A-Aminoadipate pathway

Lysine cannot be made at all by animals but is nutritionally essential. There are two distinct pathways for its formation in other organisms. Tire a-aminoadipate pathway (shown in Fig. 24-9) occurs in a few lower fungi, the higher fungi, and euglenids. 

In fungi, lysine is synthesized via an a-aminoadipate pathway [33], The conversion of homoisocitric acid to a-ketoadipic acid occurs due to enzyme homoisocitrate dehydrogenase (EC 1.1.1.87, NAD-HDH) ... 

JK Bhattacharjee. Evolution of a-aminoadipate pathway for the synthesis of lysine in fungi. In RP Mortlock, ed. The Evolution of Metabolic Function. London CRC Press, 1992, pp 47-80. 

This is Da-aminoadipic add. You will learn a little later in the chapter that the normal biosynthetic pathway of pendllin production involves the incorporation of L-a aminoadipic add. The product is called isopenidllin N. 

The essential amino acid lysine (2,5-diaminohexanoic acid) can be degraded via two pathways, viz. the so-called saccharopine pathway and the pipecolic acid (PA) pathway. Both pathways merge at the level of a-aminoadipic acid semialdehyde (AASA). It is generally accepted that the saccharopine pathway constitutes the major breakdown pathway. However, the PA pathway has attracted much attention since the discovery of the association between the presence of elevated PA levels and Zellweger syndrome almost 40 years ago. Mainly because the analysis of amino acids was the primary biochemical approach for studying presumed inborn errors of metabolism, PA in Zellweger syndrome was discovered even before it was realized that this disorder was based on a defect of peroxisomal functions. 

The biosynthesis of penicillins has been extensively studied, and the general biosynthetic pathway from a-aminoadipic acid (33), cysteine (34) and valine (35) is shown in Scheme 7. Enzymic removal of the side chain of the product (36) affords 6-APA which may then be chemically modified to form the other semisynthetic penicillins in Figure 5. 

Penicillin Formation by Penicillium Chrysogenum. The first reactions of the penicillin biosynthetic pathway are identical to the ones in A. chrysogenum (Figure 1.1-1). IPN, however, is not epimerized to penicillin N instead it is converted to 6-aminopenicillanic acid (6-APA) by removal of the L-a-aminoadipic acid side chain, which is substituted by a hydrophobic acyl group. Both steps are catalyzed by the same enzyme, the acyl coenzyme A IPN acyltransferase (IAT). The enzymatic activity of lAT is believed to be the result of the processing of a 40-kD monomeric precursor into a dimeric form consisting of two subunits with MWs of 11 and 29 kD. Due to the broad substrate specifity of lAT, various penicillin derivatives are synthesized naturally by attachment of different acyl-CoA derivatives to the 6-APA-core. For industrial purposes, to facilitate extraction by organic solvents, synthesis usually is directed to the less hydrophilic penicillin V or penicillin G. This is by addition of phenoxyacetic acid or phenylacetic acid, respectively, as precursors to the culture broth. 

In rat liver, Lys degradation (Fig.l) occurs primarily in the mitochondria. Some features of the degradation pathway appear to be a reversal of the reactions of Lys synthesis (Figs. 4 5). Saccharopine is formed, offering a direct route to 2-aminoadipic-6-semialdehyde, and bypassing the cyclic piperideine and piperidine intermediates. The semialdehyde is also produced by a second pathway, initiated by L-amino acid oxidase. The resulting oxoacid cyclizes spontaneously to A -piperideine 2-carboxylic acid. 

Succinic acid is incorporated into the 2-, 3- and 7-carbon atoms of ricinine (3-cyano-4-methoxy-l-methyl-2-pyridone). Carbon 1 of succinic acid becomes the nitrUe carbon of ricinine. " Nicotinic acid and nicotinamide are highly incorporated into ricinine, which suggests that these two compounds are closer to ricinine than is succinic acid. Ricinine and nicotine show labeling patterns that are consistent with a pathway where succinic acid or a related dicarboxylic acid is a precursor to nicotinic acid, which is an intermediate in the formation of nicotine and ricinine. The a-carbon of lysine is incorporated into carbon 6 of ricinine and the e-carbon of a-aminoadipic acid is incorporated into carbons 2 and b. " ... 

In fungi, although a-aminoadipaie is available fiom the lysine biosyniheTic pathway, it could also be obtained from a lysine catabolic pathway, similar to that fouiKl in the actinomycetes, and be channeled into penicillin biosynthesis. In keeping with this possibility, a lysine auxotroph of Pentdltium cfiryspgenum with a block before a-aminoadi-pate formation was found to produce penicillin in a lysine-supplemented medium, and it showed LAT activity (17). Therefore, in fungi, in addition to the lysine biosynthetic pathway, lysine catabolism may also provide a-aminoadipate for penicillin biosynthesis however, the relative contribution of each pathway is unclear. 

The first two steps of the common penicillin/cephalosporin biosynthetic pathway bring about the condensation of the three precursor amino acids, a-aminoadipate, cysteine, and valine, to form the tripeptide ACV, and the subsequent cyclization of ACV to form... 

Lysine is an essential amino acid for animals. Not only is this compound not synthesized, but it does not contribute significant quantities of either nitrogen or carbon to other amino acids. The biosynthesis of lysine occurs in bacteria and fungi, and presumably in higher plants. Neurospora and E. coli have been found to use different pathways. The pathway in Neurospora involves the synthesis of a-aminoadipic acid, which appears to be reduced to the semialdehyde, which then, in a transamination, yields lysine. The corresponding a-amino- -hydroxycaproic... 

Understanding of the pathway of catabolism of lysine was opened up by the discovery of Borsook and co-workers that a-aminoadipic acid is formed from lysine in guinea pig liver homogenates. This observation leads to the scheme of catabolism shown below in Fig. 11, which was suggested by Borsook and co-workers. ... 

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