A Methylamino-L-alanine

The nonprotein amino acid /3-A -methylamino-L-alanine (BMAA) is a neurotoxin found in various species of marine cyanobacteria. This nonprotein amino acid occurs both as a free amino acid and bound to proteins.Siderophores are secondary metabolites generally produced by bacteria under iron-deficient conditions. These molecules sequester and transport ferric ion via active transport in bacteria. Some known siderophores are nonribosomal peptides that contain nonprotein amino acids with terminal amines or hydroxylamine side chains, such as exochelin Many of the known nonprotein amino... 

Kisby, G.E., Ellison, M. and Spencer, P.S. (1992). Content of the neurotoxins cycasin (methylazoxymethanol-/J-D-glucoside) and BMAA (/3-A-methylamino-L-alanine) in cy-cad flour prepared by Guam Chamorros. Neurology 42 1336-1340. 

Weiss, J.H. and Choi, D.W. (1988). Beta-A -methylamino-L-alanine neurotoxicity requirement for bicarbonate as a cofactor. Science 241 973-975. 

Several of these plants are used as human food sources in Oceania and many are eaten by animals in many areas of the South Pacific and in Australia. A form of amyotrophic lateral sclerosis (ALS or Lou Gehrig s disease) used to be endemic among the Chamorros of Guam and is linked to the presence of an unusual amino acid a-amino-p-propionic acid or p-A-methylamino-L-alanine found in this cycad (Fowler, 1987 Spencer et al., 1987) (see Chapter 13). Methyl azoxymethanol has been shown to be carcinogenic (Hirono, 1972). Cycasin (84) reduces the litter size in rats if consumed prior to mating (Fig. 16.20). 

Cyanobacteria - the Jekyll and Hyde of marine organisms - are a novel source of potential new pharmaceutical compounds (2618-2620, 2662). On the other hand, toxic cyanobacterial blooms in lakes, rivers, and water storage reservoirs have occurred worldwide (2621, 2663, 2664). For example, 60 patients in a Brazil hemodialysis unit died after drinking water from a lake contaminated with cyanobacterial microcystins (2622), not unlike the toxicity of red tides (2623). Cyanobacteria also produce the highly toxic neurotoxin, p-N-methylamino-L-alanine, which may be produced by all cyanobacteria (2624, 2665). 

Copani A., Canonico P L., Catania M. V., Aronica E., Bruno V., Ratti E., Van Amsterdam F. T. M., Gaviraghi G., andNicoletti F. (1991). Interaction between /3-N-methylamino-L-alanine and excitatory amino acid receptors in brain slices and neuronal cultures. Brain Res. 558 79-86. 

Environmental and nutritional factors may also affect the development of Alzheimer disease and other mental illness. Aluminum frequently accumulates in the neurons containing neurofibrillary tangles. Copper and zinc ions can cause the amyloid Ap to aggregate. However, Zn + may actually protect against neurotoxicity. The amino acid P-N-methylamino-L-alanine, a constituent of the toxic seeds of a type of palm Cycas circimlis L.), may have induced both AES and Guam disease, a condition resembling Parkinson disease, in a population in Guam that traditionally used these seeds as food. ... 

Certain individuals on Guam and other South Sea Islands exhibit an increased incidence of amyotrophic lateral sclerosis (ALS), parkinsonism and dementia. The absence of inheritable or transmissible factors in this syndrome led to a search for environmental causes and the identification of the false sago palm Cycas circinalis) as a likely source of the causative agent. This plant contains a number of potential neurotoxins including -N-methylamino-L-alanine (BMAA), an agent with weak excitotoxic properties (Spencer et al., 1990). 

Copani, A., Canonico, P.L. and Nicoletti, F. (1990). fi-N-methylamino-L-alanine (L-BMAA) is a potent agonist of metabolotropic glutamate receptors, Eur. J. Pharmacol. 181 327-328. 

The cyanobacteria produce a plethora of natural products with a wide variety of bioactivities. Many of these compounds are potent toxins and pose a significant hazard to human health and the environment. In freshwater systems, blooms of hepatotoxic cyanobacteria are of greatest concern, while in marine environments neurotoxic species are more problematic. More than 65 neurotoxins have been isolated from cyanobacteria to date. Most notably, these include the highly potent alkaloids anatoxins and saxitoxins (also known as paralytic shellfish toxins, PSTs) however, a variety of other neurotoxic substances have also been isolated from cyanobacteria including the lipopeptides, jamaicamide, antillatoxin, and kalkitoxin, as well as the nonproteinogenic amino acid, p-W-methylamino-L-alanine (BMAA). 

The non-protein amino acid m-tyrosine (Fig. 5) is responsible for most, if not all, of the allelo-pathic activity of a Festuca rubra (red fescue) subspecies [164,165]. The compound is exuded into the soil fi om roots of the fescue plant. While some non-protein amino acids have functions in plant primary metabolism (e.g. 5-aminolevulinic acid), others are thought to be involved in protection of plants fi om a variety of biotic threats, particularly herbivores. The modes of action of these compounds range tfom direct neurotoxicity, such as produced by p-At-methylamino-L-alanine [166], to incorporation into proteins to produce aberrant molecules, leading to multiple physiological problems (e.g. [167]). 

Aimed at investigating the taste enhancing activity of the individual enantiomers of alapyridaine, enantiopure 1 was prepared upon reductive animation of 5-(hydroxymethyl)-2-furanaldehyde and L-alanine with Raney nickel/hydrogen. This reaction resulted in the corresponding ( S)-A -(1-carboxyethyl)-2-hydroxymethyl-5-(methylamino)furan (Figure 7). The latter was converted into the target pyridinium betain compound by mild oxidation with bromine in water/methanol to yield (+)-(iS)-l. Similarly, the reaction with D-alanine resulted in (-)-(R)-l. After purification, the presence of (5)-l and (R)-1 was proven by polarimetry, revealing optical rotations of +40.2° and -38.6°, respectively (72). 

Characteristic structural features of natural cyclosporins include a unique unsatuiated 3 hydroxy-tt-amino acid with a skeleton, (2S, 3R, 4R, 6E)-3-hydroxy-4-methyl-2-methylamino-oct-b-enoic acid, the N-methylation of several of the 11 amino acids, and the presence of D-alanine in the molecule. The individual cyclosporins differ from each other by variation of one or two amino acid constituents. The most frequent diversity occurs in position 2, which can be occupied by L-Z-aminobutyric acid (CyA), L-alanine (CyB), L-threonine (CyC), L-valine (CyD), or L-norvaline (CyG). N-Demethyl analogs are encountered in piositions 1,6, 9,10, and 11. Modifications ar position 5 are illustrated by L-norvaline in CyM and L-leucine in Cy26 instead of L-valine. In position 7, a second... 

Cyanuric chloride on monosubstitution with nucleophiles such as methanol or 4-amino-azobenzene followed by displacement of a second chlorine with alanine amide gave compounds which are used for precolumn derivatization of amino acids. The diastereoisomers formed are resolved by reverse-phase HPLC <92MI 6l2-0i>. Enantiomeric amino acids are separated by HPLC on bis[carbamoyl(alkyl)methylamino]-6-chloro-l,3,5-triazine derived stationary phases <93JC277>. 

Methplphenyl-a.-alanine, l-methylamino-2-phenyl-propumic acid)... 

---