Principles of Biochemistry Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Biosynthesis of Amino Acids and Nucleotides
Amino acid biosynthesis is regulated by allosteric mechanisms

The most sensitive type of regulation of Amino acid synthesis is the allosteric inhibition of the first reaction in a biosynthetic pathway by the end product of that sequence (Sections 9.18 and 13.11). The first reaction of a biosynthetic pathway is typically irreversible and is catalyzed by an allosteric enzyme. Figure 22-8 illustrates Allosteric Regulation using the synthesis of isoleucine from Threonine as an example, which we discussed earlier (Section 9.18). The end product, isoleucine, acts as a negative modulator of the first step in this pathway. This type of allosteric, or noncovalent, modulation of amino acid synthesis allows Bacteria to mount a rapid response to environmental changes.

Another noteworthy example is The regulation of Glutamine Synthetase activity in E. coli, which involves a complex set of allosteric effectors. In this bacterium, glutamine serves as an amino group donor in The Biosynthesis of numerous metabolic products (Fig. 22-9). Eight different glutamine-derived metabolic products are known to act as feedback inhibitors (negative modulators) of glutamine synthetase activity in E. coli. Glutamine synthetase is one of the most intricate regulatory Enzymes known.

Because the 20 common Amino Acids are required for Protein Synthesis in specific proportions, Cells have evolved mechanisms that not only regulate The rate of synthesis of individual amino acids but also coordinate their production. This coordination is particularly well developed in rapidly growing bacterial cells. Figure 22-10 illustrates how E. coli coordinates the synthesis of four amino acids derived from aspartate: Lysine, Methionine, threonine, and isoleucine. The step converting aspartate to aspartyl phosphate is catalyzed by three independently regulated Isoenzymes. The steps converting aspartate semialdehyde to homoserine, and threonine to a-ketobutyrate, are each catalyzed by two independently regulated isoenzymes. One of the isoenzymes catalyzing The conversion of aspartate to aspartyl phosphate can be allosterically inhibited by two different modulators—lysine and isoleucine—whose combined effect is more than additive, representing another example of concerted inhibition (Section 17.24). The pathway leading from aspartate to isoleucine features multiple overlapping feedback inhibition mechanisms: isoleucine inhibits the conversion of threonine to a-ketobutyrate, whereas threonine suppresses its own formation at three distinct stages where the substrates are homoserine, aspartate semialdehyde, and aspartate. This type of control is known as sequential feedback inhibition.

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Fig. 22-8. Biosynthesis of isoleucine from threonine in E. coli. The first reaction of this biosynthetic pathway is inhibited by its end product, isoleucine. This is one of the earliest studied Examples of allosteric feedback inhibition. Valine can overcome or prevent the inhibitory effect of isoleucine.

Fig. 22-9. Allosteric inhibition of glutamine synthetase in E. coli. In this Organism, glutamine is the precursor of the products shown here, all of which can inhibit the enzyme via feedback regulation. Such combined action of multiple negative modulators is referred to as concerted inhibition. Glutamine synthetase is also strongly inhibited by an excess of ATP, which drives it into an inactive state through the Covalent Modification of critical Tyrosine residues within its subunits essential for catalytic activity. In animal Tissues, The activity of glutamine synthetase is regulated much more simply.

Fig. 22-10. An intricate network of regulatory mechanisms controlling the biosynthesis of several aspartate-derived amino acids in E. coli. The various types of regulation shown here are described in the text, along with an explanation of the symbols used in the figure.