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 Δ1-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 Δ1-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 interrelationship 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.

Efficiency of lysine utilization by growing steers1,2

“…Plasma α-aminoadipic acid linearly increased (P = 0.02) in response to Lys supplementation. Mammalian catabolism of Lys occurs from 2 different routes: the pipecolate pathway predominates in the adult brain, whereas the saccharopine pathway is the predominant Lys degradative pathway in extracerebral tissues (Hallen et al, 2013). The main pathway yields α-aminoadipic acid as one of the intermediates (Voet et al, 2013); therefore, the increase in plasma α-aminoadipic acid probably reflects an increase in Lys catabolism as more Lys was supplied.…”

Biochemical Principles and Functional Aspects of Pipecolic Acid Biosynthesis in Plant Immunity

“…A subsequent reduction of the imine bond in the 1,2-DP molecule would then be required to generate L-Pip. Later, partially purified enzyme preparations from different mammalian tissues with imine reductase activities toward several cyclic ketimines and the ability to convert 1,2-DP to Pip were obtained Nardini et al, 1988;Hallen et al, 2013). More recently, the mammalian protein m-crystallin (CRYM) was characterized as an NAD(P)H-dependent ketimine reductase that is able to reduce 1,2-DP to the supposed product L-Pip (Hallen et al, 2011(Hallen et al, , 2015.…”

Lysine and threonine plasma concentrations in Ivorian patients living with human immunodeficiency virus

“…Concerning excess in lysine level, the absence of excess lysine observed in male PLVIH and the controls population, implied a normal catabolism of lysine by its two main pathways which are: through saccharopine (mainly mitochondrial) and pipecolate (essentially cytosolic Boyvin et al 199 and peroxisomal) (Bender, 2012;Hallen et al, 2013). In contrast, the excess lysine found in 13% of female HIV individuals could be due either to hyperlysinaemia, a rare hereditary genetic disease caused by an enzyme deficiency that prevents breaking of lysine (Zhu et al, 2002), and associated with liver and kidney metabolic disorder which is associated with lack of signaling on both catabolism pathways of lysine (saccharopine and pipecolate).…”