Radical mediated ring formation in the biosynthesis of the hypermodified tRNA base wybutosine

Abstract

Wyosine and its derivatives are highly modified, acid labile tricyclic bases found at position 37 of tRNA(Phe) in archaea and eukarya. The formation of the common 4-demethylwyosine structural feature entails condensation of pyruvate and N-methylguanosine catalyzed by TYW1. This review will focus on the mechanism of this complex radical mediated transformation.

Figure 1

Wyosine analogs and their biosynthesis. The figure shows structures of representative wybutosine analogs (A) and the biosynthetic pathway to wybutosine from GTP (B).

Figure 2

Reductive cleavage of SAM by radical SAM enzymes. 5□-Deoxyadenosyl radical generated from reductive cleavage of SAM abstracts a hydrogen atom to initiate chemistry.

Figure 3

Mechanistic proposal for catalysis by TYW1. This mechanistic proposal is adapted from Young et al. [18] and involves covalent catalysis and proposes a redox role for the auxiliary cluster.

FIgure 4

Alternative mechanistic proposal for TYW1. This mechanistic proposal was adapted from Perche-Letuvee et al. [19] and proposes a role for the auxiliary cluster in promoting aromatization.