Saccharopine pathway

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 hyperlysinemias are characterized by a block in the saccharopine pathway. Subsequently, the PA pathway is overloaded. It is assumed that the capacity of the latter pathway is not sufficient to tackle all lysine molecules. 

Ketoglutarate reductase catalyzes the formation of saccharopine from lysine, which is the first step in a major pathway for lysine catabolism. NADPH and a-ketoglutarate are cofactors in the reaction. 

L-Saccharopine. N-(5-Amino-5-carboxypemyt)-L-glutamic acid -Af-(L-glutar-2-yl)-L-lysine. CnH NjO. mol wt 276.29. C 47.82%. H 7.30%, N 10.14%, O 34.75%. A lysine precursor in the aminoadipic add-lysine pathway in yeast Darling. Larsen, Acta Chem. Scand. IS, 743 (1961) Kjaer. Larsen, ibid. 750 Kuo et al. Biochem Biophys. Res. Commun. 8, 227 (1962) Trupin, Broquist, J. Biol Chem. 240, 2524 (1965) Jones, Broquist, ibid. 241, 3430 sqq. (1966). Isoln from mycelium of the yeast Candida utilis Marimoto, Yamano, Biochem. Z. 340, 155 (1964). 

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. 

Wickwire BM, Haihs CM, Harris TM, Broquist HP. Pipecolic acid biosynthesis in Rfu zocto-nia leguminicola. 1. The lysine, saccharopine, A -piperidine-fr-carboxylaie pathway. J Biol Chem 1990 265 14742-14747. 

Jones, E. E., and H. P. Broquist Saccharopine, an intermediate of the aminoadipic acid pathway of lysine biosynthesis. J. Biol. Chem. 240, 2524 (1965). 

Fig. 13.1 Metabolism of L-lysine in mammals. (The pathway via saccharopine is the major route of metabolism).

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