title: Alternative functions of the brain transsulfuration pathway represent an underappreciated aspect of brain redox biochemistry with significant potential for therapeutic engagement.
abstract: Scientific appreciation for the subtlety of brain sulfur chemistry has lagged, despite understanding that the brain must maintain high glutathione (GSH) to protect against oxidative stress in tissue that has both a high rate of oxidative respiration and a high content of oxidation-prone polyunsaturated fatty acids. In fact, the brain was long thought to lack a complete transsulfuration pathway (TSP) for cysteine synthesis. It is now clear that not only does the brain possess a functional TSP, but brain TSP enzymes catalyze a rich array of alternative reactions that generate novel species including the gasotransmitter hydrogen sulfide (H2S) and the atypical amino acid lanthionine (Lan). Moreover, TSP intermediates can be converted to unusual cyclic ketimines via transamination. Cell-penetrating derivatives of one such compound, lanthionine ketimine (LK), have potent antioxidant, neuroprotective, neurotrophic, and antineuroinflammatory actions and mitigate diverse neurodegenerative conditions in preclinical rodent models. This review will explore the source and function of alternative TSP products, and lanthionine-derived metabolites in particular. The known biological origins of lanthionine and its ketimine metabolite will be described in detail and placed in context with recent discoveries of a GSH- and LK-binding brain protein called LanCL1 that is proving essential for neuronal antioxidant defense; and a related LanCL2 homolog now implicated in immune sensing and cell fate determinations. The review will explore possible endogenous functions of lanthionine metabolites and will discuss the therapeutic potential of lanthionine ketimine derivatives for mitigating diverse neurological conditions including Alzheimer׳s disease, stroke, motor neuron disease, and glioma.
authors.affiliation: Department of Pathology and Department of Neurosciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH 43614, USA. Electronic address: Kenneth.Hensley@utoledo.edu.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hensley
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, P.O. Box 1495, Spokane, WA 99201, USA. Electronic address: Travis.Denton@WSU.edu.
authors.forename: Travis T
authors.initials: TT
authors.lastname: Denton
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001927:Brain Diseases / Q000188:drug therapy* / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D013440:Sulfides / Q000494:pharmacology; D013455:Sulfur / Q000737:chemistry*
chemical_list: D018696:Neuroprotective Agents; D013440:Sulfides; D013455:Sulfur; D003541:Cystathionine beta-Synthase; C001520:lanthionine; D000409:Alanine
keywords: Autophagy; CRMP2; Free radical; Glutathione; Hydrogen sulfide; LanCL1; LanCL2; Lanthionine; Neuroinflammation; Transsulfuration