UDP hexosamines

Also, levels of uridine triphosphate (UTP) and uridine diphosphate glucose (UDP-glucose) fall dramatically within the first hour after the administration of galactosamine. There is also a concomitant rise in UDP-hexosamines and UDP-N-acetylhexosamines ffmure 7.40b). 

FIGURE 7.40b The effect of galactosamine on biochemical parameters. The graph shows the effect on ATP (A), UTP (t), UDP-glucose (0), UDP-N-acetylhexosamines (D) and UDP-hexosamines (M). Adapted from Decker and Kepler (1974) Rev. Physiol. Biochem. Pharmac., 77, 78. 

Typically, the native sequence GAG synthases will only transfer the authentic UDP-sugars to produce the natural polymer. However, we have now created new enzymes that can make novel polymers that are not known to exist in Nature. We used a chimeric genetic modification approach to map out the Gal/Glc specificity for UDP-hexosamines of the Pasteurella pmHAS [HA... 

Figure 7. Analysis of various chimeric synthases. Portions of the pmHAS (black) and pmCS (white) enzymes were fused to produce chimeric enzymes. The constructs were tested for sugar transfer activity (HAS, HA synthase CS, chondroitin synthase GlcUA transferase) in vitro. The last enzyme, pmCHC, had relaxed specificity and could incorporate either UDP-hexosamine.

Another, more classical, control mechanism exists for the feedback regulation of key enzymes for the synthesis of Gm-6-P04 and for N-acetylmannosamine. Each of these is the first enzyme in the metabolic commitment to hexosamine and sialic acid synthesis. Komfeld et al, (1964) showed that UDP-GlcNAc is an efficient feedback inhibitor for L-glutamine-D-fructose-6-phosphate aminotransferase and that CMP-NAN also inhibits UDP-GlcNAc-2-epimerase, which is responsible for the synthesis of A/ -acetylmannosamine. This is an example of the by now familar endproduct inhibition of the first enzyme of a metabolic pathway (see Figure 6). They were also able to demonstrate that in vivo administration of puromycin to rats, which inhibits de novo protein synthesis and also depresses sialic acid and hexosamine utilization, does not lead to an accumulation of UDP-GlcNAc. Furthermore, the turnover of the UDP-hexosamine pool was shown to be slowed down. These data suggest that impairment of the utilization of UDP-hexosamine leads to decreased synthesis of UDP-hexosamines or their precursors (i.e., classical feedback inhibition). 

G is the designation for CaS04 binder. Silica G has been used to resolve pyridine nucleotides, UDP derivatives of hexosamines and acetylhexosamines. -H is without binder. PF2S4 is used for preparation of larger quantities of bases, nucleosides and many of their derivatives. Kieselguhrs are natural deposits of primarily silica, but may vary in both composition and size of particles. 

CMP-N-acetylneuraminic acid is formed by a series of reactions which are outgrowths of the pathways of hexosamine biosynthesis. As seen from Fig. 8A, N-acetylmannosamine can be regarded as the first specific intermediate in the biosynthesis of the nucleotide sugar and may be formed by 2-epimerization from either UDP-N-acetylglucosamine or N-acetylglucosamine. The mechanisms of these two reactions have recently been investigated and will be discussed below. 

Fig. 1. Mammalian hexosamine metabolism. The de novo biosynthesis of UDP-N-acetyl-D-glucosamine (UDP-GlcNAc) from D-glucose (Glc) is shown...

Enhancement of enzyme activity may be demonstrated in relation to regulation. Glucosamine-6-phosphate deaminase is activated by GlcNAc-6-P, an intermediate in the hexosamine pathway leading to UDP-GlcNAc. The deaminase is... 

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