09 Biosynthesis of Essential Amino Acids

Histidine Biosynthesis

-Includes an Intermediate in Nucleotide Biosynthesis -Five of histidine's six C atoms are derived from 5-phosphoribosyl-α-pyrophosphate (PRPP) -The histidine's sixth carbon originates from ATP. The enzymes shown are (1) ATP phosphoribosyltransferase and (2) glutamine amidotransferase

Lysine, Methionine, and Threonine

-Synthesized from Aspartate The pathway enzymes shown are (1) aspartokinase, (2) β-aspartate semialdehyde dehydrogenase, (3) homoserine dehydrogenase, and (4) methionine synthase (a coenzyme B12-dependent enzyme).

Essential Amino Acids Overview

-Their synthetic pathways are present only in microorganisms and plants. -The enzymes were apparently lost early in animal evolution, possibly because of the ready availability of these amino acids in the DIET! MR. LL HIV WTF

Leucine, Isoleucine, and Valine

Derived from Pyruvate -In this TPP-dependent reaction, pyruvate forms an adduct with TPP that is decarboxylated to hydroxyethyl-TPP -The leucine biosynthetic pathway branches off from the valine pathway. -The final step in each of the three pathways is the PLP-dependent transfer of an amino group from glutamate to form the amino acid. -The first enzyme, acetolactate synthase (a TPP enzyme), catalyzes two reactions, one leading to valine and leucine, and the other to isoleucine. Note also that valine aminotransferase catalyzes the formation of both valine and isoleucine from their respective α-keto acids

Aromatic Amino Acids Phenylalanine, Tyrosine, and Tryptophan

Synthesized from Glucose Derivatives -The precursors of the aromatic amino acids are the glycolytic intermediate phosphoenolpyruvate (PEP) and erythrose-4-phosphate -Their condensation forms 2-keto-3-deoxy-D-arabinoheptulosonate-7-phosphate (Fig. 21-34). -This C7 compound cyclizes and is ultimately converted to chorismate, the branch point for tryptophan synthesis -Chorismate is converted to either anthranilate and then to tryptophan, or to prephenate and on to tyrosine or phenylalanine -The last step in the synthesis of tyrosine and phenylalanine is the addition of an amino group through transamination -In tryptophan synthesis, the amino group is part of the serine molecule that is added to indole -The enzymes shown are (1) 2-keto-3-deoxy-D-arabinoheptulosonate-7-phosphate synthase, (2) anthranilate synthase, (3) tryptophan synthase, α subunit, (4) tryptophan synthase, β subunit (a PLP-dependent enzyme), and (5) chorismate mutase.

Indole Is Channeled between Two Active Sites in Tryptophan Synthase

The final two reactions of tryptophan biosynthesis are both catalyzed by tryptophan synthase (α2β2 bifunctional enzyme) (1) The α subunit cleaves indole-3-glycerol phosphate, yielding indole and glyceraldehyde-3-phosphate. (2) The β subunit = indole + serine = tryptophan; PLP-dependent reaction -Either subunit alone is enzymatically active, but when they are joined in the α2β2 tetramer, the rates of both reactions and their substrate affinities increase by 1 to 2 orders of magnitude. -Indole, the intermediate product, is channeled between the two subunits. -The X-ray structure of tryptophan synthase from Salmonella typhimurium reveals that the protein forms a 150-Å-long, twofold symmetric α-β-β-α complex in which the active sites of neighboring α and β subunits are separated by ~25 Å (Fig. 21-35) -The indole-3-glycerol phosphate substrate binds to the α subunit through an opening into its active site, its "front door," and the glyceraldehyde-3-phosphate product leaves via the same route. -Similarly, the β subunit active site has a "front door" opening to the solvent through which serine enters and tryptophan leaves. -Both active sites also have "back doors" that are connected by the tunnel. -The indole intermediate presumably diffuses between the two active sites via the tunnel and does not escape to the solvent (channeling).