Lysylhydroxylase

Lysylhydroxylase refers to a family of enzymes that catalyze the hydroxylation of lysine residues in collagen and other secreted proteins. In humans this family comprises at least three isoforms, encoded by the PLOD1, PLOD2, and PLOD3 genes, commonly known as lysyl hydroxylase 1 (LH1), lysyl hydroxylase 2 (LH2), and lysyl hydroxylase 3 (LH3). These enzymes reside in the endoplasmic reticulum and participate in the maturation of collagen by converting certain lysine residues to hydroxylysine, a modification essential for subsequent cross-link formation and glycosylation.

Biochemical function and cofactors: Lysyl hydroxylases are Fe2+- and 2-oxoglutarate (α-ketoglutarate)-dependent dioxygenases that require oxygen and ascorbate to maintain iron in the active form. The reaction also produces succinate and carbon dioxide. Hydroxylysine residues serve as key sites for glycosylation and are critical for the proper assembly and tensile strength of collagen fibrils through subsequent cross-linking by lysyl oxidase.

Gene families and isoforms: PLOD1 (LH1) is broadly expressed and hydroxylates lysines in collagen helices; PLOD2 (LH2) has tissue-specific roles, contributing to cross-linking patterns in tendon and bone; PLOD3 (LH3) possesses additional glycosyltransferase activities, catalyzing glycosylation of hydroxylysine in collagen.

Clinical significance: Mutations in PLOD genes cause connective tissue disorders. PLOD1 mutations lead to Ehlers-Danlos syndrome, kyphoscoliotic type. PLOD2 mutations cause Bruck syndrome and related skeletal dysplasias. PLOD3 mutations result in a spectrum of Stickler-like or spondyloepimetaphyseal dysplasias with joint and skeletal abnormalities. These conditions reflect impaired collagen maturation and compromised tissue integrity.