d ‐Galactose‐Esterification of a Fungal Polyketide Catalyzed by a Carnitine Acyltransferase Domain
Year: 2024
Type: article
Abstract: While sugar-containing natural products are commonly biosynthesized via glycosyltranferases using sugar-UDP as the electrophile, nature has evolved alternative strategies of glyco-modification to expand the diversity of natural products. Hydroxyl groups on sugars can serve as nucleophiles in the release of polyketide products from polyketide synthases. Herein, we demonstrate a highly reducing polyketide synthase (HRPKS) from the biocontrol fungus Trichoderma afroharzianum T22, which is terminated with a carnitine acyltransferase (cAT) domain, catalyzes the biosynthesis of a d-galactose esterified polyketide named as trichogalactin. Structure-guided enzymatic assays showed that the sugar nucleophile in the esterification reaction catalyzed by cAT is α-d-galactose-1-phosphate (Gal-1-P) instead of free d-galactose. The released product, trichogalactin phosphate, is subsequently dephosphorylated by a host alkaline phosphatase to complete the biosynthesis of trichogalactin. The cAT domain is highly specific for Gal-1-P and does not accept α-d-glucose-1-phosphate or α-d-mannose-1-phosphate. Our study expands the inventory of natural products from an agriculturally important fungus and demonstrates the potential of mining cAT-containing HRPKSs to discover new glyco-esterified natural products.
Source: ChemBioChem
Authors: Kyle K. Nagasawa, Karl M. Yost, Zuodong Sun, Yi Tang
Institutions: University of California, Los Angeles, Harvard University
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G4305609567, G4316945320
OpenAlex ID: W4405705695