Amino acids ornithine

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). 

In the next step, the carbamoyl residue is transferred to the non-proteinogenic amino acid ornithine, converting it into citrulline, which is also non-proteinogenic. This is passed into the cytoplasm via a transporter. 

Among the numerous enzymes that utilize pyridoxal phosphate (PLP) as cofactor, the amino acid racemases, amino acid decarboxylases (e.g., aromatic amino acids, ornithine, glutamic acid), aminotransferases (y-aminobutyrate transaminase), and a-oxamine synthases, have been the main targets in the search for fluorinated mechanism-based inhibitors. Pharmaceutical companies have played a very active role in this promising research (control of the metabolism of amino acids and neuroamines is very important at the physiological level). 

In the urea cycle, two molecules of ammonia combine with a molecule of carbon dioxide to produce a molecule of urea and water. The overall cycle involves a series of biochemical reactions dependent on enzymes and carrier molecules. During the urea cycle the amino acid ornithine (C5H12N202) is produced, so the urea cycle is also called the ornithine cycle. A number of urea cycle disorders exist. These are genetic disorders that result in deficiencies in enzymes needed in one of the steps in the urea cycle. When a urea cycle deficiency occurs, ammonia cannot be eliminated from the body and death ensues. 

Many important neurotransmitters are primary or secondary amines, derived from amino acids in simple pathways. In addition, some polyamines that form complexes with DNA are derived from the amino acid ornithine, a component of the urea cycle. A common denominator of many of these pathways is amino acid decarboxylation, another PLP-requiring reaction (see Fig. 18-6). 

There are several classes of alkaloids. Among these are purines such as xanthine and caffeine, ter-penes (Chapter 22), polyketides (Chapter 21), and alkaloids derived from amino acids. The basic amino acids ornithine, arginine, histidine, and lysine as well as the aromatic amino acids, anthranilate, and nicoti-nate are some of the starting materials.199 201 Robinson202 203 in 1917 recognized that many alkaloids are derived directly from aromatic amino acids. He proposed that alkaloids arise from Mannich reactions (Eq. 25-12) in which an amine and an aldehyde (probably through a Schiff base) react with a nucleophilic carbon such as that of an enolate anion. Many of the... 

Careful inspection of the reported photocatalytic reactions may demonstrate that reaction products can not be classified, in many cases, into the two above categories, oxidation and reduction of starting materials. For example, photoirradiation onto an aqueous suspension of platinum-loaded Ti02 converts primary alkylamines into secondary amines and ammonia, both of which are not redox products.34) ln.a similar manner, cyclic secondary amines, e.g., piperidine, are produced from a,co-diamines.34) Along this line, trials of synthesis of cyclic imino acids such as proline or pipecolinic acid (PCA) from a-amino acids, ornithine or lysine (Lys), have beer. successfuL35) Since optically pure L-isomer of a-amino acids are available in low cost, their conversion into optically active products is one of the most important and practical chemical routes for the synthesis of chiral compounds. It should be noted that l- and racemic PCA s are obtained from L-Lys by Ti02 and CdS photocatalyst, respectively. This will be discussed later in relation to the reaction mechanism. 

The entry of activated ammonia into the urea cycle occurs by the ornithine transcarbamoylase reaction where the carbamoyl group is transferred to the side chain amino group of the non-protein amino acid, ornithine. Ornithine has five carbons its carbon chain therefore has the same length as that of arginine. The product of the ornithine transcarbamoylase reaction is the amino acid citrulline. 

Just as terpenes could be viewed as being formed from isoprene units, alkaloids can be viewed as being derived from amino acids. Four amino acids give rise to important classes of alkaloids. As shown in Table 28.1, the pyrrolidine alkaloids are derived from the amino acid ornithine (not one of the 20 standard amino acids), the piperidine alkaloids from lysine, the isoquinoline alkaloids from tyrosine, and the indole alkaloids from tryptophan. 

Nutritional and Physiological Effects of Alkali-Treated Proteins. The first effect of the alkaline treatment of food proteins is a reduction in the nutritive value of the protein due to the decrease in (a) the availability of the essential amino acids chemically modified (cystine, lysine, isoleucine) and in (b) the digestibility of the protein because of the presence of cross-links (lysinoalanine, lanthionine, and ornithinoalanine) and of unnatural amino acids (ornithine, alloisoleucine, / -aminoalanine, and D-amino acids). The racemization reaction occurring during alkaline treatments has an effect on the nitrogen digestibility and the use of the amino acids involved. 

Metabolism of arginine produces urea and the rare amino acid ornithine. Ornithine has an isoelectric point close to 10. Propose a structure for ornithine. 

Pyrrolidine alkaloids are made from the amino acid ornithine... 

Figure 1 Representative siderophores of the hydroxamate and catecholate classes. The hydroxamates are synthesized from the amino acid ornithine that has been modified through hydroxylation and acetylation. Ferrichrome (a) is a prototypical example of the tri-hydroxamate class. Structurally, ferrichrome is a cyclic hexapeptide that consists of three modified ornithine residues (each of which has a hydroxamate side chain) and three glycines. Ferrichrome coordinates ferric iron through its three bidentate hydroxamate side chains. Triacetylfusarinine C (b) is also a cyclic tri-hydroxamate, but the three modified ornithine residues are joined by ester linkages rather than by peptide linkages. Ferrioxamine B (c) is a linear tri-hydroxamate consisting of three peptide-huked modified ornithine residues. Enterobactin (d) is a prototypical example of a catecholate siderophore. It consists of a tri-ester ring from which extend three side chains of chhydroxybenzoyl serine. Each of these siderophores binds ferric iron in a hexadentate manner, which results in full saturation of d orbitals and a very stable complex. Ferric forms are shown in (a) and (b). Desferri-forms are shown in (c) and (d)...

Tetracycline targets protein synthesis in Plasmodium via a similar mechanism to that seen in bacteria inhibition of chain elongation and peptide bond formation. Eflornithine interferes with the metabolism of the amino acid ornithine in T. brucei gambiense by acting as a suicide substrate for the enzyme ornithine decarboxylase. 

Intracellular metabolism of amino acids requires their transport across the cell membrane. Transport of L-amino acids occurs against a concentration gradient and is an active process usually coupled to Na -dependent carrier systems as for transport of glucose across the intestinal mucosa (Chapter 12). At least five transport systems for amino acids (with overlapping specificities) have been identified in kidney and intestine. They transport neutral amino acids, acidic amino acids, basic amino acids, ornithine and cystine, and glycine and proline, respectively. Within a given carrier system, amino acids may compete for transport (e.g., phenylalanine with tryptophan). Na+-independent transport carriers for neutral and lipophilic amino acids have also been described, d-Amino acids are transported by simple diffusion favored by a concentration gradient. 

Ammonia is condensed with bicarbonate and ATP in the mitochondrion to form carbamoyl phosphate in a reaction catalyzed by carbamoyl phosphate synthetase I. Two molecules of ATP are used in this reaction one provides the phosphate, and the other is hydrolyzed to ADP and inorganic phosphate (P) to provide the energy that drives the reaction to products. The activated carbamoyl group is then transferred to the amino acid ornithine by the mitochondrial enzyme ornithine transcarbamoylase to form citrulline. Citrulline then is transported out of the mitochondrion to the cytosol, where the rest of the reactions... 

The urea cycle converts NH4 to urea, a less toxic molecule. The sources of the atoms in urea are shown in color. Cit-rulline is transported across the inner membrane by a carrier for neutral amino acids. Ornithine is transported in exchange for H+ or citrulline. Fumarate is transported back into the mitochondrial matrix (for reconversion to malate) by carriers for a-ketoglutarate or tricarboxylic acids. 

In 1978, Metcalf and colleagues developed a-difluoromethylornithine (DFMO), a derivative of the amino acid ornithine, that leads to irreversible inhibition of the enzyme ODC by alkylation of its active site and... 

Step 2. The carbamoyl phosphate thus produced condenses with the amino acid ornithine to produce the amino acid citrulline. This reaction also occurs in the mitochondria and is catalyzed by the enzyme ornithine transcarbamoylase. 

Cal Kulis and other patients with cystinuria have a genetically determined defect in the transport of cystine and the basic amino acids, lysine, arginine, and ornithine, across the brush-border membranes of cells in both their small intestine and renal tubules. However, they do not appear to have any symptoms of amino acid deficiency, in part because the amino acids cysteine (which is oxidized in blood and urine to form the disulfide cystine) and arginine can be synthesized in the body (i.e., they are "nonessential" amino acids). Ornithine (an amino acid that is not found in proteins but serves as an intermediate of the urea cycle) can also be synthesized. The most serious problem for these patients is the insolubility of cystine, which can form kidney stones that may lodge in the ureter, causing bleeding and severe pain. 

In some other peptides, the cyclic structure is formed by the peptide bonds themselves. Two cyclic decapeptides (peptides containing 10 amino acid residues) produced by the bacterium Bacillus brevis are interesting examples. Both of these peptides, gramicidin S and tyrocidine A, are antibiotics, and both contain D-amino acids as well as the more usual L-amino acids (Figure 3.14). In addition, both contain the amino acid ornithine (Orn), which does not occur in proteins, but which does play a role as a metabolic intermediate in several common pathways (Section 23.6). 

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