Ornithine synthesis

Ornithine Biosynthesis. Two reaction sequences leading to ornithine synthesis from glutamic acid have been described. In Neurospora and the yeast Tondopsis utilis the sequence involves the simple transamination of glutamic semialdehyde (IV). The reaction proceeds much... 

This disease has been described in two siblings with progressive neurodegeneration, joint laxity, skin hyperelasticity and bilateral subcapsular cataracts. Besides hyperprolinemia, the metabolic phenotype consisted of hyperammonemia, hypoornithinemia, hypocitrullinemia, and hypoargininemia because proline as well as ornithine synthesis are impaired [15]. The disease is expected to be treatable with dietary proline and ornithine supplements. 

The precursor for ornithine synthesis is N-acetylglutamate, which is also an obligatory activator of carbamyl phosphate synthetase. This provides a regulatory mechanism — if N-acetylglutamate is not available for ornithine synthesis (and hence there would be impaired activity of the urea synthesis cycle), then ammonium is not incorporated into carbamyl phosphate. This can be a cause of hyperammonaemia in a variety of metabolic disturbances that lead to either a lack of acetyl CoA for N-acetyl glutamate synthesis or an accumulation of propionyl CoA, which is a poor substrate for, and hence an inhibitor of, N-acetylglutamate synthetase. 

Ornithine decarboxylase is a pyridoxal dependent enzyme. In its catalytic cycle, it normally converts ornithine (7) to putrisine by decarboxylation. If it starts the process with eflornithine instead, the key imine anion (11) produced by decarboxylation can either alkylate the enzyme directly by displacement of either fluorine atom or it can eject a fluorine atom to produce viny-logue 12 which can alkylate the enzyme by conjugate addidon. In either case, 13 results in which the active site of the enzyme is alkylated and unable to continue processing substrate. The net result is a downturn in the synthesis of cellular polyamine production and a decrease in growth rate. Eflornithine is described as being useful in the treatment of benign prostatic hyperplasia, as an antiprotozoal or an antineoplastic substance [3,4]. 

Hyperammonemia Type 2. A deficiency of ornithine transcarbamoylase (reaction 2, Figure 29-9) produces this X chromosome-linked deficiency. The mothers also exhibit hyperammonemia and an aversion to high-protein foods. Levels of glutamine are elevated in blood, cerebrospinal fluid, and urine, probably due to enhanced glutamine synthesis in response to elevated levels of tissue ammonia. 

Arginine is the formamidine donor for creatine synthesis (Figure 31-6) and via ornithine to putrescine, spermine, and spermidine (Figure 31-3) Arginine is also the precursor of the intercellular signaling molecule ni-... 

Figure 31-3. Arginine, ornithine, and proline metabolism. Reactions with solid arrows all occur in mammalian tissues. Putrescine and spermine synthesis occurs in both mammals and bacteria. Arginine phosphate of invertebrate muscle functions as a phosphagen analogous to creatine phosphate of mammalian muscle (see Figure 31-6).

PyrazOle-1 -carboxamidine has been used successfully in the solid-phase peptide synthesis for converting ornithine-containing peptides into the corresponding arginine peptides.181... 

The underlying biochemical defect is a failure of mitochondrial uptake of ornithine. This results in a failure of citrulline synthesis and a consequent hyperammonemia. Urinary orotic acid is high, presumably because of underutilization of carbamyl phosphate. In contrast, excretion of creatine is low, reflecting the inhibition of glycine trans-amidinase by excessive levels of ornithine. 

Hamilton, R., Walker, B., and Walker, B.J., A convenient synthesis of N-pro-tected diphenyl phosphonate ester analogues of ornithine, lysine and homolysine, Tetrahedron Lett., 34, 2847, 1993. 

In animal studies, mirex (a nonmutagenic hepatocarcinogen) promoted mouse skin squamous carcinomas and papillomas after initiation with 7,12-dimethyl-benz[a]anthracene (DMBA) for 1 week. Mirex, also, potentiated the promotional potency of the phorbol ester tumor promoter, 12-0 -tetradecanoylphorbol-13-acetate (TPA). There was a 90% incidence (activation) of the c-Ha-ras tumor gene in these co-promoted tumors. When both mirex and TPA gave a similar tumor yield, only the TPA response was associated with biochemical markers of enhanced cell proliferation, induction of epidermal ornithine decarboxylase activity and increased DNA synthesis, and hyperplasia. Thus, there is evidence for a dual effect of mirex during co-promotion first, as an independent tumor promoter with a mechanism different than that of phorbol esters and second, as a compound that also potentiates skin tumor promotion by TPA (Meyer et al. 1993, 1994 Moser et al. 1992, 1993). 

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