Katherine Bauman

All Publications

• Enzymatic assembly of the salinosporamide gamma-lactam-beta-lactone anticancer warhead NATURE CHEMICAL BIOLOGY Bauman, K. D., Shende, V. V., Chen, P., Trivella, D. B., Gulder, T. M., Vellalath, S., Romo, D., Moore, B. S. 2022; 18 (5): 538-+

  Abstract

  The marine microbial natural product salinosporamide A (marizomib) is a potent proteasome inhibitor currently in clinical trials for the treatment of brain cancer. Salinosporamide A is characterized by a complex and densely functionalized γ-lactam-β-lactone bicyclic warhead, the assembly of which has long remained a biosynthetic mystery. Here, we report an enzymatic route to the salinosporamide core catalyzed by a standalone ketosynthase (KS), SalC. Chemoenzymatic synthesis of carrier protein-tethered substrates, as well as intact proteomics, allowed us to probe the reactivity of SalC and understand its role as an intramolecular aldolase/β-lactone synthase with roles in both transacylation and bond-forming reactions. Additionally, we present the 2.85-Å SalC crystal structure that, combined with site-directed mutagenesis, allowed us to propose a bicyclization reaction mechanism. This work challenges our current understanding of the role of KS enzymes and establishes a basis for future efforts toward streamlined production of a clinically relevant chemotherapeutic.

  View details for DOI 10.1038/s41589-022-00993-w

  View details for Web of Science ID 000771331800002

  View details for PubMedID 35314816

  View details for PubMedCentralID PMC9058210

• Genome mining methods to discover bioactive natural products NATURAL PRODUCT REPORTS Bauman, K. D., Butler, K. S., Moore, B. S., Chekan, J. R. 2021; 38 (11): 2100-2129

  Abstract

  Covering: 2016 to 2021With genetic information available for hundreds of thousands of organisms in publicly accessible databases, scientists have an unprecedented opportunity to meticulously survey the diversity and inner workings of life. The natural product research community has harnessed this breadth of sequence information to mine microbes, plants, and animals for biosynthetic enzymes capable of producing bioactive compounds. Several orthogonal genome mining strategies have been developed in recent years to target specific chemical features or biological properties of bioactive molecules using biosynthetic, resistance, or transporter proteins. These "biosynthetic hooks" allow researchers to query for biosynthetic gene clusters with a high probability of encoding previously undiscovered, bioactive compounds. This review highlights recent case studies that feature orthogonal approaches that exploit genomic information to specifically discover bioactive natural products and their gene clusters.

  View details for DOI 10.1039/d1np00032b

  View details for Web of Science ID 000714388100001

  View details for PubMedID 34734626

  View details for PubMedCentralID PMC8597713

• Refactoring the Cryptic Streptophenazine Biosynthetic Gene Cluster Unites Phenazine, Polyketide, and Nonribosomal Peptide Biochemistry CELL CHEMICAL BIOLOGY Bauman, K. D., Li, J., Murata, K., Mantovani, S. M., Dahesh, S., Nizet, V., Luhavaya, H., Moore, B. S. 2019; 26 (5): 724-+

  Abstract

  The disconnect between the genomic prediction of secondary metabolite biosynthetic potential and the observed laboratory production profile of microorganisms is well documented. While heterologous expression of biosynthetic gene clusters (BGCs) is often seen as a potential solution to bridge this gap, it is not immune to many challenges including impaired regulation, the inability to recruit essential building blocks, and transcriptional and/or translational silence of the biosynthetic genes. Here we report the discovery, cloning, refactoring, and heterologous expression of a cryptic hybrid phenazine-type BGC (spz) from the marine actinomycete Streptomyces sp. CNB-091. Overexpression of the engineered spz pathway resulted in increased production and chemical diversity of phenazine natural products belonging to the streptophenazine family, including bioactive members containing an unprecedented N-formylglycine attachment. An atypical discrete adenylation enzyme in the spz cluster is required to introduce the formylglycine moiety and represents a phylogenetically distinct class of adenylation proteins.

  View details for DOI 10.1016/j.chembiol.2019.02.004

  View details for Web of Science ID 000468134800014

  View details for PubMedID 30853419

  View details for PubMedCentralID PMC6525064