Methamphetamine-induced neuronal protein NAT8L is the NAA biosynthetic enzyme: implications for specialized acetyl coenzyme A metabolism in the CNS.
N-acetylaspartate (NAA) is a concentrated, neuron-specific brain metabolite routinely used as a magnetic resonance spectroscopy marker for brain injury and disease. Despite decades of research, the functional roles of NAA remain unclear. Biochemical investigations over several decades have associated NAA with myelin lipid synthesis and energy metabolism. However, studies have been hampered by an inability to identify the gene for the NAA biosynthetic enzyme aspartate N-acetyltransferase (Asp-NAT). A very recent report has identified Nat8l as the gene encoding Asp-NAT and confirmed that the only child diagnosed with a lack of NAA on brain magnetic resonance spectrograms has a 19-bp deletion in this gene. Based on in vitro Nat8l expression studies the researchers concluded that many previous biochemical investigations have been technically flawed and that NAA may not be associated with brain energy or lipid metabolism. In studies done concurrently in our laboratory we have demonstrated via cloning, expression, specificity for acetylation of aspartate, responsiveness to methamphetamine treatment, molecular modeling and comparative immunolocalization that NAT8L is the NAA biosynthetic enzyme Asp-NAT. We conclude that NAA is a major storage and transport form of acetyl coenzyme A specific to the nervous system, thus linking it to both lipid synthesis and energy metabolism.
Ariyannur
Prasanth S
PS
Uniformed Services University of Health Sciences, Department of Anatomy, Physiology and Genetics, Molecular and Cell Biology Program, Neuroscience Program, 4301 Jones Bridge Road, Bldg C, Rm 2069, APG, Bethesda, MD 20814, USA.
Moffett
John R
JR
Manickam
Pachiappan
P
Pattabiraman
Nagarajan
N
Arun
Peethambaran
P
Nitta
Atsumi
A
Nabeshima
Toshitaka
T
Madhavarao
Chikkathur N
CN
Namboodiri
Aryan M A
AM
D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000107:Acetylation; D000123:Acetyltransferases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000096:biosynthesis; D002460:Cell Line; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000201:enzymology*; D017966:Pyramidal Cells / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity / Q000235:genetics
D009419:Nerve Tissue Proteins; D001224:Aspartic Acid; D008694:Methamphetamine; D000105:Acetyl Coenzyme A; C000179:N-acetylaspartate; D000123:Acetyltransferases; C116373:NAT8 protein, human; C000611572:NAT8L protein, human; C046791:aspartate N-acetyltransferase