Principles of Biochemistry Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Biosynthesis of Amino Acids and Nucleotides
Regulation of Pyrimidine Nucleotide Biosynthesis

The rate of Pyrimidine Nucleotide Biosynthesis is regulated by aspartate transcarbamoylase (ATCase), which catalyzes the first reaction of this biosynthetic pathway (Fig. 22-20). ATCase is inhibited by the end product of this sequence of reactions, cytidine triphosphate (CTP). The ATCase molecule is composed of six catalytic and six Regulatory Subunits (Box 9-5). The catalytic subunits bind substrate molecules, whereas the regulatory subunits bind molecules of the allosteric inhibitor CTP. The entire enzyme molecule, as well as its individual subunits, exists in two forms—active and inactive. The enzyme exhibits maximum activity when its regulatory subunits are unoccupied. However, as CTP accumulates, it binds to the regulatory subunits and alters their conformation. This conformational change is transmitted to the catalytic subunits, which consequently also shift to an inactive conformation. ATP counteracts this effect of CTP. Figure 22-21 illustrates how The activity of ATCase is modulated by Allosteric regulators.

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Fig. 22-20. Regulation of CTP biosynthesis via feedback inhibition of aspartate transcarbamoylase by the end product of the pathway. ATP prevents the inhibitory action of CTP.

Fig. 22-21. Effect of the allosteric modulators CTP and ATP on the rate of aspartate conversion to carbamoylaspartate catalyzed by aspartate transcarbamoylase. Note that upon addition of CTP (an allosteric inhibitor of aspartate transcarbamoylase), the $K_m$ for aspartate increases. ATP completely reverses this effect.