Ornithine degradation

In the branched-chain amino acids (Val, Leu, He) and also tyrosine and ornithine, degradation starts with a transamination. For alanine and aspartate, this is actually the only degradation step. The mechanism of transamination is discussed in detail on p. 178. 

Branched-chain amino acids apparently stimulate the urea cycle. Carbamoylphosphate synthetase, which channels ammonia into the urea cycle, is induced by ornithine and N-acetylglutamate as a cofactor of urea synthesis. Here, BCAA follow two modes of action (i.) they stimulate the synthesis of N-acetylglutamate via synthetase formed from glutamate and acetyl CoA, and (2.) they inhibit omithine-keto acid transferase, which is the enzyme responsible for ornithine degradation, leading to an increase in ornithine concentration. Ammonia detoxication is thus stimuiated by two regu-iatory mechanisms, (s. fig. 40.2)... 

Fig. 38.14. The ornithine aminotransferase reaction. This is a reversible reaction dependent on pyridoxal phosphate, which normally favors ornithine degradation.

D-Arginine and D-ornithine metabolism D-Alanine metabolism Glutathione metabolism Alkaloid biosynthesis I Alkaloid biosynthesis II Metabolism of Complex Carbohydrates Starch and sucrose metabolism Biosynthesis and degradation of glycoprotein... 

The 26S proteasome also degrades non-ubiquitylated proteins [71]. The short-lived enzyme ornithine decarboxylase (ODC) and the cell-cycle regulator p21Cip provide well documented examples of ubiquitin-independent proteolysis by the 26S en-... 

Murakami, Y. et al. Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. Nature 1992, 360, 597-9. 

Murakami, Y., Matsueuji, S., Hayashi, S. I., Tanahashi, N., and Tanaka, K. ATP-Dependent inactivation and sequestration of ornithine decarboxylase by the 26 S proteasome are prerequisites for degradation. Mol Cell Biol 1999, 39, 7216-27. 

Kameji, T., Hayashi, S., Igarashi, K., Tamura, T., Tanaka, K., and Ichihara, a. Ornithine decarboxylase is degraded by the 26 S proteasome without ubiquitination. Nature 1992, 360, 597-599. 

Plasma should be separated from the blood cells within a few hours. For most amino acids the levels in plasma and red cells are comparable, but glutamate, aspartate, and taurine have extremely high intracellular levels and thus tend to rise in plasma upon hemolysis. A second effect of red cell degradation is the liberation of the enzyme arginase, which will convert arginine into ornithine. 

In mammalian cells, ornithine decarboxylase undergoes rapid turnover—that is, a constant round of enzyme degradation and synthesis. In some trypanosomes, however, the enzyme—for reasons not well understood—is stable, not readily replaced by newly synthesized enzyme. An inhibitor of ornithine decarboxylase that binds permanently to the enzyme would thus have little effect on human cells, which could rapidly replace inactivated enzyme, but would adversely affect the parasite. 

Genetic factors influence the rate of not only synthesis of proteins but also their breakdown, i.e., the rate of turnover. As we have seen in Chapter 10, some enzymes are synthesized as inactive proenzymes which are later modified to active forms, and active enzymes are destroyed, both by accident and via deliberate hydrolytic pathways. Protein antienzymes may not only inhibit enzymes but may promote their breakdown.35 An example is the antienzyme that controls ornithine decarboxylase, a key enzyme in the synthesis of the polyamines that are essential to growth.36,37 As with all cell constituents, the synthesis of enzymes and other proteins is balanced by degradation. 

The absolute configuration of (-l-)-physoperuvine, and of its N-benzoyl derivative, was determined by the positive Cotton effect around 290 nm, in the region exactly as reported5 for (R)-(+)-3-methylcycloheptanone. The racemic form accompanies the optically active one in the plant they were separated by column chromatography. Since tropane alkaloids form in vivo from ornithine via A-pyrroline,6 the biogenetic role of secotropanes is likely to be that of products of degradation rather than of intermediates in the formation of the tropane bases. 

The structure of most of these compounds must be considered as quite well established. Deferrideoxyferrichrome, prepared from the parent compound with Raney nickel and H2 at 50 lbs pressure, is identical to a synthetic cyclic hexapeptide obtained by stepwise addition of three residues of NS-acetyl-L-ornithine to triglycine, followed by cyclization (112). The amino acid sequence in ferrichrome A has been established by degradation (112, 113) and confirmed by crystallography (150). Removal of the a—p unsaturated residue of ferrichrome A, ferrirubin and ferrirho-din followed by re-acylation with acetyl gives, in each case, ferrichrysin (63). All four substances must hence have an identical amino acid sequence and we assume for all of these compounds the configuration shown in Fig. 5. 

Figure 20.19 Biosynthesis and degradation of proline, hydroxyproline and ornithine. Proline oxidase and S-pyrroIine-5-carboxylic acid dehydrogenase are both mitochondrial enzymes. A and B indicate defects in hyperprolinemia I and II, respectively.

Ornithine is required to maintain the urea cycle. Conversion of glutamate to ornithine via glutamate semialdehyde is therefore an anaplerotic reaction. Melatonin is a compound synthesized from serotonin. It has a function in the circadian rhythm activity and has nothing to do with intracellular protein degradation. 

Citrulline takes its name from the watermelon genus (Citrullus) in which it was first found in 1930. It was also discovered the same year as a bacterial degradation product of arginine. Krebs, who elucidated the form of the urea cycle, demonstrated that citrulline was the intermediate between ornithine and arginine. The urea cycle was the first metabolic cycle to be discovered. In Krebs words, it revealed a new pattern of the organization of metabolic processes. ... 

---