Neurotoxicity Research

, Volume 33, Issue 1, pp 76–86 | Cite as

Chemistry and Chemical Equilibrium Dynamics of BMAA and Its Carbamate Adducts

  • Pedro Diaz-parga
  • Joy J. GotoEmail author
  • V.V. KrishnanEmail author


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.


β-N-methylamino-L-alanine (BMAA) Carbamate NMR Chemical equilibrium 



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.


  1. Arnold H, Pahls K, Potsch D (1969) Reaktion von N-(Chloräthyl)-2-oxazolidon mit primären Aminen. Tetrahedron Lett 10(3):137–139CrossRefGoogle Scholar
  2. Atlante A, Calissano P, Bobba A, Giannattasio S, Marra E, Passarella S (2001) Glutamate neurotoxicity, oxidative stress and mitochondria. FEBS Lett 497(1):1–5CrossRefPubMedGoogle Scholar
  3. 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):1389–1392CrossRefPubMedGoogle Scholar
  4. Boillee S, Vande Velde C, Cleveland DW (2006b) ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52(1):39–59CrossRefPubMedGoogle Scholar
  5. 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):159–167CrossRefPubMedGoogle Scholar
  6. Catarzi D, Colotta V, Varano F (2006) Competitive Gly/NMDA receptor antagonists. Curr Top Med Chem 6(8):809–821CrossRefPubMedGoogle Scholar
  7. 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):3728–3746CrossRefPubMedPubMedCentralGoogle Scholar
  8. 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):1159–1165CrossRefPubMedGoogle Scholar
  9. 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 3:1482CrossRefPubMedPubMedCentralGoogle Scholar
  10. Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1(8):623–634CrossRefPubMedGoogle Scholar
  11. Cleland WW, Andrews TJ, Gutteridge S, Hartman FC, Lorimer GH (1998) Mechanism of rubisco: the carbamate as general base. Chem Rev 98(2):549–562CrossRefPubMedGoogle Scholar
  12. 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):249–252CrossRefPubMedGoogle Scholar
  13. 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):309–318CrossRefGoogle Scholar
  14. Dean JA (1992) Lange’s handbook of chemistry. In: New York. McGraw-Hill, Inc., USAGoogle Scholar
  15. Doble A (1999) The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther 81(3):163–221CrossRefPubMedGoogle Scholar
  16. 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):e75376CrossRefPubMedPubMedCentralGoogle Scholar
  17. Ewing SP, Lockshon D, Jencks WP (1980) Mechanism of cleavage of carbamate anions. J Am Chem Soc 102(9):3072–3084CrossRefGoogle Scholar
  18. 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):e65260CrossRefPubMedPubMedCentralGoogle Scholar
  19. Friedman M (1989) Absorption and utilization of amino acids. CRC PressGoogle Scholar
  20. Gahring LC, Rogers SW (2002) Autoimmunity to glutamate receptors in the central nervous system. Crit Rev Immunol 22(4):295–316CrossRefPubMedGoogle Scholar
  21. Gibbons BH, Edsall JT (1963) Rate of hydration of carbon dioxide and dehydration of carbonic acid at 25 degrees. J Biol Chem 238:3502–3507PubMedGoogle Scholar
  22. 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):7946–7953CrossRefPubMedGoogle Scholar
  23. Jeener J, Meier BH, Bachmann P, Ernst RR (1979) Investigation of exchange processes by two-dimensional NMR spectroscopy. J Chem Phys 71(11):4546–4553CrossRefGoogle Scholar
  24. Klebe G (2015) Applying thermodynamic profiling in lead finding and optimization. Nat Rev Drug Discov 14(2):95–110CrossRefPubMedGoogle Scholar
  25. Lobner D, Piana PM, Salous AK, Peoples RW (2007) Beta-N-methylamino-L-alanine enhances neurotoxicity through multiple mechanisms. Neurobiol Dis 25(2):360–366CrossRefPubMedGoogle Scholar
  26. Lorimer GH (1983) Carbon dioxide and carbamate formation: the makings of a biochemical control system. Trends Biochem Sci 8(2):65–68CrossRefGoogle Scholar
  27. Marchetti C (2014) Interaction of metal ions with neurotransmitter receptors and potential role in neurodiseases. Biometals 27(6):1097–1113CrossRefPubMedGoogle Scholar
  28. McConnell HM (1958) Reaction rates by nuclear magnetic resonance. J Chem Phys 28:430–431CrossRefGoogle Scholar
  29. Meier BH, Ernst RR (1979) Elucidation of chemical exchange networks by two-dimensional NMR spectroscopy: the heptamethylbenzenonium ion. J Am Chem Soc 101(21):6441–6442CrossRefGoogle Scholar
  30. 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 29:365–402CrossRefPubMedGoogle Scholar
  31. 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):267–269CrossRefPubMedGoogle Scholar
  32. 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):12228–12231CrossRefPubMedPubMedCentralGoogle Scholar
  33. 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):10193–10195PubMedGoogle Scholar
  34. Nunn PB (2009) Three phases of research on beta-N-methylamino-L-alanine (BMAA)—a neurotoxic amino acid. Amyotroph Lateral Scler 10(Suppl 2):26–33CrossRefPubMedGoogle Scholar
  35. 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):31–35CrossRefPubMedGoogle Scholar
  36. 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):175–183CrossRefPubMedGoogle Scholar
  37. Nunn PB, Davis AJ, O’Brien P (1991) Carbamate formation and the neurotoxicity of L-alpha amino acids. Science 251(5001):1619–1620CrossRefPubMedGoogle Scholar
  38. 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):485–504PubMedGoogle Scholar
  39. 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):216–225CrossRefPubMedGoogle Scholar
  40. Rao SD, Banack SA, Cox PA, Weiss JH (2006) BMAA selectively injures motor neurons via AMPA/kainate receptor activation. Exp Neurol 201(1):244–252CrossRefPubMedGoogle Scholar
  41. Richter KE, Mena EE (1989) L-beta-methylaminoalanine inhibits [3H]glutamate binding in the presence of bicarbonate ions. Brain Res 492(1–2):385–388CrossRefPubMedGoogle Scholar
  42. Rodgers KJ, Shiozawa N (2008) Misincorporation of amino acid analogues into proteins by biosynthesis. Int J Biochem Cell Biol 40(8):1452–1466CrossRefPubMedGoogle Scholar
  43. 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):1–29CrossRefPubMedPubMedCentralGoogle Scholar
  44. Scheiman, M. (1962). A review of monoethanolamine chemistry, DTIC DocumentGoogle Scholar
  45. 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 MinistersGoogle Scholar
  46. Szewczyk B (2013) Zinc homeostasis and neurodegenerative disorders. Front Aging Neurosci 5(33):1–12Google Scholar
  47. Takeda A (2003) Manganese action in brain function. Brain Res Brain Res Rev 41(1):79–87CrossRefPubMedGoogle Scholar
  48. 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):405–496CrossRefPubMedPubMedCentralGoogle Scholar
  49. Vega A (1967) α-amino-β-methylaminopropionic acid, a new amino acid from seeds of Cycas circinalis. Phytochemistry 6(5):759–762CrossRefGoogle Scholar
  50. 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):1885–1887CrossRefGoogle Scholar
  51. 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):3167–3196CrossRefPubMedGoogle Scholar
  52. Weiss JH, Choi DW (1988) Beta-N-methylamino-L-alanine neurotoxicity: requirement for bicarbonate as a cofactor. Science 241(4868):973–975CrossRefPubMedGoogle Scholar
  53. 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):321–326CrossRefPubMedGoogle Scholar
  54. 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) 37:75–82CrossRefGoogle Scholar
  55. Xue H, Field CJ (2011) New role of glutamate as an immunoregulator via glutamate receptors and transporters. Front Biosci (Schol Ed) 3:1007–1020CrossRefGoogle Scholar
  56. 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):239–247CrossRefGoogle Scholar
  57. 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):e0160491CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of ChemistryCalifornia State UniversityFresnoUSA
  2. 2.Department of Medical Pathology and Laboratory Medicine, School of MedicineUniversity of CaliforniaDavisUSA

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