Glutamate 5-semialdehyde, proline

Oxidation of proline and arginine residues leads also to formation of glutamate semialdehyde and, upon its further oxidation, to pyroglutamic acid (A9). Oxidized proline produces also 2-pyrrolidone (K6) (Fig. 5). 

Proline and arginine can be derived from glutamate semialdehyde, which is formed by reduction of glutamate. 

Scheme 11 Oxidation of proline causes ring opening with the resultant formation of glutamic semialdehyde...

The glutamic semialdehyde formed in the intestine can also cyclize and be reduced to form proline. Therefore, proline is not an essential amino acid in people. Any amino acid that can form glutamate can be converted to glucose. Among the amino acids that can produce glutamate, which will be examined in more detail when they are discussed individually, are glutamine, arginine via ornithine formation, proline, and histidine. 

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).

In higher plants metabolism of ornithine labeled in the a- or 8-amino group with is metabolized to proline with the loss of the a-amino group (Duranton and Wurtz, 1965 Liebisch and Schutte, 1967). Similar conclusions were reached after administration of [2- H, 5- C] or [5- H, 5- C]ornithine to leaves of three species because the ratio of tritium to C in proline decreased only from [2- H, 5- C]omithine (Mestichelli et al., 1979). These findings mean that ornithine is converted to OAV and not glutamic semialdehyde en route to proline. These results are not easily explained by enzymatic studies. 

Glutamic acid as an intermediate is formed from proline by the action of the cyclophorase system in the absence of AMP and Mg++. Under these conditions the oxidation is incomplete, and its accumulation was demonstrated by tests with the glutamic acid decarboxylase of E. coli, and by the action of chloramine-T, which yielded an equivalent amount of succinic acid. In addition to glutamic acid, a bisulfite-binding intermediate is produced in about equal amount, which may be glutamic semialdehyde. 

Evidence in favor of the key role of glutamic semialdehyde in ornithine catabolism is the observation that deuteuroornithine is converted in the rat to proline and glutamic acid 169) and that liver and kidney slices... 

The key compound in the interconversions of the amino acids, glutamic acid, ornithine, and proline is glutamic semialdehyde. This cyclizes spontaneously in aqueous solution to A -p3Troline-5-carboxylic acid and the two compounds are in equilibrium with each other. 

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).

Proline. Prohne forms dehydroprohne, glutamate-y-semialdehyde, glutamate, and, ultimately, a-ketoglu-tarate (Figure 30—3, top). The metabohc block in type I kyperprolinemia is at proline dehydrogenase. 

Figure 30-3. Top Catabolism of proline. Numerals indicate sites of the metabolic defects in type I and type II hyper-prolinemias. Bottom Catabolism of arginine. Glutamate-y-semialdehyde forms a-ketoglutarate as shown above. , site of the metabolic defect in hyperargininemia.

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 praline 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 cyclization and is then reduced further to yield proline. 

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