Aspartate transcarbamylase structure

Many protein molecules are composed of more than one subunit, where each subunit is a separate polypeptide chain and can form a stable folded structure by itself. The amino acid sequences can either be identical for each subunit (as in tobacco mosaic virus protein), or similar (as in the a and )3 chains of hemoglobin), or completely different (as in aspartate transcarbamylase). The assembly of many identical subunits provides a very efficient way of constructing... 

Fig. 93. Topology diagrams for the doubly wound and miscellaneous a/p domains illustrated in Figs. 76 through 78. Arrows represent the P strands thin connections lie behind the p sheet and fat ones above it. The darkest upper box surrounds the classic doubly wound sheets successively lighter solid boxes include domains that are progressively less like the classic topology the dotted box encloses the miscellaneous a/P structures. K = kinase P = phospho DH = dehydrogenase ATCase = aspartate transcarbamylase.

The examples given in the preceding pages have demonstrated that zinc in metalloenzymes may have catalytic, regulatory or structural functions. In addition there are some cases where the zinc appears to have no obvious function. Its most common role is that of catalysis, while a structural role has been demonstrated conclusively in only two cases, aspartate transcarbamylase and B. subtilis a-amylase. 

Figure II-4 Examples of the quaternary structure of proteins, (a) A drawing of glutamine synthetase of coli showing the orientation of the 12 identical subunits of the enzyme. (b) A drawing of aspartate transcarbamylase of coli showing the proposed orientation of the 6 catalytic subunits (labeled C, each MW = 33,000), and 6 regulatory subunits (labeled R, each MW =...

Three-dimensional structure of E. coli aspartate transcarbamylase. Half of the native c6r6 molecule (see Fig. II-4) is shown. The catalytic (c) submit, which binds the substrates aspartate and carbamyl phosphate is shown in light shading. The regulatory (r) subunit, which binds the allosteric effectors CTP and ATP, is shown in dark shading. From Kantrowitz, E.R., et al. (1980). E. coli Aspartate Transcarbamylase. Part 11 Structure and Allosteric Interactions. Trends Biochem Sci 5 150 and Stryer, L. (1995). Biochemistry, 4th ed. New York Freeman, Figure 10-5, p. 240. Reprinted by permission. 

Monaco, H. L., Crawford, J. L., Lipscomb, W. N. (1978). Three-dimensional structures of aspartate transcarbamylase from Escherichia coli and of its complex with cytidine triphosphate. Proc. Natl. Acad. Sci. USA 75,5276-5280. 

While the studies of Boyland and Roller and Elion and co-workers, which were conducted in vivo, do suggest that urethane has a specificity for pyrimidine biosynthesis, Kaye could not demonstrate in vitro any significant inhibition by urethane of several enzymes involved in nucleic acid metabolism. Both urethane and its A -hydroxy metabolite bear a structural resemblance to carbamyl phosphate and carbamyl-L-aspartate. The enzyme aspartate transcarbamylase begins pyrimidine biosynthesis by catalyzing the formation of carbamyl-L-aspartate from carbamyl phosphate and l-aspartate. Giri and Bhide have reported that in vivo administration of urethane decreased aspartate transcarbamylase activity of lung tissue of adult male and (to a lesser extent) female mice no in vitro inhibition could be demonstrated. 

Kihara, H., Takahashi-Ushijima, E Amemiya, Y Honda, Y., Vachette, P., Tauc, P., Barman, T. E., Jones, P. T. Moody, M. F. (1987). Kinetics of structure and activity changes during the allosteric transition of aspartate transcarbamylase. Journal of Molecular Biology, 198, 745-8. 

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