Glycosyltransferases and sugar nucleotide recycling systems
The application of enzymes to organic synthesis is a particularly powerful approach, and in some cases a single enzymatic transformation can be substituted in place of numerous sequential chemical reactions. In the case of complex oligosaccharide synthesis, the enzymatic approach is especially noteworthy for glycosidic bond formation. Several efficient chemical glycosylation methods have been developed over the past few decades (Barresi and Hindsgaul, 1995; Schmidt, 1986), yet none rival the regio- and stereospecificity that results when the catalyst is a glycosyltransferase.
Glycosyltransferases have been applied as catalysts in the construction of numerous complex glycoconjugates (Wong et al., 1995b). On a preparative scale, it is advantageous to employ protocols for the regeneration of sugar nucleotides in conjunction with glycosyltransferase catalysis (Figure 2A,B). In this manner, the expense of sugar nucleotides, and product inhibition of the glycosyltransferase by the resulting nucleoside di- or mono-phosphates (NDPs or NMPs) are overcome. Recycling systems for UDP-Gal incorporating UDP-Gal 4-epimerase (UDPGE; Wong et al., 1982) Gal-1-phosphate uridyltransferase (Gal-1-P UT; Wong et al., 1992), or sucrose synthetase (Elling et al., 1993) for use with β1,4-GalT have been reported for the large-scale synthesis of N-acetyllactosamine (LacNAc). In conjunction with α2,3-SiaT or α2,6-SiaT, CMP-NeuAc recycling systems (Ichikawa et al., 1991a) have been utilized for the sialylation of LacNAc-based glycoconjugates. For example, solution- and solid-phase syntheses of complex structures such as 3′-sialyl-LacNAc (3′-SLN) and sialyl Lewis x (sLex; Halcomb et al., 1994; Wong et al., 1995b) have been accomplished by these methods. Other sugar nucleotide recycling systems have also been explored, including GDP-Fuc (Ichikawa et al., 1992), GDP-Man (Wang et al., 1993; Herrmann et al., 1994), UDP-GlcNAc (Look et al., 1993), and UDP-GlcUA (Gygax et al., 1991). However, these systems are not generally utilized as extensively, as some of the enzymes required for the regeneration schemes are difficult to obtain.
Recent advances in sugar nucleotide recycling systems include efforts in engineering and chemical synthesis. Genetic manipulation of sugar nucleotide biosynthetic pathways in microorganisms has yielded coupled systems for the preparative scale synthesis of UDP-Gal (Koizumi et al., 1998) and CMP-NeuAc (Endo et al., 2000). Notably, this strategy allowed the synthesis of the globotriose trisaccharide without side-products from simple and inexpensive starting materials (Figure 3). In addition, chemical synthesis has provided new coupling methods (Wittmann and Wong, 1997) for high yielding production of GDP-Fuc, GDP-Man, and UDP-Gal. Generation of fusion enzymes such as CMP-NeuAc synthetase/α2,3-SiaT (Gilbert et al., 1998), UDPGE/α1,3-GalT (Wang et al., 1999), and UDPGE/β1,4-GalT (Paulson et al., unpublished observations) are a result of progress in enzyme engineering. Furthermore, new inexpensive kinase catalyst systems such as polyphosphate kinase/polyphosphate serve as an alternative to the pyruvate kinase/PEP system (Noguchi and Shiba, 1998).
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