Figure 6 Structure comparison of SrCYP76AK6-8 andSmCYP76AK1 reveals the  divergent evolution.
a Downstream pathway of carnosol and tanshinone biosynthesis, starting from geranylgeranyl diphosphate. Immediate are shown in structure and labeled by bold. Enzymes involved in each step are labeled by italic. The divergence of carnosol and tanshinone biosynthesis start from 11-hydroxy-ferruginol. CYP76AK6-8 catalyze 11-hydroxy-ferruginol and synthesize carnosol precursors in S. rosmarinus , which is colored by pink block. CYP76AK1 synthesize tanshinone precursors in S. miltiorrhiza . Dotted arrows indicate omitted reaction. b Homology modeling and docking analysis ofSrCYP76AK6-8 and SmCYP76AK1 from S. rosmarinus andS. miltiorrhiza . a Homology modeling ofSrCYP76AK6-1 . Docking poses of SrCYP76AK7-1 b ,SrCYP76AK5-2 c , SrCYP76AK7-2 (d),SrCYP76AK6-2 (e), SrCYP76AK6-3 (f), SmCYP76AK1 (g). Compound structure is depicted as stick with carbons colored pink and oxygens red. Heme is depicted as stick with carbons colored yellow and iron blue. Distance between C-20 and heme iron is indicated by dashed line with the length indicated in Å. c Residues within 8 Å around docking sites of SrCYP76AKs , which are different fromSmCYP76AK1 . a Residues pose of SmCYP76AK1 in pink color and ligand 11-hydroxy-ferruginol in white. Residues pose ofSrCYP76AK5-2 in blue color b , SrCYP76AK6-1 in yellow c , SrCYP76AK6-2 in green (d). Residues in active pocket are shown in sticks, with oxygen atom in red, hydrogen in white and nitrogen atom in blue. Ligand 11-hydroxy-ferruginol is shown in white sticks. d The expression of SrCYP76AKs andSmCYP76AK1 in roots and leaves. Red, high expression; blue, low expression. Genes are labeled in italic which are shown based on functionally annotation in bold. Genes of S. rosmarinus are marked in green and genes of S. miltiorrhiza are marked in orange. e Syntenic blocks of CYP76AK regions within S. rosmarinus, S. miltorrhiza  and S. splendens . Green curves represent the colinearity of CYP76AKs.SrCYP76AK5-8 in S. rosmarinus can be linked toSmCYP76AK1 in S. miltiorrhiza through SsCYP76AK7 inS. splendens , which provide evidence for the evolutionary ofCYP76AK subfamily.