The generation of the S configuration at C7 is well explained by the preference of CrISY to transfer a hydride from the pro-S face to 8-oxogeranial, as demonstrated in biochemical assays (11), and can be structurally rationalized by the crystal structure of the enzyme bound to a geranic acid inhibitor (25). We hypothesize that the active site residues of AmISY are at least partially responsible for binding the 8-oxogeranial substrate in the opposite orientation (Fig. 4), thereby changing the stereochemistry of hydride addition to generate the R stereocenter. The newly discovered R-selective cyclization by AmISY may offer valuable biocatalytic access to a larger range of poorly accessible iridodial- and nepetalactol-related synthons (32).