Lysine metabolism in mammalian brain: an update on the importance of recent discoveries

Abstract

The lysine catabolism pathway differs in adult mammalian brain from that in extracerebral tissues. The saccharopine pathway is the predominant lysine degradative pathway in extracerebral tissues, whereas the pipecolate pathway predominates in adult brain. The two pathways converge at the level of ∆(1)-piperideine-6-carboxylate (P6C), which is in equilibrium with its open-chain aldehyde form, namely, α-aminoadipate δ-semialdehyde (AAS). A unique feature of the pipecolate pathway is the formation of the cyclic ketimine intermediate ∆(1)-piperideine-2-carboxylate (P2C) and its reduced metabolite L-pipecolate. A cerebral ketimine reductase (KR) has recently been identified that catalyzes the reduction of P2C to L-pipecolate. The discovery that this KR, which is capable of reducing not only P2C but also other cyclic imines, is identical to a previously well-described thyroid hormone-binding protein [μ-crystallin (CRYM)], may hold the key to understanding the biological relevance of the pipecolate pathway and its importance in the brain. The finding that the KR activity of CRYM is strongly inhibited by the thyroid hormone 3,5,3'-triiodothyronine (T3) has far-reaching biomedical and clinical implications. The inter-relationship between tryptophan and lysine catabolic pathways is discussed in the context of shared degradative enzymes and also potential regulation by thyroid hormones. This review traces the discoveries of enzymes involved in lysine metabolism in mammalian brain. However, there still remain unanswered questions as regards the importance of the pipecolate pathway in normal or diseased brain, including the nature of the first step in the pathway and the relationship of the pipecolate pathway to the tryptophan degradation pathway.

Fig. 1

The saccharopine pathway for the metabolism of l-lysine in mammals. In contrast to the pipecolate pathway (Fig. 2), which is predominantly cytosolic and peroxisomal, the saccharopine pathway occurs only in the mitochondria. The saccharopine pathway is the predominant pathway for l-lysine degradation in extracerebral tissues and developing brain. However, in the adult brain, the pipecolate pathway predominates. The two pathways converge at Δ¹-piperideine-6-carboxylate/α-aminoadipate δ-semialdehyde (P6C/AAS). Enzymes: 1 the bifunctional enzyme l-lysine-α-ketoglutarate reductase/saccharopine dehydrogenase (LKR/SDH); 2 α-aminoadipate semialdehyde dehydrogenase (AASDH); 3 α-aminoadipate aminotransferase/kynurenine aminotransferase II (AADT/KAT II); 4 a series of mitochondrial enzymes common to l-lysine as well as tryptophan degradation (Fig. 4). Interconversion between AAS and P6C occurs spontaneously (non-enzymatically). Note that some of the enzyme steps shown here occur in other figures. The numbering of each enzyme-catalyzed step is maintained in the subsequent figures. Note also that some of the coenzymes and reactants/products in this pathway and other pathways (Figs. 2, 4) are omitted for simplicity

Fig. 2

The pipecolate pathway for the metabolism of l-lysine in mammals. This pathway is the main degradative pathway for l-lysine in adult mammalian brain. Enzymes 1 and 2 are cytosolic. The enzymes 2 (AASDH) and 3 (AADT/KAT II) are the same as those in the saccharopine pathway. These enzyme activities are present in both mitochondria and cytosol. Nevertheless, the pathway for the conversion of l-lysine to AKA can be considered predominantly cytosolic with a peroxisomal component (as discussed in the text). Enzymes: 5 an enzyme that catalyzes conversion of the α-amino group of l-lysine to a keto function, possibly kynurenine aminotransferase III/glutamine transaminase L (KAT III/GTL); 6 d-amino acid oxidase (DAAO); 7 CRYM/ketimine reductase (CRYM/KR); 8 l-pipecolate oxidase (POX); 2–4 as per Fig. 1. Conversion between Δ¹-piperideine-2-carboxylate (P2C) and α-keto-ε-aminocaproate (KAC) as well as between Δ¹-piperideine-6-carboxylate (P6C) and α-aminoadipate δ-semialdehyde (AAS) is spontaneous (non-enzymatic). Thyroid hormones may play a major part in regulating this pathway as CRYM/KR (step 7) has been shown to be strongly regulated by T₃, the active form of thyroxine

Fig. 3

Structures of several known CRYM/KR substrates and one putative substrate [Pyr2C]. The known substrates include P2C and the sulfur-containing ketimines, aminoethylcysteine ketimine (AECK), lanthionine ketimine (LK), and cystathionine ketimine (CysK). LK in particular has been shown to have neurotrophic properties (see the text). The five-membered ring analog of P2C, namely, Δ¹-pyrroline-2-carboxylate (Pyr2C), has been reported to be a substrate for semi-purified P2C/Pyr2C reductases (Meister et al. 1957). However, although it seems likely to be a substrate, Pyr2C has not yet been tested as a substrate of highly purified CRYM/KR

Fig. 4

The interconnection of l-lysine and l-tryptophan degradative pathways in mammals. Enzymes: 2-8 as per Figs. 1 and 2; 1a indoleamine dioxygenase/tryptophan dioxygenase (IDO/TDO); 2a kynurenine formylase; 3a kynurenine monooxygenase (depicted as occurring on the mitochondrial outer membrane); 4a enzymes catalyzing the conversion of 3-hydroxykynurenate to α-ketoadipate (AKA). Note that as discussed in the text, the conversion of l-lysine to KAC in the pipecolate pathway may be catalyzed by KAT III/GTL. The most important aminotransferase that catalyzes the conversion of α-aminoadipate to α-ketoadipate in the pipecolate pathway for l-lysine degradation is the same enzyme that catalyzes the conversion of kynurenine to kynurenate [i.e., α-aminoadipate aminotransferase/kynurenine aminotransferase II (AADT/KAT II); enzyme 3 in this figure and Figs. 1, 2]. Thus, any perturbation in one pathway will influence the other. This interconnection between lysine and tryptophan degradative pathways has implications in psychiatric as well as neurological illnesses as discussed in the text

Fig. 5

The remarkable amino acid substrate versatility of α-aminoadipate aminotransferase/kynurenine aminotransferase II (AADT/KAT II). Not only is the enzyme active with AAD and Kyn, but it can also transaminate thyroid hormones (e.g., T₃) and halogenated tyrosines as discussed in the text. The thyroid hormone T₃ is a strong inhibitor of CRYM/KR, and AADT/KAT II activity is also potentially regulated by circulating thyroid hormones. In the text, we postulate that thyroid hormones play a pivotal role in the development of the pipecolate pathway in mammalian brain. The biological importance of T₃ transamination is unknown although it has been suggested that KAT (i.e., KAT II) may be important for the metabolism of thyroid hormones (Tobes and Mason 1978)