LanCL proteins are not Involved in Lanthionine Synthesis in Mammals

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.

LanCL1 promotes motor neuron survival and extends the lifespan of amyotrophic lateral sclerosis mice

“…Surprisingly, a cell-permeable ester derivative of LK (LKE) appears to possess antioxidative stress and antiapoptotic function in NSC-34 MN-like cells and increase survival in SOD1 G93A transgenic mice [59,60]. Even though the hypothesis that LanCL1 is involved in LK biosynthesis remains controversial at present [61], it is possible that other functional link between LanCL1 and LK may exist and therefore contributes to neuronal protection.…”

Abscisic Acid as Pathogen Effector and Immune Regulator

“…LANCL2 is homologous to the earlier proposed ABA receptor in plants: GCR2 (Liu et al, 2007 ; Chen and Ellis, 2008 ) and bacterial LanC lanthionine synthesis proteins. However, the mammalian LanC-like homologs do not show any evidence of having a conserved role in lanthionine biosynthesis (He et al, 2017 ). It is not yet known whether a currently unknown catalytic activity of LANCL2 could contribute to ABA signaling.…”

“…On the other hand are there no spontaneous phenotypes reported for LANCL2 deficient mice (Leber et al, 2016 ). The lack of spontaneous phenotype in LancL2 knock-out mice is also not due to redundancy with the other mammalian LanC-like proteins, since the LancL1-3 triple knock-out mice still are viable and do not show any gross abnormalities (He et al, 2017 ). The downstream PPARγ is known to be required for alternative (M2) activation of macrophages (Odegaard et al, 2007 ).…”

Abscisic Acid: A Conserved Hormone in Plants and Humans and a Promising Aid to Combat Prediabetes and the Metabolic Syndrome

“…Although the current general consensus is that the PYR/PYL/RCAR family of intracellular receptors are the principal ABA receptors in land plants [ 25 ], the homology between mammalian LANCL proteins and plant GCR2 suggested to explore the possibility that they were implicated in ABA sensing. A role for the LANCL protein family in lanthionine biosynthesis has since been ruled out [ 26 ]. The LANCL family comprises three proteins: LANCL1 is the most highly expressed in mammals, particularly in the brain, and is a cytosolic protein, LANCL2 is membrane-anchored through its myristoylated N-terminal [ 27 ] and LANCL3 has the lowest expression levels of the LANCL proteins and appears to be cytosolic.…”

“…He et al published a study on the triple knock out of LANCL1-2-3 in mice, demonstrating that these proteins are not involved in the synthesis of lanthionine, which conversely could have been hypothesized based on their homology with bacterial LanC enzymes. It would be informative to compare glucose tolerance and insulin sensitivity on the LANCL2 KO and on the double (LANCL1 + 2) KO [ 26 ].…”