9ICZ

C-Methyltransferase SeMT from Saccharopolyspora erythraea

Summary for 9ICZ

• Entry DOI: 10.2210/pdb9icz/pdb
• Descriptor: S-adenosylmethionine (SAM)-dependent methyltransferase, UNKNOWN LIGAND, SULFATE ION, ... (5 entities in total)
• Functional Keywords: methyl transfer, rossmann fold, s-adenosyl methionine, transferase
• Biological source: Saccharopolyspora erythraea
• Total number of polymer chains: 2
• Total formula weight: 64685.51

Authors

Weiergraeber, O.H.,Haase, M.,Pietruszka, J. (deposition date: 2025-02-14, release date: 2025-12-10)

Primary citation

Haase, M.,Weiergraber, O.H.,Pietruszka, J.
Re-engineering a transferase scaffold for indole C3 methylation in diketopiperazines.
Protein Sci., 34:e70254-e70254, 2025

PubMed Abstract: The pyrroloindole (hexahydropyrrolo[2,3-b]indole, HPI) structural motif is present in a wide range of natural products with various biological activities, yet its chemical synthesis poses a challenge, particularly regarding methylation at the indole C3 position. In nature, S-adenosyl methionine (SAM)-dependent methyltransferases efficiently catalyze this reaction with high stereoselectivity. This study presents the investigation and rational re-design of a potential methyltransferase, termed SeMT, from the actinomycete Saccharopolyspora erythraea. While its three-dimensional structure elucidated via X-ray crystallography confirmed extensive structural similarity to cyclic dipeptide-processing methyltransferases such as SgMT, its putative catalytic center is clearly divergent. Accordingly, wild-type SeMT displayed minimal activity with diketopiperazine (DKP) substrates, triggering an extensive mutagenesis effort aimed at iteratively enhancing this methyltransferase function. This work yielded a variant with appreciable activity, which was comprehensively characterized. Notably, a specific mutation within the catalytic triad of SeMT proved critical not only for its own function but also for the temperature-activity profile of its homolog protein SgMT. Beyond the specific properties of SeMT, these findings hence provide important insights into the active center architecture of indole C3-methyltransferases, supporting further development of these enzymes into refined biocatalysts for synthetic applications.

PubMed: 40878043
DOI: 10.1002/pro.70254

Experimental method

X-RAY DIFFRACTION (1.58 Å)