Glutamate 5-semialdehyde, proline synthesis

We have already described the biosynthesis of glutamate and glutamine. Proline is a cyclized derivative of glutamate (Fig. 22-10). In the first step of proline synthesis, ATP reacts with the y-carboxyl group of glutamate to form an acyl phosphate, which is reduced by NADPH or NADH to glutamate y-semialdehyde. This intermediate undergoes rapid spontaneous cychzation and is then reduced further to yield proline. 

Prohne is converted back to glutamate semialdehyde, which is reduced to form glutamate. The synthesis and degradation of proline use different enzymes even though the intermediates are the same. Hydroxyproline, however, has an entirely different degradative pathway (not shown). The presence of the hydroxyl group in hydroxyproline will allow an aldolase-like reaction to occur once the ring has been hydrolyzed, which is not possible with proline. 

Fig. 3. Proline and arginine synthesis and degradation to show interrelationships between the pathways. The structures are glutamic acid (GLU), ornithine (ORN), citrulline (CIT), arginine (ARG), urea. 2-oxo-5-amino valeric acid (OAV), A -pyrroline-2-carboxylic acid (P2C), proline (PRO), A -pyrroline-5-carboxylic acid (P5C), glutamic semialdehyde (GSA).

Figure 1. Contribution of different pathways to the ornithine usedfor citrulline synthesis. De novo synthesis of ornithine Proline is oxidised by action of proline oxidase (1) to generate pyrrolidine-5-car boxy late (P5C). P5C interconverts spontaneously with glutamate semialdehyde (GSA). Glutamine is deamidated by action of glutaminase (2) and the resulting glutamate is converted into GSA by pyrrolidine-5-carboxylate synthase (3). GSA is used by ornithine aminotransferase (OAT 4) to generate ornithine. Note that OAT is usedfor both synthesis and disposal of ornithine. Preformed ornithine ornithine is generatedfrom the hydrolysis of arginine by arginase (5), or can be transported from plasma. Ornithine is used for citrulline synthesis by action of ornithine transcarbamylase (OTC 6).

Enzymes catalyze almost every metabolic reaction in extant cells. A few tmusually facile reactions, such as cyclization of L-glutamate 7-semialdehyde to form pyrroline-5-carboxylate in the proline biosynthesis pathway and decarboxylation of 2-amino-3-oxo-4-phosphonooxybutyrate in the pyridoxal phosphate (PLP) synthesis pathway, do not require acceleration to satisfy the demands of the cell. For all other reactions, catalysis is required because the rates of nonenzymatic reactions are very slow. Modern enzymes are marvelous catalysts. They accelerate reactions by up to 20 orders of magnitude, prevent side reactions of reactive intermediates, and catalyze stereoselective and stereospecific reactions. Further, they are often exquisitely regulated by small molecule ligands. 

Figure 21.2 shows the sequence of reactions that converts glutamate to ornithine (a urea cycle intermediate). In this pathway, the energy-requiring reduction of glutamate to glutamicy-semialdehyde (see here) is comparable to the reduction of aspartate to aspartic semialdehyde (see here) and also leads to synthesis of proline (see here). In the synthesis of proline, however, cyclization is desirable because the cyclized product can be reduced with NADPH to proline. 

In the synthesis of proline, glutamate is first phosphorylated and then converted to glutamate 5-semialdehyde by reduction of the side chain carboxyl group to an... 

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