Extreme longevity of a diiron(III)-peroxo intermediate in DOHH, an oxygenase involved in hypusination (Póster)

ZHENGGANG HAN; NAOKI SAKAI; LARS BOETTGER; SEBASTIÁN KLINKE; ALFRED TRAUTWEIN; ROLF HILGENFELD

Göttingen

Congreso; 23rd Annual Conference of the German Crystallographic Society; 2015

German Crystallographic Society

Deoxyhypusine hydroxylase (DOHH) is a non-heme diiron enzyme involved in the posttranslational modification of a critical lysine residue of eukaryotic translation initiation factor 5A (eIF-5A), to yield the unusual amino-acid residue hypusine. This modification is essential for the role of elF-5A in translation and nuclear export of a group of specific mRNAs. Human DOHH (hDOHH) is a potential drug target for the treatment of HIV/AIDS, chronic myeloid leukemia, and diabetes. The diiron center of hDOHH forms an intermediate species, peroxo-diiron(III), when its reduced form is activated by exogenous oxygen. The peroxo-diiron(III) intermediate in hDOHH has a lifetime exceeding that of other diiron enzymes by several orders of magnitude. Here we report the crystal structure of hDOHH, determined in two forms, the peroxo-diiron (III) intermediate and a complex with the product analogue glycerol, both of them at 1.7 Angstroms. The structure of the intermediate reveals the presence of a mu-1,2-peroxo-diiron(III) species at the active site. The crystal structures offer explanations for the extreme longevity of the peroxo-diiron(III) intermediate in hDOHH and illustrate how the enzyme specifically recognizes its only substrate, deoxyhypusine-eIF-5A.