From Isoprene Units to Polyprenols and Dolichols: 70 Years of Polyisoprenoid Biosynthesis Research.

Polyisoprenoids (polyprenols and dolichols) are a class of linear hydrophobic polymers present across all domains of life, serving essential functions for cellular viability and survival. Research on polyisoprenoids has progressed steadily since their discovery in the 1950s; however, these advances continue to highlight gaps in our understanding. This review provides a comprehensive overview of their biosynthesis, which occurs in three sequential stages: the formation of five-carbon precursors via the mevalonate (MVA) and methylerythritol phosphate (MEP) pathways, the elongation of the prenyl chain by prenyltransferases (PTs), and the final conversion into specific alcohol forms. Recent discoveries have substantially revised the classical understanding of dolichol biosynthesis, indicating a paradigm shift in the field. Furthermore, we discuss the essential biological roles of polyisoprenoids as lipid carriers for protein glycosylation, modulators of membrane fluidity, and key mediators in physiological defense systems against environmental stress, as well as their relevance to human disease and diagnostic applications. Finally, this article addresses critical knowledge gaps, focusing on the largely unexplored molecular mechanisms that regulate prenyltransferase activity and the yet-to-be-defined roles of these compounds in long-term stress adaptation.