A radically different enzyme

Abstract

The enzyme co-substrate S-adenosylmethionine is a potential source of two different free radicals, yet only one seemed to occur in nature. The discovery of an unusual enzyme reveals that both radicals can be formed. Diphthamide, the target of diphtheria toxin, is a post-translationally modified histidine residue in archaeal and eukaryotic translation elongation factor 2 (EF2). It has been studied for more than three decades, but some aspects of its mechanism of biosynthesis remain elusive. The process is thought to involve three steps, the first being the formation of a C–C bond between the histidine residue and the 3-amino-3-carboxypropyl group of S-adenosyl-l-methionine (SAM). A study of the archaeon Pyrococcus horikoshii now shows that in this organism at least, the first step in diphthamide biosynthesis requires an unusual iron–sulphur cluster enzyme, Dph2. Biochemical data suggest that — in contrast to the mechanism in other radical SAM enzymes — Dph2 breaks the CγMet–S bond of the SAM cofactor. The enzyme then transfers the 3-amino-3-carboxylpropyl group to EF2, possibly via a radical mechanism.