glycosaminoglycan

**Structure** - Repeating disaccharide: amino sugar (N-acetylglucosamine or N-acetylgalactosamine) + acidic sugar (glucuronic or iduronic acid). Keratan sulfate has galactose instead of a uronic acid. - Highly negatively charged because of carboxyl and sulfate groups. This attracts cations (Na+) and water, giving hydration, turgor, and resistance to compression. Sulfation is the main source of the charge. - Synthesized in the Golgi (elongation and sulfation) and attached to a core protein, usually through a serine-linked tetrasaccharide (xylose-galactose-galactose-glucuronic acid). Hyaluronic acid is the exception: it is not sulfated, is not covalently bound to a protein, and is made at the plasma membrane. - Proteoglycans are mostly GAG (~95%) with a small protein core, like a "bottle brush."

**Major GAGs and where they are found** - **Hyaluronic acid (hyaluronan):** synovial fluid, vitreous humor, cartilage, skin, umbilical cord (Wharton jelly). Lubricant and shock absorber. Not sulfated. - **Chondroitin sulfate:** cartilage, tendons, bone, cornea. Resists compression. Most abundant GAG in the body. - **Heparan sulfate:** basement membranes (e.g., glomerular basement membrane, whose negative charge repels albumin), cell surfaces (syndecan, glypicans). - **Heparin:** mast cell granules, liver, lung, and skin. It is more highly sulfated than heparan sulfate and is the most negatively charged GAG. It binds antithrombin III to enhance its inhibition of factors IIa and Xa. It is the only GAG that is intracellular and has anticoagulant activity. - **Dermatan sulfate:** skin, blood vessels, heart valves. - **Keratan sulfate:** cornea (transparency), cartilage, intervertebral disc. Contains galactose and no uronic acid.

**Degradation and disease: mucopolysaccharidoses (MPS)** - GAGs are degraded in lysosomes by sequential lysosomal hydrolases (exoenzymes). Deficiency causes accumulation of partially degraded GAGs. - Typically presents with coarse facial features, hepatosplenomegaly, joint stiffness or dysostosis multiplex, and developmental delay (varies by type), with urinary excretion of GAGs. - **Hurler (MPS I):** α-L-iduronidase deficiency. Accumulates heparan and dermatan sulfate. Corneal clouding, developmental delay, coarse facies, hepatosplenomegaly, and airway obstruction. Autosomal recessive. - **Hunter (MPS II):** iduronate-2-sulfatase deficiency. Also accumulates heparan and dermatan sulfate. **X-linked recessive** ("Hunter sees clearly": no corneal clouding). Aggressive behavior, mild-to-severe intellectual disability. - Other: Sanfilippo (MPS III, heparan sulfate; severe neurologic disease with mild somatic features), Morquio (MPS IV, keratan sulfate; skeletal dysplasia, normal intelligence), Maroteaux-Lamy (MPS VI). - Diagnosis: urine GAGs (screen) and enzyme assay. Treatment is enzyme replacement therapy, and hematopoietic stem cell transplant for Hurler. - In contrast to I-cell disease (mucolipidosis II), MPS patients have normal lysosomal enzyme targeting, since the problem is one specific missing hydrolase.

**Other clinical correlations** - **Osteoarthritis:** loss of proteoglycans and aggrecan in cartilage. Chondroitin sulfate and glucosamine are widely used supplements, but evidence for benefit is limited. - **Nephrotic syndrome (minimal change disease):** loss of the heparan sulfate negative charge barrier leads to albuminuria. - **Heparin:** therapeutic anticoagulant. Heparin-induced thrombocytopenia (HIT) is an antibody reaction to the heparin-platelet factor 4 complex. - **Hyaluronic acid:** intra-articular injections for OA, and dermal fillers. Hyaluronidase is used to dissolve fillers and is also a bacterial spreading factor (e.g., group A strep, S. aureus). - **Extracellular matrix:** GAGs bind growth factors (e.g., FGF) and aid cell signaling, migration, and wound healing.

**High-yield mnemonics and pearls** - Most GAGs are sulfated, except hyaluronic acid. - Heparin is the most highly sulfated and negatively charged. - Hunter = X-linked, "Hunters need clear (no corneal clouding) eyes to aim"; Hurler = corneal clouding. - Think "GAGs hold water": they give resistance to compression and a hydrated gel matrix.