POFUT2 is a GDP-fucose protein O-fucosyltransferase that catalyzes O-linked fucosylation of thrombospondin type 1 repeats (TSRs) in the endoplasmic reticulum 1. The enzyme specifically recognizes and modifies a conserved serine or threonine residue within the C1-X-X-S/T-C2 consensus sequence of TSRs, where substrate specificity is determined by the three-dimensional fold rather than primary sequence 1. POFUT2 employs a classical SN2 reaction mechanism facilitated by water-mediated interactions and a dynamic recognition network 2. The enzyme targets multiple protein families including ADAMTS, thrombospondin, and spondin proteins, and is essential for proper secretion of ADAMTS family members such as ADAMTS13 1. O-fucosylation by POFUT2 stabilizes TSR domains in their correct three-dimensional fold, supporting quality control mechanisms 3. Disease relevance is evident in preterm prelabor rupture of membranes (pPROM), where IL-1β-induced NF-κB activation upregulates both ADAMTS9 and POFUT2, promoting ADAMTS9 secretion and subsequent extracellular matrix degradation 4. Additionally, POFUT2 is one of three essential fucosyltransferases for proper mammalian development 5. Beyond TSRs, POFUT2 represents part of an expanding O-fucosylation repertoire that includes modification of elastin microfibril interface domains 6.