Two observations support this scenario. First, the cyclization step is not only relatively poorly controlled, but the product ratio is also insensitive to mutations with large impact on the overall NADPH consumption rate (see the supplemental information of Ref. 25). Second, the enantiomeric enolate intermediates produced by CrISY and AmISY (Fig. 1) constitute a sensitive probe for the environment in which cyclization happens. Any selectivity imposed on the cyclization by a chiral protein binding pocket would be highly unlikely to affect these enantiomeric enolates and the transition states for the observed product range in the same fashion. However, the products of both CrISY and AmISY appear to be exact mirror images, as shown by the superimposable achiral GC-MS chromatograms and CD signals of opposite sign.