Human UMP synthase is a bifunctional protein containing two separate catalytic domains, orotate phosphoribosyltransferase (EC 2.4.2.10) and orotidine-5`-phosphate decarboxylase (EC 4.1.1.23). These studies address the question of why the last two reactions in pyrimidine nucleotide synthesis are catalyzed by a bifunctional enzyme in mammalian cells, but by two separate enzymes in microorganisms. From existing data on subunit associations of the respective enzymes and calculations showing the molar concentration of enzyme to be far lower in mammalian cells than in microorganisms, we hypothesize that the covalent union in UMP synthase stabilizes the domains containing the respective catalytic centers. Evidence supporting this hypothesis comes from studies of stability of enzyme activity in vitro, at physiological concentrations, of UMP synthase, the two isolated catalytic domains prepared by site-directed mutagenesis of UMP synthase, and the yeast ODCase. The two engineered domains have activities very similar to the native UMP synthase, but unlike the bifunctional protein, the domains are quite unstable under conditions promoting the dissociated monomer.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				K. Tokuoka, Y. Kusakari, S. R. Krungkrai, H. Matsumura, Y. Kai, J. Krungkrai, T. Horii, and T. Inoue Structural Basis for the Decarboxylation of Orotidine 5'-Monophosphate (OMP) by Plasmodium Falciparum OMP Decarboxylase J. Biochem., January 1, 2008; 143(1): 69 - 78. [Abstract] [Full Text] [PDF]

				P. Geigenberger, B. Regierer, A. Nunes-Nesi, A. Leisse, E. Urbanczyk-Wochniak, F. Springer, J. T. van Dongen, J. Kossmann, and A. R. Fernie Inhibition of de Novo Pyrimidine Synthesis in Growing Potato Tubers Leads to a Compensatory Stimulation of the Pyrimidine Salvage Pathway and a Subsequent Increase in Biosynthetic Performance PLANT CELL, July 1, 2005; 17(7): 2077 - 2088. [Abstract] [Full Text] [PDF]

				A. T. Deyrup, S. Krishnan, B. Singh, and N. B. Schwartz Activity and Stability of Recombinant Bifunctional Rearranged and Monofunctional Domains of ATP-Sulfurylase and Adenosine 5'-Phosphosulfate Kinase J. Biol. Chem., April 16, 1999; 274(16): 10751 - 10757. [Abstract] [Full Text] [PDF]

				S. Hinderlich, R. Stasche, R. Zeitler, and W. Reutter A Bifunctional Enzyme Catalyzes the First Two Steps in N-Acetylneuraminic Acid Biosynthesis of Rat Liver. PURIFICATION AND CHARACTERIZATION OF UDP-N-ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE J. Biol. Chem., September 26, 1997; 272(39): 24313 - 24318. [Abstract] [Full Text] [PDF]

				T. W. Traut and B. R. S. Temple The Chemistry of the Reaction Determines the Invariant Amino Acids during the Evolution and Divergence of Orotidine 5'-Monophosphate Decarboxylase J. Biol. Chem., September 8, 2000; 275(37): 28675 - 28681. [Abstract] [Full Text] [PDF]

				B. G. Miller, A. M. Hassell, R. Wolfenden, M. V. Milburn, and S. A. Short Anatomy of a proficient enzyme: The structure of orotidine 5'-monophosphate decarboxylase in the presence and absence of a potential transition state analog PNAS, February 29, 2000; 97(5): 2011 - 2016. [Abstract] [Full Text] [PDF]