(ASKING FOR QUESTION NUMBER 1.) Background Aspartate transcarbamoylase (ATCase)
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(ASKING FOR QUESTION NUMBER 1.)
Background Aspartate
transcarbamoylase (ATCase) catalyzes an early step in the synthesis of the pyrimidine nucleotides UTP and CTP. The enzyme catalyzes the condensation of carbamoyl phosphate and aspartate to form carbamoyl aspartate. The reaction pathway is shown in Figure 16.1. The enzyme has been fairly well characterized. It is known to consist of six regulatory subunits and six catalytic subunits. In this case, we examine the properties of ATCase isolated from E. coli to illustrate some of the important regulatory properties of multi-subunit enzymes. As an early enzyme in a multi-step pathway, the ATCase reaction is a logical one to regulate the synthesis of pyrimidine nucleotides. Both purine nucleotides and pyrimidine nucleotides are needed in roughly equal amounts as substrates for DNA synthesis in rapidly dividing cells. The regulation of the ATCase enzyme ensures a proper balance of purine and pyrimidine pools in E. coli. The goal in this case was to identify the cellular metabolites that serve as activators and inhibitors of ATCase.
QUESTION 1.Gerhart and Pardee measured ATCase activity in the presence of a variety of purine and pyrimidine derivatives. Their results are presented in Table 16.2. What compound(s) were the most effective inhibitors? activators? Explain the significance of the metabolites that served as inhibitors or activators in the context of the biosynthetic pathway presented in Figure 16.1.
HCO3 Glutamine ATP ATCase Carbamoyl phosphate Aspartate N-carbamoylasparitate UMP UTP Figure 16.1: Pyrimidine synthetic pathway. CTPExplanation / Answer
Answer:
1. a. Inhibitors:
CTP functions as an inhibitor and cytidine and deoxycytidine, which contain the sugar, show a slight amount of inhibition. There is an increasing amount of inhibition with CMP, CDP and CTP, indicating that inhibition is facilitated with an increasing number of phosphate groups.
(UTP could not inhibit the enzyme, indicating that the amino group may be required for inhibition. Cytosine alone cannot inhibit)
Activators: ATP and dATP functioned as stimulators of the enzyme.
b. Significance of the metabolites that act as inhibitors or activators:
CTP functions as an inhibitor because it is the product of the pathway. High concentrations of CTP signals the enzyme that CTP is no longer needed.
ATP stimulates the pathway because a high concentration of purines must be matched by a high concentration of pyrimidines for efficient DNA and RNA synthesis.
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