Microbial engineering for natural and unnatural glycosaminoglycans biosynthesis.

Abstract

Covering: up to 2025Microbial synthesis of glycosaminoglycans (GAGs) facilitates sustainable biomanufacturing using cost-effective carbon feedstocks. This transformative framework is driven by three core innovations: de novo GAGs biosynthesis, sulfation engineering, and new-to-nature GAGs analogs creation. Despite these advances, critical challenges hinder industrial-scale efficiency, such as suboptimal distribution of metabolic flux, insufficient sulfation environments, and host incompatibility with unnatural analogs. In this review, we present a systematic analysis of microbial hosts, biosynthetic pathways, and microbial engineering strategies for GAGs production. We first describe how strategic host optimization and pathway manipulation can tap the full potential of microorganisms for efficient GAGs biosynthesis. Then, we analyze the development of microbial cell factories (MCFs) for GAGs biosynthesis from the simple pathway transplantation to systemic de novo construction of metabolic systems, thereby establishing programmable platforms to surpass natural biosynthesis limits. Next, we present a tripartite engineering framework for GAGs sulfation that integrates precursor synthesis modules, sulfate donor accumulation systems, and sulfotransferase networks, thereby progressing sulfation control from biomimetic mechanisms to programmable artificial systems. Further, we discuss the microbial synthesis of new-to-nature GAGs analogs through the incorporation of unnatural precursors or the reprogramming of natural precursors, thereby enabling MCFs to construct non-canonical glycopolymers with designed function. Finally, we prospect the development of multifunctional customized MCFs to drive breakthroughs in industrial-scale GAGs bioproduction.