Newsletter 06/2020

The International Meeting on D-Amino Acid Research – IDAR2021 – originally planned in Illinois (USA) in June 2021, has been postponed to 2022. All news will be published by this Newsletter.

Do you have news concerning the D-amino acids field to announce? Is there a relevant published paper to mention? Write us and take the advantage of this bimonthly Newsletter.

ROLE OF D-AAs:

• D-Serine and D-Alanine Regulate Adaptive Foraging Behavior in Caenorhabditis elegans via the NMDA Receptor.

Yasuaki Saitoh, Masumi Katane, Tetsuya Miyamoto, Masae Sekine, Kumiko Sakai-Kato and Hiroshi Homma. Journal of Neuroscience 2020, 40 (39) 7531-7544; DOI: https://doi.org/10.1523/JNEUROSCI.2358-19.2020
 

This paper demonstrated that in the nematode Caenorhabditis elegans, the serine racemase homolog SERR-1 and D-amino acid oxidase DAAO-1 control an adaptive foraging behavior. The ability of nematode to start local search for food when transferred to a new environment was abolished for serr-1 deletion mutants, whereas daao-1 deletion mutants immediately engaged in long-range dispersal after food removal. D-Ser and D-Ala are both synthesized and suppressed during food deprivation. A behavioral pharmacological analysis showed that the long-range dispersal behavior requires NMDA receptor desensitization. Long-term pretreatment with D-Ala, as well as with an NMDA receptor agonist, expanded the area searched by the wild-type nematode immediately after food removal, whereas the same pretreatment with D-Ser did not. The authors concluded that D-Ser and D-Ala are endogenous regulators that cooperatively induce the long-range dispersal behavior in C. elegans through actions on the NMDA receptor. MORE

• Identification of an L-serine/L-threonine dehydratase with glutamate racemase activity in mammals.

Katane M, Nakasako K, Yako K, Saitoh Y, Sekine M, Homma H. Biochem J. 2020 Nov 13;477(21):4221-4241. doi: 10.1042/BCJ20200721

Following the identification of D-glutamate cyclase as the main degradative enzyme in mammals, the same group now identifies glutamate racemase as the putative enzyme responsible of D- and L-glutamate interconversion. A cDNA encoding L-serine dehydratase-like (SDHL) was identified in rat; it shows ∼60% sequence identity with that L-serine dehydratase. Recombinant SDHL is a multifunctional enzyme with glutamate racemase activity in addition to L-serine/l-threonine dehydratase activity. Studies on cultured mammalian cells confirmed that D-Glu was synthesized and L-Ser and L-Thr were decomposed. MORE

D-AAs AND PHYSIOLOGY:

• Factors regulating serine racemase and D-amino acid oxidase expression in the mouse striatum.

Shunsuke Takagi, Darrick T. Balu, Joseph T. Coyle 
Brain Research, 2020, 147202, https://doi.org/10.1016/j.brainres.2020.147202

Metabolism of D-serine is due to the cytosolic enzyme serine racemase (SR) and the peroxisomal enzyme D-amino acid oxidase (DAAO). This study focused on the expression of SR and DAAO in adult mouse brain by different centrally active drugs. The NMDAR antagonist MK801 and cocaine both reduce the expression of the two enzymes. This regulation is brain region selective, and in the case of cocaine, is reversed in part by NBQX, an AMPAR antagonist. On the other hand, D-Ser and antipsychotics do not regulate SR and DAAO protein levels. In a genetic model of SR disruption, this work reports that DAAO expression is unaltered in SR conditional KO mice, in which tissue D-Ser content remains fairly stable despite marked reduction in SR expression. This study reports a new mechanism by which AMPAR activity could regulate NMDAR function acting on D-Ser levels. MORE

• D-Amino acids in mammalian endocrine tissues.

Chieffi Baccari G., Falvo S., Santillo A., Di Giacomo Russo F, Di Fiore MM. 
Amino Acids 52, 1263–1273 (2020). https://doi.org/10.1007/s00726-020-02892-7

Starting from the assessment that “the current knowledge of physiological roles of D-amino acids in endocrine tissues is far from exhaustive”, here the Di Fiore’s group revised the knowledge in the field. In addition to D-Asp, which is known to act at all levels of the hypothalamus–pituitary–testis axis playing a key role in reproductive biology in several vertebrate classes, a main role is emerging for different D-amino acids in the endocrine function of the pancreas. D-Asp has been immunolocalized in insulin-containing secretory granules in INS-1 E clonal β cells and is co-secreted with insulin. The immunolocalization of D-Ala in pituitary ACTH-secreting cells and pancreatic β-cells suggest its involvement in blood glucose regulation in mammals. Furthermore, D-Ser probably participates in the control of systemic glucose metabolism by modulating insulin secretion. MORE

D-AAs AND PATHOLOGIES:

• Elevated plasma levels of D-serine in some patients with amyotrophic lateral sclerosis.

Aven Lee, Buddhika Jayakody Arachchige, Robert Henderson, David Pow, Sarah Reed, James Aylward & Pamela Ann McCombe. (2020) Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, DOI: 10.1080/21678421.2020.1832120

In this investigation, the levels of D-serine in plasma of 30 ALS patients and 30 controls were measured by HPLC-MS. Plasma levels of D-Ser in ALS patients (mean 39.27 ± 28.61 ng/ml) were significantly higher than those of healthy control subjects (mean 21.07 ± 14.03 ng/ml), and ∼43% of patients had plasma D-Ser levels that were 2 to 4-folds higher than those of controls. No association between plasma D-Ser levels and disability, duration of disease or age of subjects was apparent. Since D-Ser acts as a co-agonist of NMDAR, its increases could affect glutamatergic neurotransmission and potentially contribute to excitotoxicity in some ALS patients. MORE

• D-serine mitigates cell loss associated with temporal lobe epilepsy.

Beesley S, Sullenberger T, Crotty K, Ailani R, D’Orio C, Evans K, Ogunkunle EO, Roper MG, Kumar SS. Nat Commun. 2020; 11(1):4966. doi: 10.1038/s41467-020-18757-2

Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy in adults: a feature of TLE is the characteristic loss of layer 3 neurons in the medial entorhinal area (MEA) that underlies seizure development. This work shows that both neurons and glia together give rise to the pathology that is mitigated by D-Ser whose levels are potentially diminished in epilepsy. Administration of D-Ser to the MEA attenuates neuronal loss thereby preventing epileptogenesis in an animal model of TLE, reduces astrocyte counts in the MEA, alters their reactive status, and attenuates proliferation and/or infiltration of microglia to the region thereby reducing the consequences of neuroinflammation. Altogether, D-Ser offers new hope as a therapeutic agent for refractory TLE. MORE

• Effect of Sodium Benzoate vs Placebo Among Individuals With Early Psychosis: A Randomized Clinical Trial.

Scott JG, Baker A, Lim CCW, Sharon Foley, Frances Dark, Anne Gordon, DavidWard, George Bruxner, K. Martin Beckmann, Sean Hatherill, Stephen Stathis, Krystal Dixon, Alexander E. Ryan, Brett C. McWhinney, Jacobus P. J. Ungerer, Michael Berk, Olivia M. Dean, Sukanta Saha, John McGrath.
JAMA Netw Open. 2020;3(11):e2024335. doi:10.1001/jamanetworkopen.2020.24335

Sodium benzoate (BZ) was proposed as an effective adjunctive treatment for schizophrenia. Here, using a placebo-controlled double-masked parallel-group design, the results from a randomized clinical trial were reported. The study comprised 100 participants with a mean age of 21.4 years, of whom 73 were male individuals. No improvement in total PANSS score in the BZ group compared with the placebo group was apparent, as well as there were no differences in any subscales of the PANSS, any secondary measures, nor any amino acid concentrations. Altogether, there was no evidence that adjunctive use of 500 mg of BZ twice daily is an effective treatment for individuals with early psychosis. MORE

ANALYTICAL METHODS:

• Determination of phenylalanine enantiomers in the plasma and urine of mammals and ᴅ-amino acid oxidase deficient rodents using two-dimensional high-performance liquid chromatography.

Hsiao SW, Ishii C, Furusho A, Hsieh CL, Shimizu Y, Akita T, Mita M, Okamura T, Konno R, Ide T, Lee CK, Hamase K. Biochim Biophys Acta Proteins Proteom. 2020;1869(1):140540. doi: 10.1016/j.bbapap.2020.140540

In this work, a 2D-HPLC system equipped with a reversed-phase column (in the first dimension) and an enantioselective column (in the second dimension) has been designed, following the derivatization of the amino acid enantiomers with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F). The analytical method was validated using both plasma and urine samples, and successfully applied to human, rat and mouse fluids. Trace levels of ᴅ-Phe were determined in the plasma, and about 0.1% of ᴅ-amino acids were present for all species. In the urine, relatively large amounts of ᴅ-Phe were observed, with 3.99, 1.76 and 5.25% of the ᴅ- enantiomers for humans, rats and mice were respectively. High ᴅ-Phe amounts were observed (around 0.3% in the plasma and around 50% in the urine) in the DAO deficient rats and mice. MORE

ENZYMES ACTIVE ON D-AAs &  BIOTECHNOLOGICAL APPLICATIONS:

• Structural basis for stereospecificity to D-amino acid of glycine oxidase from Bacillus cereus ATCC 14579.

Jihye Seok, Yeo-Jin Kim, Il-Kwon Kim, Kyung-Jin Kim
Biochemical and Biophysical Research Communications, 2020, https://doi.org/10.1016/j.bbrc.2020.09.093

Glycine oxidase (GO) is a relevant flavoenzyme for biotechnological applications that catalyzes the oxidation of the primary and secondary amines of various chemicals. This paper reports on the resolution of the structure of GO from Bacillus cereus at a 2.36 Å resolution. Structural analysis provided information on the structural basis for the stereospecificity of the enzyme to D-amino acids. MORE

The D-amino acids International Research Center “DAAIR“ has been established in Gerenzano (Varese, Italy) in 2019 with the aim to support and perform scientific research projects and activities on the field of D-amino acids. The Center, located inside the Fondazione Istituto Insubrico Ricerca per la Vita, is aimed to represent a pole of excellence at international level for dissemination and research involving the D-amino acids (Director Silvia Sacchi).

The guiding principle is support the research projects aimed to investigate the involvement of D-amino acids in main physiological processes, from bacteria to humans. The ultimate goal is to actively participate to the elucidation of the mechanisms by which the D-amino acids perform specific functions, and to identify their presence and concentration in different organisms and compartments, also with regards to well-established functional states, with particular emphasis to pathological states. Understand the involvement of D-amino acids in important diseases as a way to set up novel therapeutic strategies.

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