Compositions and methods for the production of compounds

A method of producing a compound, the method comprising:

• (a) providing a parent nucleic acid encoding a parent polyketide synthase;
• (b) modifying at least a first codon of a ketoreductase domain of the parent nucleic acid to produce a modified nucleic acid encoding a modified polyketide synthase capable of producing a compound, wherein modifying the first codon produces a modified ketoreductase domain comprising at least one of the following modifications:
• (i) a substitution of an amino acid other than tyrosine at a position corresponding to a tyrosine in a conserved YAAAN (SEQ ID NO:
• 97) catalytic motif and a deletion of a region corresponding to a conserved αFG helix of SEQ ID NO:
• 1,
• (ii) a substitution of a glutamic acid residue at a position corresponding to alanine 6632 of an S9-pksA ORF of SEQ ID NO:
• 2, or
• (iii) a deletion of amino acids corresponding to amino acids 3386 to 3516 of a WT S12-pksB ORF of SEQ ID NO:
• 3;
• and
• wherein the one or more modifications decrease the enzymatic activity of the modified ketoreductase domain in comparison to the enzymatic activity of the ketoreductase domain of the parent polyketide synthase
• (c) introducing the modified nucleic acid to one or more host cells;
• and
• (d) culturing the one or more host cells under conditions suitable to allow expression of the compound by the modified polyketide synthase;
• thereby producing the compound.