1-Deoxy-D-xylulose 5-phosphate synthase: structural perspectives on an essential enzyme in isoprenoid biosynthesis

Isoprenoids represent one of the largest and functionally diverse class of natural products, playing essential roles in cellular processes across all domains of life. Unlike humans, many pathogenic organisms such as bacteria and protozoa produce their isoprenoid precursors through the 2-C-methylerythritol phosphate (MEP) pathway. 1-deoxy-D-xylulose 5-phosphate synthase (DXPS) is the first and rate-limiting enzyme of this pathway. Despite its biological importance and potential as a drug target, structural studies on DXPS were limited due to its intrinsic flexibility and difficulties in crystallisation. Recent advances, including the development of more crystallisation-friendly constructs and the application of single-particle cryo-electron microscopy (cryo-EM), have significantly expanded our structural understanding of DXPS. This review provides a comprehensive overview of the structural insights gained over the past decades, focusing on the overall architecture of DXPS, its catalytic mechanism, and emerging relevance in structure-based drug discovery.