Diaminopimelate pathway

The 5-carbon 2-oxoglutarate is the starting compound. Bacteria, other lower fungi, and green plants all use the diaminopimelate pathway (Fig. 24-14) which originates with the 4-carbon aspartate. 

Palva AM, Vanderwall DE, Blanchard JS, et al. Inhibitors of hydrodipicolinate reductase, a key enzyme of the diaminopimelate pathway of Mycobacterium tuberculosis. Biochim Biophys Acta 2001 1545 67-77. 

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... 

FIGURE 22-15 Biosynthesis of six essential amino acids from oxalo-acetate and pyruvate in bacteria methionine, threonine, lysine, isoleucine, valine, and leucine. Here, and in other multistep pathways, the enzymes are listed in the key. Note that L,L-a,e-diaminopimelate, the product of step (HI), is symmetric. The carbons derived from pyruvate (and the amino group derived from glutamate) are not traced beyond this point, because subsequent reactions may place them at either end of the lysine molecule. 

Outline of the biosynthesis of the 20 amino acids found in proteins. The de novo biosynthesis of amino acids starts with carbon compounds found in the central metabolic pathways. The central metabolic pathways are drawn in black, and the additional pathways are drawn in red. Some key intermediates are illustrated, and the number of steps in each pathway is indicated alongside the conversion arrow. All common amino acids are emphasized by boxes. Dashed arrows from pyruvate to both diaminopimelate and isoleucine reflect the fact that pyruvate contributes some of the side-chain carbon atoms for each of these amino acids. Note that lysine is unique in that two completely different pathways exist for its biosynthesis. The six amino acid families are screened. 

In addition to the 20 amino acids most frequently found in proteins a large group of amino acids occur in plants, bacteria, and animals that are not found in proteins. Some are found in peptide linkages in compounds that are important as cell wall or capsular structures in bacteria or as antibiotic substances produced by bacteria and fungi. Others are found as free amino acids in seeds and other plant structures. Some amino acids are never found in proteins. These nonprotein amino acids, numbering in the hundreds, include precursors of normal amino acids, such as homoserine and diaminopimelate intermediates in catabolic pathways, such as pipecolic acid d enantiomers of normal amino acids and amino acid analogs, such as azetidine-2-carboxylic acid and canavanine, that might be formed by unique pathways or by modification of normal amino acid biosynthetic pathways. 

The oomycetes, hyphochytrids, labyrinthuloids, and thraustochytrids are included in the kingdom Heterokontobionta or pseudofungi [54] based on the presence of cellulose in their cell walls, a tubular mitochondrial crista, hetero-kont flagella, one decorated with tripartite hairs, and the a, (3-diaminopimelic acid lysine biosynthetic pathway. The slime molds were classified into the kingdom Protozoa [38]. 

Alkaloid metabolism in lupine was proved by Wink and Hartmann to be associated with chloroplasts (34). A series of enzymes involved in the biosynthesis of lupine alkaloids were localized in chloroplasts isolated from leaves of Lupinus polyphylls and seedlings of L. albus by differential centrifugation. They proposed a pathway for the biosynthesis of lupanine via conversion of exogenous 17-oxosparteine to lupanine with intact chloroplasts. The biosynthetic pathway of lupinine was also studied by Wink and Hartmann (35). Two enzymes involved in the biosynthesis of alkaloids, namely, lysine decarboxylase and 17-oxosparteine synthetase, were found in the chloroplast stoma. The activities of the two enzymes were as low as one-thousandth that of diaminopimelate decarboxylase, an enzyme involved in the biosynthetic pathway from lysine to diaminopimelate. It was suggested that these differences are not caused by substrate availability (e,g., lysine concentration) as a critical factor in the synthesis of alkaloids. Feedback inhibition would play a major role in the regulation of amino acid biosynthesis but not in the control of alkaloid formation. 

Bacteria synthesize lysine through one of three different pathways that are not present in mammals. " An intermediate in these pathways, wj ro-diaminopimelic acid (mDAP), is also an essential component of the bacterial cell wall. " " Consequently, the enzymes in these pathways are targets for the development of antibiotics for treatment of Gram-negative and Gram-positive bacterial infections. The enzyme DapE catalyzes the hydrolysis of N-succinyl-L,L-diaminopimelic acid to form L,L-diaminopimelic acid and succinate in the succinylase pathway of lysine biosynthesis (Figure 6(i)). 

Enzymes which could catalyze the next four reactions in the pathway have not been isolated from plants. Assuming that these reactions are analogous to those which occur in microorganisms, the NAD(P)H-dependent reduction of 2,3-dihydropicolinate to A -piperidine-2,6-dicarboxylate would be followed by acylation of the amino group (the latter reaction may involve prior nonen-zymatic hydrolysis of the C-N double bond). Acylation serves to protect the 2-amino group during the synthesis of the diamino intermediate either acetyl-CoA or succinyl-CoA is utilized in microorganisms. Deacylation of A -acyl-2,6-diaminopimelate results in the formation of a symmetrical l,l... 

Fig. 1. Bio thetic pathways for the essential aspartate-family amino adds. The numbers represent enzymes catalyzing the reaction 1, aspartate kinase 2, homoserine dehydrogenase 3, homoserine kinase 4, threonine thase 5, threonine dehydrogenase 6, acetolactate thase 7, dihydrodipicolinate thase 8, diaminopimelate decarboiylase.

The biosynthesis of lysine in higher plants involves the formation of a, e-diaminopimelate from aspartate and pyruvate. Transamination of this intermediate to the diketo compound and reduction of one carboxyl group to an aldehyde function may produce a compound capable of cyclization via aldol condensation, i.e., the C4 -I- C3 pathway. ... 

Fig.5. L-iysine. Diaminopimelic acid pathway of L-lysine biosynthesis.

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