HS3ST5 (heparan sulfate-glucosamine 3-sulfotransferase 5) is a sulfotransferase enzyme that catalyzes the transfer of a sulfo group to position 3 of glucosamine residues in heparan sulfate using PAPS as a cofactor. This modification is rate-limiting in heparan sulfate biosynthesis and is critical for forming the antithrombin pentasaccharide binding site, generating anticoagulant heparan sulfate [UniProt summary]. The enzyme also generates modified heparan sulfate that serves as a binding receptor for Herpes simplex virus-1 entry [UniProt summary]. Beyond anticoagulation, HS3ST5 expression patterns are altered in colorectal cancer, with changes in non-metastatic tumors affecting N-sulfation and HS chain modification 1. Genetically, HS3ST5 variants are associated with multiple neurodegenerative phenotypes: rs9654628 in HS3ST5 shows interaction with dietary sodium on systolic blood pressure 2, and the locus near HS3ST5/HDAC2/MARCKS is associated with shared genetic risk in Alzheimer's disease and amyotrophic lateral sclerosis 3. HS3ST5 expression is developmentally regulated during embryonic stem cell differentiation 4, and deletions involving HS3ST5 are implicated in neurodevelopmental disorders including microcephaly with pontine and cerebellar hypoplasia 5 and movement disorders 6.