A Review of Phylogenetic and Metabolic Relationships Between the Acylamino Acids, N‐Acetyl‐l‐Aspartic Acid and N‐Acetyl‐l‐Histidine, in the Vertebrate Nervous System

Abstract

N-Acetyl-L-histidine (NAH) and N-acetyl-Laspartic acid (NAA) are major constituents of vertebrate brain and eye with distinct phylogenetic distributions. They are characterized by high tissue concentrations, high tissue/extracellularfluid gradients, and a continuous regulated efflux into the extracellular fluid. As a result of parallel investigations over the past three decades, evidence has accumulated that suggests that the metabolism of NAA in the CNS of both homeothermic and poikilothermic vertebrates and the metabolism of NAH in the CNS of poikilothermic vertebrates are related. Tissue distribution and concentrations are similar, as well as timing of appearance during embryological development and their synthetic and degradative biochemistry. Both amino acids appear to be involved in a rapid tissue-to-fluidspace cycling phenomenon across a membrane. Evidence accumulating for each amino acid suggests a dynamic and important role in the CNS and the eye of vertebrates. A genetic disease in humans, Canavan's disease, is associated with NAA aciduria and aspartoacylase deficiency with concomitant accumulation of NAA and a spongy degeneration of the brain. In this article, evidence linking NAA and NAH metabolism is reviewed, and the hypothesis that NAA and NAH complement each other and are metabolic analogues involved with membrane transport is developed. Their enzyme systems also appear to exhibit plasticity in relation to osmoregulatory forces on an evolutionary time scale, with an apparent interface at the fish-tetrapod boundary. Key Words: NAcetyl-L-aspartic acid-N-Acetyl-L-histidine-Phylogenetic distribution-Cycling phenomenon-EvolutionCanavan's disease-Osmoregulatory forces-Efflux. J. Neurochem. 68, 1335-1344 (1997).The vertebrate brain has been found to contain very high concentrations of two acetylated amino acids, Nacetyl-L-aspartic acid (NAA) and N-acetyl-L-histidine (NAH). NAA was first isolated in extracts of cat brain by Tallan et a!. (1956). Two years later, NAH was isolated as an unknown in an imidazole fraction (TM 1) in cold-blooded vertebrates by Correale (1958) and later identified as NAH from the IM~fraction of frog tissues by Anastasi et al. (1964). Baslow (1963Baslow ( , 1964 independently isolated an unknown imidazole compound from the brain of fish and frogs and named it neurosine. Later, neurosine was identified as NAH (Baslow, 1965). Kuroda and Ikoma (1966) independently isolated and identified NAH in frog heart. Since the identification of these acetylated amino acids in very high concentrations in the brain of vertebrates, they have been the subject of many investigations into their possible function in both cold-blooded (poikilothermic) and warm-blooded (homeothermic) vertebrates. The studies, for the most part, have treated these amino acids as separate entities, probably because high concentrations of NAH are only present in the brain of poikilothermic vertebrates and high concentrations of NAA are found primarily in the brain of homeothermic vertebrates. In only a single ...

Increased Anterior Cingulate/Medial Prefrontal Cortical Glutamate and Creatine in Bipolar Depression

“…NAA synthesis occurs in the neuronal mitochondrion through the NAA-synthase-catalyzed union of acetyl-CoA with aspartate: Acetyl-CoA + Asp-NAA + CoAsh (Baslow, 1997;Patel and Clark, 1979). Thus, inhibition of aspartate release may increase intracellular synthesis of NAA.…”

Accumulation of N‐Acetyl‐L‐Aspartate in the Brain of the Tremor Rat, a Mutant Exhibiting Absence‐Like Seizure and Spongiform Degeneration in the Central Nervous System

“…NAA exists predominantly in the CNS in high concentrations in the mammalian brain, being second only in concentration of free amino acids to glutamate (Baslow, 1997). Indeed, NAA has been found in the brains of eight mammalian species with a range of 1.60 -10.08 mol/g (average 5.7 mol/g).…”

“…However, this apparent discrepancy might be explained by the different location of NAA between human epileptic patients and NAA-injected rats. NAA is found predominantly within the cellular matrix but rarely in extracellular fluid (Baslow, 1997). This high membrane gradient of NAA between the cellular matrix and the extracellular fluid is considered to be maintained by a tissue-to-fluid cycling system, which is balanced by a synthetic enzyme and a hydrolytic enzyme (aspartoacylase).…”

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

“…The osmotic damage hypothesis of Canavan disease may have had its origins in work on osmoregulation in ocular tissues of fish (Baslow and Yamada, 1997). N-acetylhistidine is present at high concentrations in the lens of poikilotherms including fish, and Baslow proposed that it could be involved in tissue fluid balance (Baslow, 1997). It was also proposed that what appeared to be an inverse phylogenetic relationship between the concentrations of NAA and N-acetylhistidine in brain, eye and other tissues might indicate that they served similar membrane transport or fluid balance functions in different physiological contexts.…”