Is d-aspartate produced by glutamic-oxaloacetic transaminase-1 like 1 (Got1l1): a putative aspartate racemase?

Abstract

d-Aspartate is an endogenous free amino acid in the brain, endocrine tissues, and exocrine tissues in mammals, and it plays several physiological roles. In the testis, d-aspartate is detected in elongate spermatids, Leydig cells, and Sertoli cells, and implicated in the synthesis and release of testosterone. In the hippocampus, d-aspartate strongly enhances N-methyl-d-aspartate receptor-dependent long-term potentiation and is involved in learning and memory. The existence of aspartate racemase, a candidate enzyme for d-aspartate production, has been suggested. Recently, mouse glutamic-oxaloacetic transaminase 1-like 1 (Got1l1) has been reported to synthesize substantially d-aspartate from l-aspartate and to be involved in adult neurogenesis. In this study, we investigated the function of Got1l1 in vivo by generating and analyzing Got1l1 knockout (KO) mice. We also examined the enzymatic activity of recombinant Got1l1 in vitro. We found that Got1l1 mRNA is highly expressed in the testis, but it is not detected in the brain and submandibular gland, where d-aspartate is abundant. The d-aspartate contents of wild-type and Got1l1 KO mice were not significantly different in the testis and hippocampus. The recombinant Got1l1 expressed in mammalian cells showed l-aspartate aminotransferase activity, but lacked aspartate racemase activity. These findings suggest that Got1l1 is not the major aspartate racemase and there might be an as yet unknown d-aspartate-synthesizing enzyme.

Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity

“…Moreover, we observed that acute D-Asp administration also elicits a transient increase of extracellular L-Asp, without affecting the amount of this L-amino acid in homogenates. To explain this data, we suggest that abnormal accumulation of D-Asp in the brain may perturb one or more of the still unclear cellular mechanisms regulating the local racemization of D-Asp into L-Asp2829, L-Asp vesicular storage3031 and release32. In addition, we cannot exclude that non-physiological, high D-Asp extracellular concentration may displace L-Asp from its binding to L-Glu/L-Asp transporters, which regulate the uptake of both Asp enantiomers33, thus resulting in increased extracellular L-Asp levels.…”

Distinctive Roles of D-Amino Acids in the Homochiral World: Chirality of Amino Acids Modulates Mammalian Physiology and Pathology

“…Indeed, glutamic-oxaloacetic transaminase-1 like 1 (Got1l1) was identified as a putative aspartate racemase and is involved in adult neurogenesis. 79 A later study, however, demonstrated that systemic knockout of Got1l1 in mice does not alter the level of d-Asp in the brain or testis, 80 indicating the presence of an unknown authentic synthetic enzyme in mammals. Interestingly, recent studies suggest that mammalian serine racemase (SR), an endogenous synthetic enzyme for d-Ser, 81 is involved, at least in part, in d-Asp synthesis in the brain but not in the testis.…”

The Role of Amino Acids in Neurotransmission and Fluorescent Tools for Their Detection

“…Moreover, contrary to the long-standing belief that NMDA is not endogenous in mammals, d -aspartate was also suggested to be a precursor to NMDA in rats [ 44 ]. Although serine racemase, to a degree, is able to produce d -aspartate from l -aspartate, the main synthetic pathway for d -aspartate remains an open question since reports of an aspartate racemase have been questioned [ 36 , 45 , 52 , 53 , 54 ]. However, to the best of our knowledge, like l -aspartate, the transporter responsible for loading d -aspartate into vesicles has not been identified.…”