Emerging biological importance of central nervous system lanthionines

Abstract

Lanthionine (Lan), the thioether analog of cystine, is a natural but nonproteogenic amino acid thought to form naturally in mammals through promiscuous reactivity of the transsulfuration enzyme cystathionine-beta-synthase (CbetaS). Lanthionine exists at appreciable concentrations in mammalian brain, where it undergoes aminotransferase conversion to yield an unusual cyclic thioether, lanthionine ketimine (LK; 2H-1,4-thiazine-5,6-dihydro-3,5-dicarboxylic acid). Recently, LK was discovered to possess neuroprotective, neuritigenic and anti-inflammatory activities. Moreover, both LK and the ubiquitous redox regulator glutathione (gamma-glutamyl-cysteine-glycine) bind to mammalian lanthionine synthetase-like protein-1 (LanCL1) protein which, along with its homolog LanCL2, has been associated with important physiological processes including signal transduction and insulin sensitization. These findings begin to suggest that Lan and its downstream metabolites may be physiologically important substances rather than mere metabolic waste. This review summarizes the current state of knowledge about lanthionyl metabolites with emphasis on their possible relationships to LanCL1/2 proteins and glutathione. The potential significance of lanthionines in paracrine signaling is discussed with reference to opportunities for utilizing bioavailable pro-drug derivatives of these compounds as novel pharmacophores.

Scheme 1

The classic transsulfuration pathway.

Scheme 2

Formation of lanthionine (Lan) through alternative reactions of the transsulfuration pathway, and subsequent conversion to lanthionine ketimine by action of GTK (KAT1). Lan may also form by the action of CβS upon two molecules of Cys, in which case H₂S is liberated [11].

Figure 1

A: Structure and numbering convention for lanthionine ketimine (LK) tautomers and synthetic derivatives. For natural lanthionine ketimine, R₁ = R₂ = H. B: Tautomerism between the imine and ene-amine forms of LK.

Figure 2

LK-5-ethyl ester (LKE) promotes neurite extension in primary, dissociated chick dorsal root ganglia (DRG) cultures. Neurons were treated with LKE or saline vehicle for 24h and quantitatively assessed for neurite morphometry as described in the text.

Figure 3

LKE slows progression of paralytic disease in the SOD1^G93A mouse model of familial amyotrophic lateral sclerosis (ALS).

Scheme 3

Summary of known and hypothesized routes for enzymatic formation of lanthionine ketimine, via either the transsulfuration and aminotransferase pathways, or through a hypothetical glutathione-lanthionine (gLan) intermediate. As of the publication of this review, gLan has not been found naturally in biological tissues. The involvement of LanCL proteins in gLan synthesis is theoretically possible. If gLan is formed in vivo, Lan would be expected to form upon exposure to ambient γ-glutamyl transpeptidase (γGT) and carboxypeptidase. Lanthionine conversion to LK then could occur through GTK. Dha = dehydroalanine.

Figure 4

Treatment with synthetic gLan improves motor function in SOD1^G93A mice. Mice were treated with daily intraperitoneal injections of gLan, at the indicated dose, 5 days/ week beginning at 90 d, and motor performance was evaluated by rotarod task as described in the text. Data points indicate mean ± SEM.