Chemistry:Lanthionine Ketimine

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Lanthionine Ketimine
Lanthionine ketimine (3,4-dihydro-2H-1,3-thiazine-3,5-dicarboxylic acid)
Names
IUPAC name
3,4-dihydro-2H-1,3-thiazine-3,5-dicarboxylic acid
Identifiers
3D model (JSmol)
Properties
C6H7NO4S
Molar mass 189.18908 g/mole
Appearance white powder
Melting point 160 (decomposes)
30 g/L (water, pH 7)
Hazards
Main hazards irritation
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Lanthionine ketimine (3,4-dihydro-2H-1,3-thiazine-3,5-dicarboxylic acid) is a naturally occurring sulfur amino acid metabolite found in the mammalian brain and central nervous system (CNS).[1][2] Synthetic derivatives of lanthionine ketimine have been documented to possess various biological activities suggesting that the molecules are plausible lead candidates for the treatment of neurodegenerative disease.[3]

Background

Lanthionine ketimine was documented as a natural metabolite as early as 1983 by Professor Dorianno Cavallini, who published regarding its synthesis and chemical properties.[1][2] Cavallini and others showed that lanthionine ketimine forms from alternative reactions of the transsulfuration pathway enzyme cystathionine-β-synthase, which normally condenses the amino acids homocysteine and serine to form cystathionine. In an alternate pathway, cysteine and serine (or two equivalents of cysteine) condense to form lanthionine.[2][3][4][5] The product of these transformations is lanthionine or cystathionine ketimine,[2] respectively.

Additional sources of lanthionine ketimine have been proposed. Lanthionine ketimine also binds the brain protein lanthionine synthase-like protein-1 (LANCL1), a glutathione-binding protein of uncertain function.[5][6] It has been hypothesized, but not proved, that LANCL1 might catalyze formation of glutathione-lanthionine conjugates in a pathway leading to lanthionine ketimine.[5]

Lanthionine ketimine and a synthetic, cell-penetrating ester derivative called lanthionine ketimine-5-ethyl ester (LKE) reportedly potentiate growth factor-dependent extension of neuron processes (neurites) in cell culture.[6][7] This neurotrophic activity may occur through interaction of lanthionine ketimine with a protein called collapsin response protein-2 (CRMP2, also known as dihydropyrimidinase-like protein-2 or DPYSL2). Normally CRMP2 functions to promote or inhibit neurite growth. Lanthionine ketimine interacts with CRMP2 in affinity proteomics experiments and alters CRMP2 binding to other proteins in brain lysate preparations.[6]

Beside its neurotrophic effects, lanthionine ketimine and its ester LKE reportedly protect neurons against oxidative stress[6] and inhibit the activation of microglia (brain macrophages) triggered by exposure to inflammatory cytokines. Administration of LKE to the SOD1G93A mouse model of the motor neuron disease amyotrophic lateral sclerosis (ALS), reportedly slows progression of paralytic disease in this mouse.[5]

Derivatives of lanthionine ketimine have been patented as experimental therapeutics to treat neurological diseases and diseases possessing a pathological inflammatory component.[8]

Preparation

Lanthionine ketimine or its ethyl esters can be synthesized by condensation of cysteine derivatives (e.g. L-cysteine-ethyl ester hydrochloride) with 3-bromopyruvate or 3-bromopyruvate derivatives in water, followed by filtration and thorough aqueous washing of the precipitate. When dried, the precipitate can be resolubilized in aqueous medium by slow titration with NaOH or other base.[6][8]

References

  1. ^ Cavallini, D.; Ricci, G.; Federri, G. (1983) The ketimine derivatives of thialysine, lanthionine, cystathionine, cysteine: Preparation and properties. In Sulfur Amino Acids: Biochemical and Clinical Aspects, Alan R. Liss Inc., pp. 355–364.
  2. ^ Cavallini, D.; Ricci, G.; Dupre, S.; Pecci, L.; Costa, M.; Matarese, R.M.; Pensa, B.; Antonuci, A.; Solinas, S.P.; Fontana, M. (1991) Sulfur-containing cyclic ketimines and imino acids. A novel family of endogenous products in search for a role. European Journal of Biochemistry, 202, 217-223.
  3. ^ Hensley,K, Gabbita SP, Venkova K, Hristov A, Johnson MF, Eslami P, Harris-White ME, A Derivative of the Brain Metabolite Lanthionine Ketimine Improves Cognition and Diminishes Pathology in the 3×Tg-AD Mouse Model of Alzheimer Disease, Journal of Neuropathology and Experimental Neurology, Oct 2013, Volume=72, Issue=10, pages=955-969, doi=10.1097/NEN.0b013e3182a74372, PMID 24042198
  4. ^ Cooper, A.J.L. (2004) The role of glutamine transaminase K (GTK) in sulfur and alpha-keto acid metabolism in the brain, and in the possible bioactivation of neurotoxicants. Neurochem International, 44, 557-577.
  5. ^ Singh, S.; Padovani, D.; Leslie, R.A.; Chiku, T.; Banerjee, R. (2009) Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions. Journal of Biological Chemistry, 284, 22457-22466.
  6. ^ Hensley, K. (2010) Emerging Biological Importance of Central Nervous System Lanthionines. Molecules, 15: 5581-5594.
  7. ^ Hensley, K.; Christov, A.; Kamat, S.; Zhang, X.C.; Jackson, K.W.; Snow, S.; Post, J. (2010) Proteomic Identification of Binding Partners for the Brain Metabolite Lanthionine Ketimine (LK) and Documentation of LK Effects on Microglia and Motoneuron Cell Cultures. Journal of Neuroscience, 30, 2979-2988.
  8. ^ Hensley, K.; Venkova, K.; Christov, A.; Gunning, W.; Park, J. (2011) Collapsin response mediator protein-2: An emerging pathologic feature and therapeutic target for neurodisease indications. Molecular Neurobiology, 43, 180-191.
  9. ^ Hensley, K. Lanthionine-related compounds for the treatment of inflammatory diseases. US Patent No. 7,683,055. Issued 3/23/2010




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