Summary Acyltransferase (AT)‐less type I polyketide synthases (PKSs) produce complex natural products due to the presence of many unique tailoring enzymes. The 3‐hydroxy‐3‐methylglutaryl coenzyme A synthases (HCSs) are responsible for β ‐alkylation of the growing polyketide intermediates in AT‐less type I PKSs. In this study, we discovered a large group of HCSs, closely associated with the characterized and orphan AT‐less type...