedings of the National Academy of Sciences USA (PNAS 2009, 106,14814-14819; doi:10.1073/pnas.0904553106), graduate student Van Vu and collaborators at Carnegie Mellon University and the National Institutes of Health report studies on the recombinant human enzyme (hDOHH) and find that hDOHH has a non-heme diiron cluster in its active site. While similar active sites have been found in other O2-activating non-heme diiron enzymes, including methane monooxygenases from bacteria and fatty acid desaturases from plants, hDOHH represents the first human hydroxylase demonstrated to have such an active site. Thus the diiron motif is a recurring strategy Nature employs to activate O2 in order to attack strong C-H bonds, even in mammals.

Surprisingly, as isolated hDOHH has an unusual blue color that persists at room temperature for several days. Spectroscopic studies show that this chromophore arises from an unusually stable diiron-O2 adduct. For comparison, O2 adducts of related diiron enzymes are more reactive and can have lifetimes as short as milliseconds. Nevertheless, as isolated hDOHH can in fact carry out the hydroxylation of the deoxyhypusine residue in eIF5A. Future efforts are aimed at understanding why this peroxo species is stable and how it becomes activated, thereby providing further insight into the oxygen activation mechanisms of the non-heme diiron enzyme family.


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