Skip to main content

Advertisement

SpringerLink
Log in

Chemistry and Chemical Equilibrium Dynamics of BMAA and Its Carbamate Adducts

  • ORIGINAL ARTICLE
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Beta-N-methylamino-L-alanine (BMAA) has been demonstrated to contribute to the onset of the ALS/Parkinsonism-dementia complex (ALS/PDC) and is implicated in the progression of other neurodegenerative diseases. While the role of BMAA in these diseases is still debated, one of the suggested mechanisms involves the activation of excitatory glutamate receptors. In particular, the excitatory effects of BMAA are shown to be dependent on the presence of bicarbonate ions, which in turn forms carbamate adducts in physiological conditions. The formation of carbamate adducts from BMAA and bicarbonate is similar to the formation of carbamate adducts from non-proteinogenic amino acids. Structural, chemical, and biological information related to non-proteinogenic amino acids provide insight into the formation of and possible neurological action of BMAA. This article reviews the carbamate formation of BMAA in the presence of bicarbonate ions, with a particular focus on how the chemical equilibrium of BMAA carbamate adducts may affect the molecular mechanism of its function. Highlights of nuclear magnetic resonance (NMR)-based studies on the equilibrium process between free BMAA and its adducts are presented. The role of divalent metals on the equilibrium process is also explored. The formation and the equilibrium process of carbamate adducts of BMAA may answer questions on their neuroactive potency and provide strong motivation for further investigations into other toxic mechanisms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Arnold H, Pahls K, Potsch D (1969) Reaktion von N-(Chloräthyl)-2-oxazolidon mit primären Aminen. Tetrahedron Lett 10(3):137–139

    Article  Google Scholar 

  • Atlante A, Calissano P, Bobba A, Giannattasio S, Marra E, Passarella S (2001) Glutamate neurotoxicity, oxidative stress and mitochondria. FEBS Lett 497(1):1–5

    Article  CAS  PubMed  Google Scholar 

  • Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW (2006a) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312(5778):1389–1392

    Article  CAS  PubMed  Google Scholar 

  • Boillee S, Vande Velde C, Cleveland DW (2006b) ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52(1):39–59

    Article  CAS  PubMed  Google Scholar 

  • Brownson DM, Mabry TJ, Leslie SW (2002) The cycad neurotoxic amino acid, beta-N-methylamino-L-alanine (BMAA), elevates intracellular calcium levels in dissociated rat brain cells. J Ethnopharmacol 82(2–3):159–167

    Article  CAS  PubMed  Google Scholar 

  • Catarzi D, Colotta V, Varano F (2006) Competitive Gly/NMDA receptor antagonists. Curr Top Med Chem 6(8):809–821

    Article  CAS  PubMed  Google Scholar 

  • Chiu AS, Gehringer MM, Welch JH, Neilan BA (2011) Does alpha-amino-beta-methylaminopropionic acid (BMAA) play a role in neurodegeneration? Int J Environ Res Public Health 8(9):3728–3746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiu AS, Gehringer MM, Braidy N, Guillemin GJ, Welch JH, Neilan BA (2012) Excitotoxic potential of the cyanotoxin beta-methyl-amino-L-alanine (BMAA) in primary human neurons. Toxicon 60(6):1159–1165

    Article  CAS  PubMed  Google Scholar 

  • Chiu AS, Gehringer MM, Braidy N, Guillemin GJ, Welch JH, Neilan BA (2013) Gliotoxicity of the cyanotoxin, beta-methyl-amino-L-alanine (BMAA). Sci Rep 3:1482

    Article  PubMed  PubMed Central  Google Scholar 

  • Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1(8):623–634

    Article  CAS  PubMed  Google Scholar 

  • Cleland WW, Andrews TJ, Gutteridge S, Hartman FC, Lorimer GH (1998) Mechanism of rubisco: the carbamate as general base. Chem Rev 98(2):549–562

    Article  CAS  PubMed  Google Scholar 

  • Davis AJ, Hawkes GE, Haycock PR, O’Brien P, Kidd BL, Mapp PI, Naughton D, Grootveld M (1993a) Generation of substance P carbamate in neutral aqueous solution. Relevance to inflammatory joint diseases. FEBS Lett 329(3):249–252

    Article  CAS  PubMed  Google Scholar 

  • Davis AJ, O’Brien P, Nunn PB (1993b) Studies of the stability of some amino acid carbamates in neutral aqueous solution. Bioorg Chem 21(3):309–318

    Article  CAS  Google Scholar 

  • Dean JA (1992) Lange’s handbook of chemistry. In: New York. McGraw-Hill, Inc., USA

    Google Scholar 

  • Doble A (1999) The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther 81(3):163–221

    Article  CAS  PubMed  Google Scholar 

  • Dunlop RA, Cox PA, Banack SA, Rodgers KJ (2013) The non-protein amino acid BMAA is misincorporated into human proteins in place of L-serine causing protein misfolding and aggregation. PLoS One 8(9):e75376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ewing SP, Lockshon D, Jencks WP (1980) Mechanism of cleavage of carbamate anions. J Am Chem Soc 102(9):3072–3084

    Article  CAS  Google Scholar 

  • Faassen EJ, Beekman W, Lurling M (2013) Evaluation of a commercial enzyme linked immunosorbent assay (ELISA) for the determination of the neurotoxin BMAA in surface waters. PLoS One 8(6):e65260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Friedman M (1989) Absorption and utilization of amino acids. CRC Press

  • Gahring LC, Rogers SW (2002) Autoimmunity to glutamate receptors in the central nervous system. Crit Rev Immunol 22(4):295–316

    Article  CAS  PubMed  Google Scholar 

  • Gibbons BH, Edsall JT (1963) Rate of hydration of carbon dioxide and dehydration of carbonic acid at 25 degrees. J Biol Chem 238:3502–3507

    CAS  PubMed  Google Scholar 

  • Glover WB, Liberto CM, McNeil WS, Banack SA, Shipley PR, Murch SJ (2012) Reactivity of beta-methylamino-L-alanine in complex sample matrixes complicating detection and quantification by mass spectrometry. Anal Chem 84(18):7946–7953

    Article  CAS  PubMed  Google Scholar 

  • Jeener J, Meier BH, Bachmann P, Ernst RR (1979) Investigation of exchange processes by two-dimensional NMR spectroscopy. J Chem Phys 71(11):4546–4553

    Article  CAS  Google Scholar 

  • Klebe G (2015) Applying thermodynamic profiling in lead finding and optimization. Nat Rev Drug Discov 14(2):95–110

    Article  CAS  PubMed  Google Scholar 

  • Lobner D, Piana PM, Salous AK, Peoples RW (2007) Beta-N-methylamino-L-alanine enhances neurotoxicity through multiple mechanisms. Neurobiol Dis 25(2):360–366

    Article  CAS  PubMed  Google Scholar 

  • Lorimer GH (1983) Carbon dioxide and carbamate formation: the makings of a biochemical control system. Trends Biochem Sci 8(2):65–68

    Article  CAS  Google Scholar 

  • Marchetti C (2014) Interaction of metal ions with neurotransmitter receptors and potential role in neurodiseases. Biometals 27(6):1097–1113

    Article  CAS  PubMed  Google Scholar 

  • McConnell HM (1958) Reaction rates by nuclear magnetic resonance. J Chem Phys 28:430–431

    Article  CAS  Google Scholar 

  • Meier BH, Ernst RR (1979) Elucidation of chemical exchange networks by two-dimensional NMR spectroscopy: the heptamethylbenzenonium ion. J Am Chem Soc 101(21):6441–6442

    Article  CAS  Google Scholar 

  • Monaghan DT, Bridges RJ, Cotman CW (1989) The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system. Annu Rev Pharmacol Toxicol 29:365–402

    Article  CAS  PubMed  Google Scholar 

  • Murch SJ, Cox PA, Banack SA, Steele JC, Sacks OW (2004a) Occurrence of beta-methylamino-l-alanine (BMAA) in ALS/PDC patients from Guam. Acta Neurol Scand 110(4):267–269

    Article  CAS  PubMed  Google Scholar 

  • Murch SJ, Cox PA, Banack SA (2004b) A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam. Proc Natl Acad Sci U S A 101(33):12228–12231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Myers TG, Nelson SD (1990) Neuroactive carbamate adducts of beta-N-methylamino-L-alanine and ethylenediamine. Detection and quantitation under physiological conditions by 13C NMR. J Biol Chem 265(18):10193–10195

    CAS  PubMed  Google Scholar 

  • Nunn PB (2009) Three phases of research on beta-N-methylamino-L-alanine (BMAA)—a neurotoxic amino acid. Amyotroph Lateral Scler 10(Suppl 2):26–33

    Article  CAS  PubMed  Google Scholar 

  • Nunn PB, O’Brien P (1989) The interaction of beta-N-methylamino-L-alanine with bicarbonate: an 1H-NMR study. FEBS Lett 251(1–2):31–35

    Article  CAS  PubMed  Google Scholar 

  • Nunn PB, O’Brien P, Pettit LD, Pyburn SI (1989) Complexes of zinc, copper, and nickel with the nonprotein amino acid L-alpha-amino-beta-methylaminopropionic acid: a naturally occurring neurotoxin. J Inorg Biochem 37(2):175–183

    Article  CAS  PubMed  Google Scholar 

  • Nunn PB, Davis AJ, O’Brien P (1991) Carbamate formation and the neurotoxicity of L-alpha amino acids. Science 251(5001):1619–1620

    Article  CAS  PubMed  Google Scholar 

  • Nunn PB, Bell EA, Watson AA, Nash RJ (2010) Toxicity of non-protein amino acids to humans and domestic animals. Nat Prod Commun 5(3):485–504

    CAS  PubMed  Google Scholar 

  • Pablo J, Banack SA, Cox PA, Johnson TE, Papapetropoulos S, Bradley WG, Buck A, Mash DC (2009) Cyanobacterial neurotoxin BMAA in ALS and Alzheimer’s disease. Acta Neurol Scand 120(4):216–225

    Article  CAS  PubMed  Google Scholar 

  • Rao SD, Banack SA, Cox PA, Weiss JH (2006) BMAA selectively injures motor neurons via AMPA/kainate receptor activation. Exp Neurol 201(1):244–252

    Article  CAS  PubMed  Google Scholar 

  • Richter KE, Mena EE (1989) L-beta-methylaminoalanine inhibits [3H]glutamate binding in the presence of bicarbonate ions. Brain Res 492(1–2):385–388

    Article  CAS  PubMed  Google Scholar 

  • Rodgers KJ, Shiozawa N (2008) Misincorporation of amino acid analogues into proteins by biosynthesis. Int J Biochem Cell Biol 40(8):1452–1466

    Article  CAS  PubMed  Google Scholar 

  • Rossi-Bernardi L, Roughton FJ (1967) The specific influence of carbon dioxide and carbamate compounds on the buffer power and Bohr effects in human haemoglobin solutions. J Physiol 189(1):1–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scheiman, M. (1962). A review of monoethanolamine chemistry, DTIC Document

  • Sundh UM, Andersoon C, Rosén J, Fonnum F, Knudsen I, Sippola S (2007) Analysis, occurrence, and toxicity of ß-methylaminoalanine (BMAA). Denmark, Nordic Council of Ministers

    Google Scholar 

  • Szewczyk B (2013) Zinc homeostasis and neurodegenerative disorders. Front Aging Neurosci 5(33):1–12

    Google Scholar 

  • Takeda A (2003) Manganese action in brain function. Brain Res Brain Res Rev 41(1):79–87

    Article  CAS  PubMed  Google Scholar 

  • Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62(3):405–496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vega A (1967) α-amino-β-methylaminopropionic acid, a new amino acid from seeds of Cycas circinalis. Phytochemistry 6(5):759–762

    Article  CAS  Google Scholar 

  • Vega A, Bell EA, Nunn PB (1968) The preparation of l- and d-α-amino-β-methylaminopropionic acids and the identification of the compound isolated from Cycas circinalis as the l-isomer. Phytochemistry 7(10):1885–1887

    Article  CAS  Google Scholar 

  • Viso A, Fernandez de la Pradilla R, Garcia A, Flores A (2005) Alpha,beta-diamino acids: biological significance and synthetic approaches. Chem Rev 105(8):3167–3196

    Article  CAS  PubMed  Google Scholar 

  • Weiss JH, Choi DW (1988) Beta-N-methylamino-L-alanine neurotoxicity: requirement for bicarbonate as a cofactor. Science 241(4868):973–975

    Article  CAS  PubMed  Google Scholar 

  • Weiss JH, Christine CW, Choi DW (1989) Bicarbonate dependence of glutamate receptor activation by beta-N-methylamino-L-alanine: channel recording and study with related compounds. Neuron 3(3):321–326

    Article  CAS  PubMed  Google Scholar 

  • Xie H, Wang P, He N, Yang X, Chen J (2015) Toward rational design of amines for CO2 capture: substituent effect on kinetic process for the reaction of monoethanolamine with CO2. J Environ Sci (China) 37:75–82

    Article  Google Scholar 

  • Xue H, Field CJ (2011) New role of glutamate as an immunoregulator via glutamate receptors and transporters. Front Biosci (Schol Ed) 3:1007–1020

    Article  Google Scholar 

  • Yamamoto Y, Hasegawa J, Ito Y (2012) Kinetic investigation on carbamate formation from the reaction of carbon dioxide with amino acids in homogeneous aqueous solution. J Phys Org Chem 25(3):239–247

    Article  CAS  Google Scholar 

  • Zimmerman D, Goto JJ, Krishnan VV (2016) Equilibrium dynamics of beta-N-methylamino-L-alanine (BMAA) and its carbamate adducts at physiological conditions. PLoS One 11(8):e0160491

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

JG and VVK thank Dr. Paul Cox at the Institute of Ethnomedicine for organizing the 2016 BMAA symposium where part of the work was presented. PD acknowledges the support by the Bridges to Doctorate Program (R25 GM115293). The authors thank David Zimmerman for part of the work related to NMR studies of carbamate formation. The authors thank C. Cortney for critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Department of Chemistry, California State University, Fresno, CA, 93740, USA

    Pedro Diaz-parga, Joy J. Goto & V.V. Krishnan

  2. Department of Medical Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, CA, 95616, USA

    V.V. Krishnan

Authors
  1. Pedro Diaz-parga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joy J. Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V.V. Krishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Joy J. Goto or V.V. Krishnan.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Diaz-parga, P., Goto, J.J. & Krishnan, V. Chemistry and Chemical Equilibrium Dynamics of BMAA and Its Carbamate Adducts. Neurotox Res 33, 76–86 (2018). https://doi.org/10.1007/s12640-017-9801-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-017-9801-2

Keywords

Search

Navigation