Structures and functions
of hybrid natural product assembly lines

Topics

Pyrimidine biosynthesis

Pyrimidines are aromatic six-membered heterocycles containing two N atoms in the ring. Substituted pyrimidines are common in medically relevant compounds.

Some bioactive compounds containing substituted pyrimidines. Pyrimidine cores are highlighted in red.

Several of these compounds are natural products. In complex glycopeptide natural products like bleomycin, zorbamycin, and tallysomycin, the precise mechanism by which pyrimidine scaffolds are installed by hybrid FAS-like/NRPS systems has remained obscure. A firmer grasp of pyrimidine construction by hybrid systems will accelerate synthetic biology efforts to create novel pyrimidine-containing compounds.

The pyrimidine core of bleomycin is assembled by FAS-like and NRPS modules. These modules and the features they install on bleomycin A2 are highlighted in bold. How the enzyme-bound substrates are stitched together to form the pyrimidine precursor is poorly understood.

Kalimantacin biosynthesis

PKS and NRPS modules are often found together in hybrid PKS/NRPS assembly lines, such as that which produces the kalimantacin antibiotics. Clarifying how these modules communicate with one another will inform synthetic biology experiments to prepare new derivatives of kalimantacin and other hybrid compounds

Hybrid interfaces in the kalimantacin assembly line. A single NRPS module installs an amino acid residue in kalimantacin A. This module interacts with PKS modules at both of its termini.
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