Abstract
LanC-like (LanCL) proteins are mammalian homologs of bacterial LanC enzymes, which catalyze the addition of the thiol of Cys to dehydrated Ser residues during the biosynthesis of lanthipeptides, a class of natural products formed by post-translational modification of precursor peptides. The functions of LanCL proteins are currently unclear. A recent proposal suggested that LanCL1 catalyzes the addition of the Cys of glutathione to protein- or peptide-bound dehydroalanine (Dha) to form lanthionine, analogous to the reaction catalyzed by LanC in bacteria. Lanthionine has been detected in human brain as the downstream metabolite lanthionine ketimine (LK), which has been shown to have neuroprotective effects. In this study, we tested the proposal that LanCL1 is involved in lanthionine biosynthesis by constructing LanCL1 knock-out mice and measuring LK concentrations in their brains using a mass spectrometric detection method developed for this purpose. To investigate whether other LanCL proteins (LanCL2/3) may confer a compensatory effect, triple knock-out (TKO) mice were also generated and tested. Very similar concentrations of LK (0.5–2.5 nmol/g tissue) were found in LanCL1 knock-out, TKO and wild type (WT) mouse brains, suggesting that LanCL proteins are not involved in lanthionine biosynthesis.
Highlights
Since the discovery of LanCL proteins, much effort has focused on understanding their function(s)
Since LanCL1 binds to the Cys of glutathione[3], and because bacterial LanC catalyzes addition of Cys to dehydrated Ser residues in peptides, it was suggested that glutathione could be one of the substrates of LanCL1 during lanthionine formation (Fig. 1)[24]
Concentrations of about 0.5–2.5 nmol/g tissue were detected in both wild type (WT) and LanCL1 KO mouse brains, suggesting LanCL1 may not play a major role in lanthionine synthesis in vivo
Summary
Since the discovery of LanCL proteins, much effort has focused on understanding their function(s). Huang et al reported an anti-oxidant function of LanCL1 in the central nervous system based on studies using LanCL1 knockout mice[8]. In a mouse model of Alzheimer’s disease, administration of LKE substantially mitigated cognitive decline[25], and LKE was found to protect neuronal cells in a mouse model of cerebral ischemia[26]. These in vivo results suggest neuroprotective and neuritogenic activity of LK. Concentrations of about 0.5–2.5 nmol/g tissue were detected in both WT and LanCL1 KO mouse brains, suggesting LanCL1 may not play a major role in lanthionine synthesis in vivo. The LK levels in WT and TKO mice were similar, confirming that despite the chemically appealing hypothesis, LanCL proteins are likely not involved in LK synthesis
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