Abstract
Heparan sulfate (HS), a highly sulfated polysaccharide, is biosynthesized through a pathway involving several enzymes. C(5)-epimerase (C(5)-epi) is a key enzyme in this pathway. C(5)-epi is known for being a two-way catalytic enzyme, displaying a "reversible" catalytic mode by converting a glucuronic acid to an iduronic acid residue, and vice versa. Here, we discovered that C(5)-epi can also serve as a one-way catalyst to convert a glucuronic acid to an iduronic acid residue, displaying an "irreversible" catalytic mode. Our data indicated that the reversible or irreversible catalytic mode strictly depends on the saccharide substrate structures. The biphasic mode of C(5)-epi offers a novel mechanism to regulate the biosynthesis of HS with the desired biological functions.
Highlights
C5-epimerase converts a glucuronic acid to an iduronic acid residue in the heparan sulfate biosynthetic pathway
One unit of increase in molecular weight (Mr) for epi-oligosaccharide suggests that one GlcA residue is converted
Conclusions— the biosynthesis of Heparan sulfate (HS) is not a template-driven process, our results support the notion that HS biosynthetic pathway adopts an exquisite way to fine tune the extents of modifications through substrate control [22]
Summary
C5-epimerase converts a glucuronic acid to an iduronic acid residue in the heparan sulfate biosynthetic pathway. C5-epi is known for being a two-way catalytic enzyme, displaying a “reversible” catalytic mode by converting a glucuronic acid to an iduronic acid residue, and vice versa. Distributed sulfo groups and IdoA residues play critical roles in determining the functions of HS [2]; it remains unclear how to regulate the biosynthesis of these specific sulfated saccharide sequences in vivo. Three approaches have been reported to measure the activity of C5-epi (9 –11) Because all these methods utilized structurally heterogeneous polysaccharide substrates and the products were identified by a disaccharide analysis, none of these approaches is capable of locating the GlcA residues participated in the epimerization beyond a disaccharide domain. Reactivity and reaction modes of C5-epi toward the substrates with different structures
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