TleD is an S-adenosyl-L-methionine dependent methyltransferase and acts as one of the key enzymes in the teleocidin B biosynthesis pathway. Besides the methyl transferring, TleD also rearranges the geranyl and indole moiety of the precursor to form a six-membered ring. Moreover, it does not show homologies to any known terpenoid cyclases. In order to elucidate how such a remarkable reaction could be achieved, we determined the complex crystal structures of TleD and the cofactor analogue S-adenosyl-L-homocysteine with or without substrate teleocidin A1. A domain-swapped pattern via an additional N-terminal α-helix is observed in TleD hexamers. The structural comparison and alignment shows this additional N-terminal α-helix is the common feature of SAM-MTase-like cyclases TleD and SpnF. The residue Tyr21 anchors the additional N-terminal α-helix to "core SAM-MT fold" and is a key residue for catalytical activity. Molecular dynamic simulation results suggest that the dihedral angle C23-C24-C25-C26 of teleocidin A1 is preferred to 60° - 90° in the TleD and substrate complex structure, which tend to adopt a Re-face stereocenter at C25 position after reaction and is according to in vitro enzyme reaction experiments. Our results also demonstrate methyl transfer can be a new chemical strategy for carbocation formation in the terpene cyclization, which is the key initial step.
- terpene cyclization
- S-adenosylmethionine (SAM)
- ©2016 The Author(s)
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