Download MendeleyCrystal structure and enantioselectivity of terpene cyclization in SAM-dependent methyltransferase TleD
Yu, F., Li, M.J., Xu, C.Y., Sun, B., Zhou, H., Wang, Z.J., Xu, Q., Xie, M.Y., Zuo, G., Huang, P., Guo, H., Wang, Q.S., He, J.H.(2016) Biochem J 473: 4385-4397
- PubMed: 27613858
- DOI: https://doi.org/10.1042/BCJ20160695
- Primary Citation of Related Structures:
5GM1, 5GM2 - PubMed Abstract:
TleD is a SAM (S-adenosyl-l-methionine)-dependent methyltransferase and acts as one of the key enzymes in the teleocidin B biosynthesis pathway. Besides methyl transferring, TleD also rearranges the geranyl and indole moieties of the precursor to form a six-membered ring. Moreover, it does not show homologies with 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 the substrate teleocidin A1. A domain-swapped pattern via an additional N-terminal α-helix is observed in TleD hexamers. Structural comparison and alignment shows that this additional N-terminal α-helix is the common feature of SAM methyltransferase-like cyclases TleD and SpnF. The residue Tyr 21 anchors the additional N-terminal α-helix to a 'core SAM-MT fold' and is a key residue for catalytic activity. Molecular dynamics 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 that methyl transfer can be a new chemical strategy for carbocation formation in the terpene cyclization, which is the key initial step.
Organizational Affiliation:
Shanghai Institute of Applied Physics, Chinese Academy of Sciences, 239 Zhang Heng Road, Pudong New District, Shanghai 201203, P.R. China.
