Newsletter 03/2021

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.

The Editor’s pick selection of the most intriguing papers is highlighted in yellow.

D-AAs AND PHYSIOLOGY:

• Serum D-serine levels are altered in early phases of Alzheimer’s disease: towards a precocious biomarker

Piubelli, L., Pollegioni, L., Rabattoni, V., Mauri, M., Princiotta Cariddi, L., Versino, M., Sacchi, S.
Translational Psychiatry, Volume 11, Issue 1, June 2021, Article number 77. 

This work evaluated the serum levels of L- and D-enantiomers of serine and aspartate (by HPLC using a pre-column derivatization procedure and a selective enzymatic degradation) from healthy subjects (HS) and AD patients by considering age, gender, and disease progression. Minor changes were apparent for the levels of aspartate enantiomers in AD patients compared to HS. A positive correlation for the D-serine level and age was apparent in the AD cohort. Notably, the serum D-serine level and the D-/total serine ratio significantly increased with the progression of the disease (the latter parameter allows to discriminate CDR 2 and CDR 1 patients from HS). These two latter parameters have been proposed as novel and valuable biomarkers for the progression of AD. MORE

• Mouse strain specificity of DAAO inhibitors-mediated antinociception 

Liu, H., Zhou, Y.-C., Wang, Z.-Y., Gong, N., Lu, J.-M., Apryani, E., Han, Q.-Q., Wang, Y.-X., Ou, M.-X. 
Pharmacology Research and Perspectives, Volume 9, Issue 2, April 2021, Article number e00727.

It is known that the spinal astroglial D-amino acid oxidase (DAAO) produces hydrogen peroxide, and that this pathway is involved in the process of pain and morphine antinociceptive tolerance. In this work, the mouse strain specificity of DAAO inhibitors on antinociception was investigated: benzoic acid, CBIO, and SUN significantly inhibited formalin-induced tonic pain in Balb/c and Swiss mice, but had no antinociceptive effect in C57 mice. The intrathecal injection of D-serine greatly increased spinal H2O2 levels in Swiss and Balb/c mice while reduced spinal H2O2 levels in C57 mice. While no difference in spinal DAAO activities was observed among Swiss, Balb/c and C57 mice, the spinal expression of glutathione and glutathione peroxidase activity were significantly higher in C57 mice. In conclusion, the DAAO inhibitors produced antinociception in a strain-dependent manner in mice: the strain specificity might be associated with the difference in spinal glutathione and glutathione peroxidase activity. MORE

• Dynamics of D-amino acid oxidase in kidney epithelial cells under amino acid starvation 

Sogabe H, Shishido Y, Miyazaki H, Kim SH, Rachadech W, Fukui K. 
J Biochem. 2021 Mar 16:mvab029. doi: 10.1093/jb/mvab029.

In the kidney D-amino acid oxidase (DAAO) is expressed in proximal tubules and is involved in the catabolism of D-amino acids into the corresponding α-keto acids. When LLC-PK1 cells, a pig renal proximal tubule cell line, were used it was observed that trypsinization of cells in culture rapidly reduced the intracellular DAAO protein level. A decrease in DAAO level was also observed when cells were subjected to amino acid starvation. DAAO degradation was found to be inhibited by chloroquine, but not by MG132 treatment. In conclusion, DAAO is degraded by autophagy due to amino acid starvation. MORE

• Cellular studies of the two main isoforms of human D-aspartate oxidase

Rabattoni V, Pollegioni L, Tedeschi G, Maffioli E, Sacchi S. 
FEBS J. 2021 Mar 1. doi: 10.1111/febs.15797.

In the mammalian central nervous system, D-Asp behaves as a classical neurotransmitter which appears to be involved in several pathological states, such as schizophrenia and Alzheimer’s disease (AD). The human DDO gene produces alternative transcripts encoding for three putative human D-aspartate oxidase (hDASPO) isoforms, made by 341 (the ‘canonical’ form), 369, and 282 amino acids. The hDASPO_369 isoform only has been identified in hippocampus of female AD patients, while peptides corresponding to the remaining part of the protein were present in samples from male and female healthy controls and AD. The hDASPO_369 isoform is active, localizes to the peroxisomes, is very stable and is degraded through the ubiquitin-proteasome system, like the canonical hDASPO_341 form, only its solubility was lower. MORE

• The Role of D-Amino Acids in Alzheimer’s Disease

Piubelli L, Murtas G, Rabattoni V, Pollegioni L. 
J Alzheimers Dis. 2021;80(2):475-492. doi: 10.3233/JAD-201217.

In past years, alterations in physiological levels of various D-amino acids have been linked to several pathological states. In this review the experimental findings linking D-serine and D-aspartate, through NMDA receptor modulation, to Alzheimer’s disease (AD) and cognitive functions has been reported. AD progression has been associated with the enzymes related to D-amino acid metabolism as well as with glucose and serine metabolism. MORE

D-AAs AND BACTERIA:

• Host-microbe cross-talk governs amino acid chirality to regulate survival and differentiation of B cells.

Suzuki, M., Sujino, T., Chiba, S., Harada, Y., Goto, M., Takahashi, R., Mita, M., Hamase, K., Kanai, T., Ito, M., Waldor, M.K., Yasui, M., Sasabe, J.
Science Advances, Volume 7, Issue 10, 3 March 2021, Article number eabd6480.

This work reports about the relevance of amino acids enantiomers, balanced by bacteria-mammal cross-talk, on intestinal B cell fate and immunoglobulin A production. Bacterial D-amino acids stimulate M1 macrophages and promote survival of intestinal naïve B cells. The intestinal catabolism of D-amino acids limits the amount of B cells and restricts growth of symbiotic bacteria that activate T cell–dependent IgA class switching of the B cells. When catabolism of D-amino acids is reduced, an excessive IgA production and dysbiosis with altered IgA coating on bacteria is observed. The authors conclude that chiral conversion of amino acids is linked to bacterial recognition by mammals to control symbiosis with bacteria. MORE

ANALYTICAL METHODS:

• Recent developments in separation methods for enantiomeric ratio determination of amino acids specifically involved in cataract and Alzheimer’s disease.

Furman, C., Howsam, M., Lipka, E.
TrAC Trends in Analytical Chemistry, Volume 141, 2021, 116287, https://doi.org/10.1016/j.trac.2021.116287.

This review fosuses on: i) the relevance of racemization of amino acid in Alzheimer’s disease and cataract; ii) the chiral separation methods, both indirect and direct approaches: iii) recent applications of these methods for determination of the D/L-amino acid ratio and of peptides containing D-amino acids. MORE

D-AAs &  BIOTECHNOLOGICAL APPLICATIONS:

• Understanding and controlling amyloid aggregation with chirality.

Foley, A.R., Raskatov, J.A. 
Current Opinion in Chemical Biology, Volume 64, October 2021, Pages 1-9.

This review reports about recent advances concerning the use of mirror-image peptides/proteins and of peptides incorporating D-amino acids to modulate amyloid aggregation in pathologies such as Alzheimer’s disease, Parkinson’s disease, and type II diabetes. These approaches offered new mechanistic tools to study cellular interactions, and to identify key positions within the peptide/protein sequence that influence amyloid fibril growth and toxicity. MORE

• Covalently immobilize crude D-amino acid transaminase onto UiO-66-NH2 surface for D-Ala biosynthesis

Wang, B., Zhou, J., Zhang, X.-Y., Yang, Y.-S., Liu, C.-H., Zhu, H.-L., Jiao, Q.-C.
International Journal of Biological Macromolecules, Volume 175, 1 April 2021, 451-458.

In this study, D-amino acid transaminase (DAT), a relevant enzyme for industrial synthesis of D-Ala, was covalently immobilized on the surface of a star MOFs material, UiO-66-NH2. The nanoscale hybrid enzyme UiO-66-NH2-Gd-DAT maintained the high catalytic efficiency and allowed efficient and stereo-selective conversion without a complex purification process. MORE

ENZYMES ACTIVE ON D-AAs:

• Interactions between isoalloxazine and o-aminobenzoate in o-aminobenzoate−D-amino acid oxidase complex. Molecular dynamics and molecular orbital studies.

Nueangaudom, A., Pianwanit, S., Tamaoki, H., Nishina, Y., Tanaka, F, Taniguchi, S., Chosrowjan, H. 
Journal of Photochemistry and Photobiology A: Chemistry, Volume 408, 1 March 2021, Article number 113090.

The molecular interactions between o-aminobenzoate (oAB) and isoalloxazine ring (Iso) in the o-aminobenzoate-D-amino acid oxidase complex (ODC) were studied by molecular dynamics simulation and molecular orbital method. The ODC displays a broad absorption band around 570 nm, considered a charge transfer (CT) between oAB and Iso. The authors concluded that a part of oAB could move to form CT complex with Iso in the ground state (displaying the CT absorption band) but others could not move in the protein without CT interaction, which displays the fluorescence. 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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