glycosaminoglycans

**Structure** - Repeating disaccharide: amino sugar (N-acetylglucosamine or N-acetylgalactosamine) + usually a uronic acid (glucuronic or iduronic acid). Keratan sulfate has galactose instead of a uronic acid. - Highly negatively charged (carboxyl and sulfate groups). They attract cations (Na+) and water, giving tissues hydration, turgor, and resistance to compression. - Most are sulfated and covalently attached to a core protein to form proteoglycans (e.g., aggrecan in cartilage). Hyaluronic acid is the exception: it is non-sulfated, is not covalently bound to a core protein, and is synthesized at the plasma membrane.

**Major GAGs and locations** - Hyaluronic acid: synovial fluid, vitreous humor, umbilical cord (Wharton jelly), cartilage. Lubricant and shock absorber. Elevated in wound healing and in some tumors. - Chondroitin sulfate: cartilage, tendons, bone, cornea. Most abundant GAG in the body. Resists compression. - Heparan sulfate: basement membranes (e.g., glomerular basement membrane), cell surfaces. Its negative charge forms the glomerular charge barrier, and loss of this charge contributes to albuminuria in nephrotic syndrome. Also a co-receptor for growth factors. - Heparin: mast cell granules, liver, lung, and skin. Activates antithrombin III and is an anticoagulant. It is the most highly sulfated GAG and has the highest negative charge density. - Dermatan sulfate: skin, blood vessels, heart valves. - Keratan sulfate: cornea (transparency), cartilage, and intervertebral discs. It has the least amount of negative charge.

**Synthesis** - Synthesized in the Golgi (except hyaluronic acid). Chain elongation begins with a tetrasaccharide linker (xylose-galactose-galactose-glucuronic acid) attached to a serine on the core protein. - Sulfation uses PAPS (3'-phosphoadenosine-5'-phosphosulfate) as the sulfate donor.

**Degradation and clinical correlate: mucopolysaccharidoses (MPS)** - GAGs are degraded in lysosomes by sequential action of lysosomal enzymes (endoglycosidases, exoglycosidases, and sulfatases). Deficiency of any one causes accumulation of partially degraded GAGs in tissues and urine. - Most are autosomal recessive. Hunter syndrome is X-linked recessive. - Hurler syndrome (MPS I): α-L-iduronidase deficiency. Accumulates heparan and dermatan sulfate. Presents with coarse facies, gargoylism, corneal clouding, hepatosplenomegaly, developmental delay, and airway obstruction. Death often occurs in childhood. - Hunter syndrome (MPS II): iduronate-2-sulfatase deficiency. Accumulates heparan and dermatan sulfate. X-linked recessive. Clinically similar to Hurler but with NO corneal clouding, aggressive behavior, and milder course. Mnemonic: "Hunters see clearly (no corneal clouding) and aim for the X (X-linked)." - Diagnosis: urine GAGs (elevated), then enzyme assay (leukocytes or fibroblasts). Treatment: enzyme replacement therapy; hematopoietic stem cell transplant for Hurler syndrome. - Findings: lysosomal inclusion bodies (metachromatic or Alcian blue-positive material).

**Other clinical associations** - Osteoarthritis: loss of proteoglycan and GAG content in cartilage. Glucosamine/chondroitin supplements are marketed but have unproven benefit. - Ehlers-Danlos, Marfan, and other connective tissue disorders involve the extracellular matrix but are not primary GAG disorders. - Hyaluronidase: spreading factor used by bacteria (e.g., group A strep, S. aureus) to degrade hyaluronic acid and spread through tissue. - Hyaluronic acid injections are used in osteoarthritis of the knee. Dermal fillers also use hyaluronic acid.

**High-yield pearls** - GAGs = repeating disaccharides, negatively charged, bind water. - Heparan sulfate = glomerular charge barrier. - Heparin = most negatively charged, binds antithrombin. - Hurler (corneal clouding, α-L-iduronidase) vs. Hunter (no clouding, X-linked, iduronate sulfatase).