Biosynthetic Advance is Monthly Publication Highlight

Aug 28, 2013

The research described in August’s COP Publication Highlight entitled, “Structural and Functional Characterization of CalS11, a TDP-rhamnose 3'-O-methyltransferase Involved in Calicheamicin Biosynthesis” and was published in ACS Chemical Biology, and details the study of a representative ‘decorative’ or ‘tailoring’ enzyme CalS11 – a methyltransferase that decorates the anticancer natural product calicheamicin (the warhead for the first clinically-approved antibody-drug conjugate).

Subtle chemical decorations of drugs that derive from nature can dramatically influence their pharmaceutical properties yet, such decorations are often difficult to achieve due to the technical challenges associated with the chemical modification of complex natural products. One alternative to a classical synthetic chemistry approach is to harness enzymes involved in decorating natural products. Methyltransferases modify many biomolecules (nucleic acids, proteins, lipids) and small molecules and, in the context of natural products, methylation can improve a natural product’s therapeutic activity or be invoked as a resistance mechanism. CalS11 is a sugar O-methyltransferase, and the sugar O-methyltransferases studied to date all act upon a sugar, after the sugar has been attached to a complex natural product (a process known as glycosylation). Though researchers hypothesized that some sugar O-methyltransferases could act prior to the glycosylation step, the current study is the first confirmation of this phenomenon and therefore presents a validated catalyst prototype for the field. It turns out that CalS11 is also structurally unique as it is the first methyltransferase found to adopt an unusual decameric quaternary structure. The research described in this month’s publication highlight on the published CalS11 structural/functional studies set the stage for future studies to engineer alterative methyl decorations in the context of calicheamicin, as well as many other pharmaceutically-active natural products.

Authors of the study include Shanteri Singh and Jon S. Thorson, UK College of Pharmacy CPRI and Pharmaceutical Sciences faculty members; Aram Chang and Kate E. Helmich, graduate students at the University of Wisconsin; Craig A. Bingman, Russell L. Wrobel,Emily T. Beebe, Shin-ichi Makino, and David J. Aceti, staff scientists at the University of Wisconsin; Kevin Dyer and Greg L. Hura, staff scientists at the Lawrence Berkeley National Laboratory; Manjula Sunkara, staff scientist at the University of Kentucky Department of Cardiovascular Medicine; Andrew J. Morris, faculty member at the UK Department of Cardiovascular Medicine; and George N. Phillips, Jr., a faculty member at Rice University.

This work was supported by a grant from the National Cancer Institute (NCI RO1 CA84374) and the NatPro initiative – a National Institute of General Medical Sciences (NIGMS)-funded Protein Structure Initiative (NIGMS U01 GM098248) focused upon natural product biosynthetic enzymes. Professor George Phillips, Jr. is the lead PI of the NatPro initiative and Professors Singh and Thorson are founding members of NatPro along with Professors Michael Thomas and Craig Bingman (University of Wisconsin-Madison) and Professor Ben Shen (Scripps Florida). UK’s role in this large collaborative effort is to nominate novel enzyme targets for structure elucidation by NatPro and to use the structural information revealed via NatPro to guide further biochemical and enzyme engineering studies - ultimately to enable chemoenzymatic strategies to produce new natural products with pharmaceutical potential.

“This project from the College’s Center for Pharmaceutical Research and Innovation is a notable advance in the field of natural product biosynthesis and engineering and represents a new catalyst prototype for the field,” said Linda Dwoskin, Associate Dean for Research for the UK College of Pharmacy. “This study reveals a unique higher order assembly for an important and ubiquitous enzyme family, and the work will be appreciated by a broad readership spanning the chemistry/biology interface. I applaud this outstanding collaborative team for their work and look forward to results of future research that stems from this finding.”

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