| Abstract: | As researchers who study enzyme chemistry embrace increasingly complex systems, especially biological machines, our attention is also shifting from steps involving covalent bond formation or cleavage to those that exclusively involve changes in non‐covalent bonding. Assembly line polyketide synthases are an example of this growing challenge. By now, the chemical reactions underpinning polyketide biosynthesis can be unequivocally mapped to well‐defined active sites and are, for the most part, readily explicable in the language of physical organic chemistry. Yet, all of these insights merely serve as a backdrop to the real problem of explaining how the catalytic functions of dozens of active sites are synchronized in order to allow these remarkable machines to turn over with remarkable specificity. Notwithstanding the fact that the time‐honored language of physical organic chemistry can teach us a lot, it is often insufficient to describe many of these events, and must therefore evolve. |
