Keratan is a complex carbohydrate molecule found throughout the body, playing diverse roles in various biological processes. It is a significant component of the extracellular matrix, the intricate network providing structural support and biochemical cues to cells. Its presence contributes to maintaining tissue health and function.
Understanding Keratan’s Structure and Location
Keratan is a type of glycosaminoglycan (GAG), a long, linear polysaccharide. Unlike other GAGs, keratan does not contain uronic acid residues. Instead, it is made up of N-acetyllactosamine subunits, repeating units of galactose and N-acetylglucosamine. These disaccharide units are linked and can be sulfated at the 6-position of either or both residues. This sulfation pattern varies by tissue and keratan type.
Keratan exists as part of larger molecules called proteoglycans, where keratan chains attach to a core protein. These keratan sulfate proteoglycans (KSPGs) are widely distributed, with high concentrations in the cornea, cartilage, bone, and the central nervous system.
Three main types of keratan have been identified based on their linkage to the core protein. Keratan sulfate type I (KS I) is attached via an N-glycan linkage to an asparagine residue. Keratan sulfate type II (KS II) is linked through an O-glycan to serine or threonine residues. A third type, keratan sulfate type III (KS III), found in brain tissue, is O-linked to serine or threonine residues via a mannose sugar.
Keratan’s Essential Roles in the Body
Keratan plays diverse roles across various tissues, with its unique sulfation patterns dictating specific functions. In the cornea, keratan sulfate proteoglycans (KSPGs) are abundant and contribute to maintaining corneal transparency. These KSPGs, such as lumican and keratocan, regulate the spacing and diameter of collagen fibrils in the corneal stroma, essential for light transmission. Keratan also helps regulate corneal hydration, acting as a dynamic buffer for water content, important for maintaining optical properties.
In cartilaginous tissues, keratan sulfate is a component of aggrecan, a large proteoglycan contributing to structural integrity and compression resistance. Aggrecan, with its attached keratan sulfate and chondroitin sulfate chains, traps water, providing cartilage with cushioning and resilience. The sulfation patterns on keratan chains convey molecular recognition information, influencing cell behavior through interactions with various proteins.
Keratan is also found in the central nervous system, where it participates in neural development and cell migration. Specific keratan sulfate proteoglycans like ABAKAN act as molecular barriers, restricting axonal growth and forming boundaries between different functional areas of the developing brain. Keratan’s sulfated regions interact with numerous proteins, including kinases and nerve regulatory proteins, influencing cell signaling pathways, cytoskeletal organization, and cellular proliferation.
Keratan and Human Health
Dysfunction or altered levels of keratan are associated with several health conditions. Macular Corneal Dystrophy (MCD) is an inherited disorder where unsulfated keratan sulfate accumulates in the corneal stroma, leading to progressive vision impairment. This condition arises from mutations in the CHST6 gene, coding for carbohydrate sulfotransferase 6, an enzyme that adds sulfate groups to keratan. The lack of proper sulfation results in the deposition of abnormal glycosaminoglycans, causing corneal opacities.
Keratan is also implicated in certain lysosomal storage disorders, inherited metabolic conditions caused by enzyme deficiencies in lysosomes. In these disorders, the body cannot properly break down complex molecules, leading to their accumulation. For instance, some mucopolysaccharidoses (MPS) involve defects in the degradation of glycosaminoglycans, including keratan sulfate. While not all MPS types directly involve keratan, their general impact on GAG metabolism highlights the importance of proper keratan processing.
Keratan sulfate levels can serve as a biomarker in conditions like osteoarthritis. Elevated levels of a highly sulfated keratan sulfate epitope in the serum of individuals with generalized osteoarthritis indicate increased rates of cartilage proteoglycan breakdown. Monitoring these levels can provide insights into cartilage degradation, potentially aiding in understanding disease progression.