Biochemistry - The Chemical Reactions of Living Cells, Volume 3 - D. Metzler 1980

Metabolism of Nitrogenous Compounds
Compounds Derived from Aspartate
Catabolism of Lysine

Lysine Catabolism is unusual in that no equilibrium is established between the α-amino group and the general "nitrogen pool." Nevertheless, catabolism begins with deamination and proceeds via β-oxidation. There is evidence for at least six Variants of the β-oxidation process involved in lysine degradation. The evolutionary differences concern the pathways by which the two Amino groups are cleaved from the carbon Skeleton. In the pathway that appears simplest (pathway A in Fig. 14-8) — which is used by Flavobacterium fuscum [51] — the ε-amino group is removed via direct (though atypical) Transamination. The resulting α-aminoadipate semialdehyde is oxidized to α-aminoadipate. The latter is degraded through a sequential series of reactions characteristic of Amino Acid Catabolism: transamination is followed by Oxidative Decarboxylation of the resulting α-keto acid and β-oxidation of the acyl-CoA derivative. During lysine degradation, the β-oxidation reaction sequence is additionally supplemented by a decarboxylation step at the terminal carboxyl group.

Transamination, which initiates pathway A, apparently involves certain chemical difficulties, and therefore most organisms utilize more complex reaction sequences leading to The formation of $\alpha$-ketoadipate. When the process proceeds via pathway B (which takes place in Liver Cell/35.html">Mitochondria and is considered the primary one in mammals) [52], the $\varepsilon$-amino group is attached to $\alpha$-ketoglutarate via a Condensation and reduction reaction, forming saccharopine. In the latter, the bond on the other side of the bridging nitrogen atom is oxidized, yielding glutamic acid and $\alpha$-aminoadipate semialdehyde as products. The overall equation of the process coincides with that of direct transamination and, essentially, represents the aminoadipate Biosynthesis pathway operating in reverse. 

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FIG. 14-8. Lysine catabolism.

It was initially believed that pathway B played a major role in mammalian METABOLISM; however, it turned out that it can only be utilized for the degradation of D-lysine. This pathway, elucidated in Pseudomonas putida [53], likewise involves transamination proceeding via successive reduction and oxidation steps. In this case, the process is intramolecular in nature: the carbonyl group acting as the oxidant is formed through the transamination of the lysine $\alpha$-amino group. In pathway D, which appears to be utilized in Yeast [54], Acetylation of the $\alpha$-amino group preceding transamination prevents the formation of cyclic intermediates. Subsequently, the $\alpha$-keto group is effectively blocked by reduction to an alcohol, the acetyl group that blocked the $\epsilon$-amino groups is then cleaved, and this end of the molecule is directly oxidized to yield a carboxyl group.

At this stage, the hydroxyl group introduced at position 2 is apparently oxidized back to a carbonyl, thereby regenerating the $\alpha$-ketoadipate. (However, it remains fully unclear at exactly which point pathway D converges with the other pathways.)

Some Bacteria, notably Pseudomonas putida [53], degrade the L-lysine molecule using an oxygenase [Eq. (10-49)] to convert it into δ-aminovaleramide:

The product is hydrolyzed and oxidized to glutaryl-CoA, thereby entering the metabolic pathways shown in Fig. 14-8. A remarkable and entirely different approach to lysine degradation has been discovered in bacteria of the genus Clostridium [55], which derive energy through Fermentation as described by Equation (14-27).

The reaction is coupled with the formation of one ATP molecule from ADP and P_i. The process proceeds via two pathways. In the first pathway, under the action of a Pyridoxal phosphate-dependent L-lysine-2,3-aminomutase [56] [Eq. (14-28), step a], lysine is converted into β-lysine (3,6-diaminohexanoate). The latter is further isomerized [Eq. (14-28), step b] by β-lysine mutase, which requires both Vitamin B1₂ and PLP as Cofactors [57]. Subsequent Oxidative Deamination, yielding a 3-keto compound [Eq. (14-28), step c], enables chain Cleavage. Readers should easily be able to outline possible further reactions of chain cleavage, ATP synthesis, and ammonia elimination [58], taking into account the balance of redox stages. There is another pathway starting with the action of a racemase [Eq. (14-28), step d] and the isomerization of the resulting D-lysine by another B₁₂- and PLP-dependent enzyme [Eq. (14-28), step e]. This is presumably followed by oxidative deamination. As for The Mechanism of chain cleavage, it remains unclear. It is only known to occur between the C-4 and C-5 atoms, as indicated by the dashes in Equation 14-28.

How can the existence of so many pathways for lysine catabolism be explained? The answer probably lies in the propensity of intermediates to spontaneously cyclize, as observed in the pipecolate pathway (Fig. 14-8, pathway B). Such compounds may prove too stable for efficient metabolism, thus necessitating the evolution of alternative routes. In the case of fermentation, additional constraints are imposed by the need to maintain a balance of redox processes that lower the Free energy.