Jun 18, 2007

Combinatorial biosynthesis, but not as we know it

Combinatorial biosynthesis can be understood as a special case of metabolic engineering, where genes responsible for individual metabolic reactions from different organisms are combined to generate hybrid metabolic pathways. An ideal result consists of a genetically-modified organism (or a collection of such microorganisms) that is useful for in vivo production of novel compounds. Nevertheless, there are examples of in vitro combinatorial biosynthesis (*), such as glycorandomization (a biocatalytic technique that uses purified enzymes to activate and attach sugars to natural products).

One step beyond, a recent report in ACS Chemical Biology describes a new in vitro approach for the generation of combinatorial libraries of compounds derived from natural products. As a proof of concept, the authors combined three type-III polyketide synthases (PKSs), 16 different precursors (acyl-CoA esters) and three post-PKS tailoring enzymes. Remarkably, this strategy was adapted to a convenient microarray format (30-nanoliter reactions), to enable high-throughput synthesis. Even better, the same microarray slide was used to screen for bioactivity of the synthesized products, through an assay for inhibition of human protein kinase FynT. This approach is, therefore, potentially useful for the identification of new non-natural compounds displaying biological activities.

Reference: Kwon SJ, Lee My, Ku B, Sherman DH, Dordick JS.
High-throughput, microarray-based synthesis of natural product analogues via in vitro metabolic pathway construction.
ACS Chem. Biol. 2007 May 25 (ASAP Article). PubMed link.

[(*) I understand that some people may prefer to keep the term "combinatorial biosynthesis" only for in vivo approaches. Perhaps they're right, but I view biocatalysis (in vitro utilization of purified enzymes for chemical transformations) as a special type of biosynthesis.]

[Another note: I'm not a Star-Trek fan, but I think that the line "It's life, Jim, but not as we know it" was told by the Doc to the captain on seeing new life on a strange planet. However, I didn't learn the line directly from Star Trek, but from an article titled "Life, Jim, but not as we know it"? Transmissible dementias and the prion protein, Br. J. Psychiatry (1991) 158: 457-4710, authored by PJ Harrison & GW Roberts. I got to know this article while learning about neurodegenerative diseases during my M.S. studies (uf, feels like late Pleistocene). It was such a great title for a story on prions, it just stuck in my mind.]

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