Biosynthesis of the fungal glyceraldehyde-3-phosphate dehydrogenase inhibitor heptelidic acid and mechanism of self-resistance
Yan Yan, Xin Zang, Cooper S. Jamieson, Hsiao‐Ching Lin, K. N. Houk, Jiahai Zhou, Yi Tang
Abstract
-GAPDH covalently bound with HA. A GAPDH isozyme HepG encoded in the HA cluster was characterized to be less sensitive to HA, and therefore contribute to self-resistance for the producing host. Comparison of the crystal structures of human GAPDH and HepG showed mutations both within and remote to the active site can contribute to resistance of inactivation, which was confirmed through mutagenesis. Due to the critical role GAPDH plays in aerobic glycolysis and other cellular functions, knowledge of HA mode of action and self-resistance mechanism could accelerate the development of improved inhibitors.
Topics & Concepts
Glyceraldehyde 3-phosphate dehydrogenaseGlyceraldehydeDehydrogenaseMechanism (biology)BiochemistryBiosynthesisChemistryEnzymeBiologyPhilosophyEpistemologyMicrobial Natural Products and BiosynthesisMicrobial Metabolic Engineering and BioproductionGenomics and Phylogenetic Studies