LysylHydroxylasen

Lysyl hydroxylases are a group of iron(II)- and 2-oxoglutarate–dependent dioxygenases that catalyze the post-translational hydroxylation of lysine residues in collagen and related extracellular matrix proteins. The resulting hydroxylysine residues are important sites for subsequent glycosylation and for the formation of mature collagen cross-links, influencing the stability and mechanical properties of connective tissue.

In humans, three isoforms are described: lysyl hydroxylase 1 (PLOD1), lysyl hydroxylase 2 (PLOD2), and lysyl hydroxylase 3 (PLOD3). All three proteins are localized to the endoplasmic reticulum and require Fe2+, molecular oxygen, 2-oxoglutarate, and ascorbate as cofactors. PLOD3 also possesses a glucosyltransferase activity, giving it a dual role in the maturation of collagen and related matrix components.

The enzymatic reaction involves hydroxylation of specific lysine residues within procollagen chains. Hydroxylysine residues serve as glycosylation sites and later participate in cross-link formation after secretion, following action by lysyl oxidase. This sequence of modifying steps is essential for proper collagen fibrillogenesis and ECM organization.

Genetic and clinical relevance is seen in several inherited connective tissue disorders. PLOD1 mutations cause kyphoscoliosis-type Ehlers-Danlos syndrome (EDS type VI) due to defective lysyl hydroxylation. PLOD2 mutations are associated with Bruck syndrome, featuring bone and joint instability. PLOD3 mutations yield a rare syndromic connective tissue disease with skeletal abnormalities. Dysregulation of lysyl hydroxylase activity has also been implicated in fibrosis, cancer-associated matrix remodeling, and aging.