Aspartate Transcarbamoylase ATCase

Aspartate transcarbamoylase (ATCase), the catalyst for the first reaction unique to pyrimidine biosynthesis (Figure 34-7), is feedback-inhibited by cytidine tri-... 

Aspartate transcarbamoylase (ATCase) from Escherichia coli is the most studied and best known regulatory enzyme. Yates and Pardee (1956) were the first to propose that the activity of ATCase is controlled by end product inhibition. This feedback inhibition was later studied in more detail by Gerhart and Pardee (1961, 1962, 1963). The three-dimensional structure of ATCase was determined by Lip-scombe and his coworkers [Wiley etal. (1971), Wiley and Lipscomb (1968), Warren etal. (1973)]. 

Regulation of the rate of pyrimidine nucleotide synthesis in bacteria occurs in large part through aspartate transcarbamoylase (ATCase), which catalyzes the first reaction in the sequence and is inhibited by CTP, the end product of the sequence (Fig. 22-36). The bacterial ATCase molecule consists of six catalytic subunits and six regulatory subunits (see Fig. 6-27). The catalytic subunits bind the substrate molecules, and the allosteric subunits bind the allosteric inhibitor, CTP. The entire ATCase molecule, as well as its subunits, exists in two conformations, active and inactive. When CTP is... 

It is not easy to mimic the shuffling of domains in vitro by manipulation of genes. For example, each catalytic polypeptide chain of the multimeric E. coli aspartate transcarbamoylase (ATCase) is composed of two globular domains connected by two interdomain helixes. The E. coli enzyme ornithine transcarbamoylase (OTCase) is 32% identical in sequence and thus of presumably similar structure (see section D8). None of the chimeras in which a domain from one enzyme was attached to the corresponding partner in the other is active. The specific intrachain and interchain side-chain interactions also have to evolve for the Correcting packing.32... 

Although the Michaelis-Menten model provides a very good model of the experimental data for many enzymes, a few enzymes do not conform to Michaelis-Menten kinetics. These enzymes, such as aspartate transcarbamoylase (ATCase), are called allosteric enzymes (see Topic C5). 

Fig. 2. Formation of N-carbamoylaspartate by aspartate transcarbamoylase (ATCase) is the committed step in pyrimidine biosynthesis and a key control point.

Like motor traffic, metabolic pathways flow more efficiently when regulated by signals. CTP, the final product of a multistep pathway, controls flux through the pathway by inhibiting the committed step catalyzed by aspartate transcarbamoylase (ATCase).[(Left) Richard Berenholtz/The Stock Market.]... 

Aspartate transcarbamoylase (ATCase) is an allosteric enzyme of the bacterium Escherichia coli, which has been extensively studied. This enzyme catalyzes the transfer of the carbamoyl group from carbamoyl phosphate to the amino group of aspartate ... 

The first step in the pathway, formation of carbamoyl aspartate from aspartate and carbamoyl phosphate, is the primary regulatory point in the pathway. The enzyme, aspartate transcarbamoylase (ATCase) (see here), is activated by ATP and inhibited by CTP, which is the end product of the pathway. Another point of regulation is CTP synthetase, which is feedback inhibited by CTP and activated by GTP. In bacteria, synthesis of ATCase subunits is inhibited by high levels of UTP. The inverted regulatory effects of purine and pyrimidines in the pathway are yet another way cells maintain a proper balance of nucleotides. 

Describe the reaction catalyzed by aspartate transcarbamoylase (ATCase), the regulation of ATCase by CTP and ATP, and the biological significance of this regulation. 

Aspartate transcarbamoylase (ATCase, EC 2.1.3.2) is an allosteric enzyme which controls the first step of p5oimidine de novo biosynthesis. It catalyzes the condensation of L-aspartic acid with carbamyl phosphate to produce carbamoyl-L-aspartate... 

The above divide-and-craiquer approach was also applied to the 300 kDa aspartate transcarbamoylase (ATCase), containing six regulatory (r) chains and six catalytic (c) chains [42], A 30 kDa ra dimer was used as the smaller block and... 

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