Biological functions of iduronic acid in chondroitin/dermatan sulfate

Abstract

The presence of iduronic acid in chondroitin/dermatan sulfate changes the properties of the polysaccharides because it generates a more flexible chain with increased binding potentials. Iduronic acid in chondroitin/dermatan sulfate influences multiple cellular properties, such as migration, proliferation, differentiation, angiogenesis and the regulation of cytokine/growth factor activities. Under pathological conditions such as wound healing, inflammation and cancer, iduronic acid has diverse regulatory functions. Iduronic acid is formed by two epimerases (i.e. dermatan sulfate epimerase 1 and 2) that have different tissue distribution and properties. The role of iduronic acid in chondroitin/dermatan sulfate is highlighted by the vast changes in connective tissue features in patients with a new type of Ehler-Danlos syndrome: adducted thumb-clubfoot syndrome. Future research aims to understand the roles of the two epimerases and their interplay with the sulfotransferases involved in chondroitin sulfate/dermatan sulfate biosynthesis. Furthermore, a better definition of chondroitin/dermatan sulfate functions using different knockout models is needed. In this review, we focus on the two enzymes responsible for iduronic acid formation, as well as the role of iduronic acid in health and disease.

Fig. 1

Structure of CS/DS and conformations of IdoA. (A) The domains of variable length containing blocks of IdoA, alternating IdoA and GlcA or blocks of GlcA. (B) The epimerase reaction. (C) Conformations of IdoA.

Fig. 2

(A) DS-epi1 and DS-epi2 domain structures. (B) Three-dimensional modelling of the DS-epi1 epimerase domain based on the crystal structure of heparinase II. A chondroitin sulfate tetrasaccharide is positioned in the groove containing the active site.

Fig. 3

Formation of IdoA in CS/DS. The amount and distribution of IdoA depends upon the expression level of the DS epimerases and D4ST1.

Fig. 4

Overview of the functions of IdoA in CS/DS. Role of IdoA in the storage of cytokines growth factors and collagen fibril formation (A), Borrelia infection (B), atherosclerosis (C), coagulation (D), P-selectin-dependent leukocyte recruitment (E), activation of cytokine and growth factor receptors (F) and leukocyte recruitment by ICAM (G).