Ornithine biosynthesis

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... 

Vogel discovered an alternate pathway of ornithine biosynthesis from glutamic acid involving AT-acetylglutamate 114, 116). He has obtained evidence that this is the major pathway for ornithine formation in E. colt and Neurospora 127). The pathway shown in Fig. 5 is of minor importance for ornithine biosynthesis but is the major one for proline. These conclusions have been substantiated by isotope competition experiments 128). The steps in the acetylglutamate pathway is shown in Fig. 6. 

A -Pyrroline has been prepared in low yield by oxidation of proline with sodium hypochlorite (71), persulfate (102), and periodate (103). A -Pyrroline and A -piperideine are products of enzymic oxidation via deamination of putrescine and cadaverine or ornithine and lysine, respectively (104,105). This process plays an important part in metabolism and in the biosynthesis of various heterocyclic compounds, especially of alkaloids. 

Figure 29-9. Reactions and intermediates of urea biosynthesis. The nitrogen-containing groups that contribute to the formation of urea are shaded. Reactions and occur in the matrix of iiver mitochondria and reactions , , and in iiver cytosoi. COj (as bicarbonate), ammonium ion, ornithine, and cit-ruiiine enter the mitochondriai matrix via specific carriers (see heavy dots) present in the inner membrane of iiver mitochondria.

Since pyrimidine catabolites are water-soluble, their overproduction does not result in clinical abnormalities. Excretion of pyrimidine precursors can, however, result from a deficiency of ornithine transcar-bamoylase because excess carbamoyl phosphate is available for pyrimidine biosynthesis. 

Biosynthesis of polyamines is essential for growth and multiplication of T. brucei, hence discovery of drug candidates that inhibit enzymes in the polyamine biosynthesis pathway represent an attractive approach to development of trypanocides. The consequences of gene knockout of ornithine decarboxylase (ODC), the target of eflornithine (3), have been further characterized and suggest that new inhibitors of this enzyme may be particularly effective [18]. 

The pivotal role of hygrine in the biosynthesis of cuscohygrine and of the tropane alkaloids has justified numerous investigations. The following scheme represents the now generally admitted pattern of formation of these bases. Ornithine (119) is first converted to putrescine or V-methylputrescine (120)... 

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... 

When the biosynthetic pathways given above are examined, it is apparent that several intermediates are indeed nonprotein ct-amino acids. Ornithine, homoserine, homocysteine, and ct-e-diaminopimelic acid are a few examples. This shows that some nonprotein amino acids originate as intermediates during the biosynthesis of... 

Only a few important representatives of the non-proteinogenic amino acids are mentioned here. The basic amino acid ornithine is an analogue of lysine with a shortened side chain. Transfer of a carbamoyl residue to ornithine yields citrulline. Both of these amino acids are intermediates in the urea cycle (see p.l82). Dopa (an acronym of 3,4-dihydroxy-phenylalanine) is synthesized by hydroxyla-tion of tyrosine. It is an intermediate in the biosynthesis of catecholamines (see p.352) and of melanin. It is in clinical use in the treatment of Parkinson s disease. Selenocys-teine, a cysteine analogue, occurs as a component of a few proteins—e.g., in the enzyme glutathione peroxidase (see p.284). 

Robins, R. J., Parr, A. J. and Walton, N. J. 1991. Studies on the biosynthesis of tropane alkaloids in Datura stramonium L. transformed root cultures. 2. on the relative contributions of L-arginine and L-ornithine to the formation of the tropane ring. Planta, 183 196-201. 

Eflorni thine Inhibits ornithine decarboxylase and biosynthesis of polyamines Affects cell division, differentiation... 

S.2.3.3 Treatment of Trypanosomiasis The difluoromethylornithine (DFMO), eflomithine is a mechanism-based inhibitor of ornithine decarboxylase— a pyridoxal-dependent key enzyme of the polyamine s biosynthesis from ornithine. Fluorine atoms are essential for the inhibition process (cf. Chapter 7). Eflornithine was first clinically developed for cancer, but its development has been abandoned for this indication. The activity of eflornithine on trypanosomes was then discovered. Now, despite its very low bioavailability, eflornithine is the best therapy for sleeeping sickness (trypanosomiasis)—in particular, at the cerebral stage—due to Trypanosoma brucei gambiense parasite. Eflornithine is registered with orphan drug status and is distributed by the WHO. 

Eflornithine (Vaniqa) is an irreversible inhibitor of ornithine decarboxylase, which catalyzes the rate-limiting step in the biosynthesis of polyamines. Polyamines are required for cell division and differentiation, and inhibition of ornithine decarboxylase affects the rate of hair growth. Topical eflornithine has been shown to be effective in reducing facial hair growth in approximately 30% of women when applied twice daily for 6 months of therapy. Hair growth was observed to return to pretreatment levels 8 weeks after discontinuation. Local adverse effects include stinging, burning, and folliculitis. 

Muscle activity involves processes such as aerobic and anaerobic glycolysis and is therefore accompanied by an increased pyruvate production. Consequently, the pyruvate transamination product alanine will be increased after exercise. Heavy exercise may be associated with an increased need of creatine biosynthesis from arginine. Ornithine is a by-product of this pathway and may be increased under these conditions. 

FIGURE 3-8 Uncommon amino acids, (a) Some uncommon amino acids found in proteins. All are derived from common amino acids. Extra functional groups added by modification reactions are shown in red. Desmosine is formed from four Lys residues (the four carbon backbones are shaded in yellow). Note the use of either numbers or Creek letters to identify the carbon atoms in these structures, (b) Ornithine and citrulline, which are not found in proteins, are intermediates in the biosynthesis of arginine and in the urea cycle. 

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