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



  • Mammalian D-cysteine: A novel regulator of neural progenitor cell proliferation

Robin Roychaudhuri, Solomon H. Snyder
BioEssays, published: 28 April 2022


D-Cysteine is present in neonatal brain in millimolar levels and decreases with postnatal development. D-Cys binds to MARCKS and decreases its phosphorylation in neural progenitor cells (NPCs) affecting its translocation. D-Cys controls NPC proliferation by inhibiting AKT signaling. In vitro studies show that exogenous D-Cys inhibits AKT phosphorylation at T308 and S473 in NPCs, leading to 50% reduction in phosphorylation of Foxo1 at S256 and Foxo3a at S253. The authors propose that in the developing brain endogenous D-Cys is a physiologic regulator of NPC proliferation: it may regulate mammalian neurodevelopment with roles in schizophrenia and Alzheimer’s disease.



  • D-Cysteine Activates Chaperone-Mediated Autophagy in Cerebellar Purkinje Cells via the Generation of Hydrogen Sulfide and Nrf2 Activation

Ueda E, Ohta T, Konno A, Hirai H, Kurauchi Y, Katsuki H, Seki T. 
Cells. 2022 Apr 5;11(7):1230. doi: 10.3390/cells11071230.

Chaperone-mediated autophagy (CMA) is a pathway in the autophagy-lysosome protein degradation system, which impairment has been implicated in spinocerebellar ataxia (SCA) pathogenesis. D-Cys is metabolized by D-amino acid oxidase (DAAO), leading to hydrogen sulfide generation in the cerebellum; D-Cys alleviates the disease phenotypes in SCA-model mice. Here, the authors investigated the effects of D-Cys and H2S on CMA activity: i) D-Cys activated CMA in Purkinje cells (PCs) of primary cerebellar cultures where DAAO was expressed, while it failed to activate CMA in DAAO-deficient AD293 cells; ii) Na2S activated CMA in both PCs and AD293 cells; iii) an inhibitor of nuclear factor erythroid 2-related factor 2 (Nrf2) prevented CMA activation triggered by D-Cys and Na2S; iv) long-term treatment with D-Cys increased the amounts of Nrf2 in the mouse cerebellum. The authors proposed that H2S derived from D-Cys enhances CMA activity via Nrf2 activation.



  • D-Serine controls epidermal vesicle release via NMDA receptor, allowing tissue migration during the metamorphosis of the chordate Ciona

Krasovec G, Hozumi A, Yoshida T, Obita T, Hamada M, Shiraishi A, Satake H, Horie T, Mori H, Sasakura Y. 
Sci Adv. 2022 Mar 11;8(10):eabn3264. doi: 10.1126/sciadv.abn3264.

Concerning the functions of D-serine in nonmammals, here the D-Ser-dependent vesicle release from the epidermis during metamorphosis of the tunicate Ciona was investigated. D-Ser leads to the formation of a pocket that facilitates the arrival of migrating tissue during tail regression. The epidermal pocket is formed by the release of epidermal vesicles’ content mediated by D-Ser/NMDAR (the latter is the receptor of D-Ser). This mechanism is similar to observations of keratinocyte vesicle exocytosis in mammalian skin. This work provides a better understanding of the maintenance of epidermal homeostasis in animals.





  • D-serine metabolism in the medial prefrontal cortex, but not the hippocampus, is involved in AD/HD-like behaviors in SHRSP/Ezo

Shindo T, Shikanai H, Watarai A, Hiraide S, Iizuka K, Izumi T.
Eur J Pharmacol. 2022 May 15;923:174930. doi: 10.1016/j.ejphar.2022.174930

Attention-deficit/hyperactivity disorder (AD/HD) is a mild neurodevelopmental disease charaterized by inattention, hyperactivity, and impulsivity. The serine enantiomers DL-ratio (D-/D- + L-serine) in the medial prefrontal cortex (mPFC) and hippocampus (HIP) was lower in SHRSP/Ezo than in its genetic control. The level of D-amino acid oxidase (DAAO) was higher in the mPFC while the level of serine racemase (SR) was lower in the HIP in SHRSP/Ezo. The microinjection of a DAAO inhibitor into the mPFC in SHRSP/Ezo increased DL-ratio and attenuated AD/HD-like behaviors in the Y-maze test. Injection into the HIP also increased the DL-ratio, but had no effect on behaviors. The AD/HD-like behaviors in SHRSP/Ezo are associated with an abnormal D-Ser metabolism underlying NMDA receptor dysfunction in the mPFC.



  • Protective effect of D-alanine against acute kidney injury

Iwata Y, Nakade Y, Kitajima S, Yoneda-Nakagawa S, Oshima M, Sakai N, Ogura H, Sato K, Toyama T, Yamamura Y, Miyagawa T, Yamazaki H, Hara A, Shimizu M, Furuichi K, Mita M, Hamase K, Tanaka T, Nishida M, Muramatsu W, Yamamoto H, Shichino S, Ueha S, Matsushima K, Wada T.
Am J Physiol Renal Physiol. 2022 Jun 1;322(6):F667-F679. doi: 10.1152/ajprenal.00198.2021.


The pathophysiological role of D-alanine (D-Ala) in acute kidney injury (AKI) was studied here. Hypoxic conditions altered the gene expression of Grin1, Grin2A, and Grin2B (i.e., NMDA receptor subtypes) and D-Ala protected from hypoxia-related cell injury and induced proliferation after hypoxia. D-Ala inhibited reactive oxygen species (ROS) production and improves mitochondrial membrane potential, through NMDA receptor signaling. After the induction of ischemia-reperfusion (I/R), the ratio of D-Ala to L-Ala increased in feces, plasma, and urine and the oral administration of D-Ala ameliorated kidney injury. Deficiency of NMDA subunit NR1 in tubular cells worsened kidney damage in AKI. Notably, the increased plasma level of D-Ala reflected the level of renal function in patients with AKI. The plasma level of D-Ala reflects the estimated glomerular filtration rate in patients with AKI and could represent a promising therapeutic target and potential biomarker.



  • Discovery of a Novel Class of D-Amino Acid Oxidase Inhibitors Using the Schrödinger Computational Platform

Tan Hagifeng, Jensen Kristian, Houang Evelyne, McRobb Fiona M., Bhat Sathesh, Svensson Mats, Bochevarov Art Day, Tyler Dahlgren, Markus K., Bell Jeffery A., Frye Leah, Skene Robert J.
Journal of Medicinal Chemistry 2022 DOI10.1021/acs.jmedchem.2c00118

D-amino acid oxidase (DAAO) inhibitors are used in the treatment of schizophrenia and other pathologies. Here, powered by the Schrödinger computational modeling platform, a new class of DAAO inhibitors with the best-in-class properties were identified.The reported modeling technology not only has enhanced the efficiency of structure-activity relationship development but also helped to identify a previously unexplored subpocket for further optimization.



  • Coumarin derivatives as inhibitors of D-amino acid oxidase and monoamine oxidase

Elizabeth Bester, Anél Petzer, Jacobus P. Petzer
Bioorganic Chemistry, Volume 123, 2022, 105791, ISSN 0045-2068,

Literature reports that 3-hydroxycoumarin is a potent inhibitor of D-amino acid oxidase (DAAO). This investigation focused on a series of synthetic and commercially available coumarin derivatives, as well as a synthetic series of 3,4-dihydroisoquinolin-1(2H)-one derivatives. Among the 37 compoundd evaluated, four inhibited porcine kidney DAAO with IC50 < 10 µM. The most potent inhibitors are 3,7-dihydroxycoumarin and 6,7-dihydroxycoumarin (IC50 values ~ 0.2 µM). Coumarin compounds are also known to inhibit monoamine oxidases (MAO), well established targets for the treatment of depression and Parkinson’s disease. As DAAO and MAO are flavoenzymes, off-target inhibition may occur. Seven of the tested compounds inhibited also the recombinant human MAOs with IC50 < 0.1 µM, values significantly more potent than the reference inhibitors, curcumin, isatin and toloxatone.



  • AutoDesigner, a De Novo Design Algorithm for Rapidly Exploring Large Chemical Space for Lead Optimization: Application to the Design and Synthesis of D-Amino Acid Oxidase Inhibitors

Bos Pieter H., Houang Evelyne M., Ranalli Fabio, Leffler Abba E., Boyles Nicholas A., Eyrich Volker A., Luria Yuval, Katz Dana, Tang Haifeng, Abel Robert, Bhat Sathesh
Journal of Chemical Information and Modeling Volume 62, Issue 8, Pages 1905 – 191525 April 2022 DOI 10.1021/acs.jcim.2c00072

To address the limitations of a classical drug discovery program, here AutoDesigner, a de novo design algorithm was developed. AutoDesigner employs a cloud-native, multistage search algorithm to carry out successive rounds of chemical space exploration and filtering. Millions to billions of virtual molecules are explored and optimized while adhering to a customizable set of project criteria such as physicochemical properties and potency. Additionally, the algorithm only requires a single ligand with measurable affinity and a putative binding model as a starting point, making it amenable to the early stages of an SBDD project where limited data are available. AutoDesigner generated and efficiently explored over 1 billion molecules as D-amino acid oxidase inhibitors, exploring novel interactions and a previously unexplored subpocket in the active site.





  • Identification and characterization of a serine racemase in the silkworm Bombyx mori 

Tanaka Y, Yoshimura T, Hakamata M, Saito C, Sumitani M, Sezutsu H, Hemmi H, Ito T J Biochem. (2022) mvac026. doi: 10.1093/jb/mvac026

In this paper Tanaka and collaborators reported about the identification of a new type of pyridoxal 5′-phosphate (PLP)-dependent serine racemase (SR) in B. mori, catalyzing the racemization and dehydration of both serine isomers. The authors investigate the silkworm SR (BmSR) structural and functional properties showing that it possesses distinctive features compared to the mammalian one. They enzyme expression and activity are primarily detected in the fat body and this explain the marked increase in D-serine (up to 50% of total serine) during the insect development, from the laval to the pupal stage.



  • Novel transaminases from thermophiles: from discovery to application

Cárdenas-Fernández M, Sinclair O, Ward JM. 
Microb Biotechnol. (2022) 15(1):305-317. doi: 10.1111/1751-7915.13940

Transaminases (TAs) are widely distributed PLP-dependent enzymes largely utilized in the synthesis of fine chemicals and pharmaceuticals. This work explore the possible application of thermophilic TAs, which have been poorly described to date. To this aim, 94 putative TAs are successfully cloned from nine thermophilic microorganisms upon a genome mining approach and recombinatly expressed in E. coli using a chemical chaperone media containing D-sorbitol. Among them pQR2590, a steroselective class IV TA from G. stearothermophilus accepts D-serine only as a substrate (optimum temperature of 60 °C) and a very high specific activity.





  • Occurrence and D-Tryptophan Application for Controlling the Growth of Multidrug-Resistant Non-O157 Shiga Toxin-Producing Escherichia coli in Dairy Products

Elafify M, Sadoma NM, Abd El Aal SFA, Bayoumi MA, Ahmed Ismail T. 
Animals (Basel). 2022 Apr 4;12(7):922. doi: 10.3390/ani12070922

This work revealed that 20% of the milk and dairy products in Egypt were Shiga toxin-producing Escherichia coli (STEC) positive, with 64 isolates harboring some virulent genes. Antimicrobial susceptibility testing revealed that 100%, 98.4%, 92.2%, 71.9%, 65.6% and 64.1% of the isolates had a resistance against tetracycline, oxacillin, erythromycin, nalidixic acid, sulphamethoxazol, and ampicillin, respectively. The addition of 40 mM D-tryptophan to E. coli O26:H11-inoculated soft cheese and ice cream revealed a significant reduction in bacterial growth, especially when accompanied with other food stressors. D-Tryptophan is thus considered as an effective food preservative for the dairy industry.



  • D-Alanine Metabolism via D-Ala Aminotransferase by a Marine Gammaproteobacterium, Pseudoalteromonas sp. Strain CF6-2

Yu Y, Yang J, Teng ZJ, Zheng LY, Sheng Q, Li PY, Fu HH, Li CY, Chen Y, Zhang YZ, Ding JM, Chen XL.
Appl Environ Microbiol. 2022 Feb 8;88(3):e0221921. doi: 10.1128/AEM.02219-21

D-alanine, the most abundant D-amino acid in the ocean, is a key component of peptidoglycan in the bacterial cell wall. This work focused on the metabolism of D-Ala by marine bacterium Pseudoalteromonas sp. strain CF6-2. D-Ala aminotransferase (DAAT) was found to be indispensable for the catabolism of D-Ala in strain CF6-2. Bioinformatic investigation revealed that DAAT sequences are prevalent in genomes of marine bacteria and metagenomes: Gammaproteobacteria represents the predominant group. Thus, the latter is likely the dominant group to utilize D-Ala via DAAT to drive the recycling and mineralization of D-Ala in the ocean.



  • Comparison of L- and D-Amino Acids for Bacterial Imaging in Lung Infection Mouse Model

Muranaka Y., Mizutani A., Kobayashi M., Nakamoto K., Matsue M., Nishi K., Yamazaki K., Nishii R., Shikano N., Okamoto S., Kawai K. 
Int. J. Mol. Sci. 2022, 23, 2467.

This study focused on the effectiveness of L- and D-amino acids for detecting the early stage of infection in bacterial imaging. The accumulation of 3H-L-methionine (Met), 3H-D-Met, 3H-L-alanine (Ala), and 3H-D-Ala in E. coli EC-14 and HaCaT cells was studied. The results show that 11C-L- and D-Met, radioisotopes that differ only in terms of 3H labeling, could be superior to 18F-FDG for detecting bacterial infection in lung-infection-model mice.





  • Novel Enzymatic Method for Imine Synthesis via the Oxidation of Primary Amines Using D-Amino Acid Oxidase from Porcine Kidney

Kawahara N., Palasin K., Asano Y. 
Catalysts 2022, 12, 511.

The oxidative cyanation reaction catalyzed by a variant of porcine kidney D-amino acid oxidase (namely Y228L/R283G) yielded unexpectedly the formation of 1-phenyl-N-(1-phenylethylidene)ethanamine (PPEA). Since its synthesis proceeded by trapping the intermediate 1-phenylethanimine (1-PEI) by 15N-labeled n-hexylamine, the authors proposed that PPEA would be synthesized by a nucleophilic substitution of 1-PEI by another molecule of (R)-MBA. This represents a novel enzymatic method of imine synthesis by oxidation of primary amine.



  • A Membrane with Strong Resistance to Organic and Biological Fouling Using Graphene Oxide and D-Tyrosine as Modifiers

Guo J., Zhang Y., Chen F., Chai Y. 
Membranes 2022, 12, 486.

In this work, hydrophilic polyvinylidene fluoride (PVDF) nanocomposite (P-GO-DAA) membranes with antifouling and anti-biofouling characteristics were fabricated by employing graphene oxide (GO) and D-tyrosine. The introduction of GO fillers made an excellent antifouling performance compared to pure PVDF. Significant results were gathered when the anti-biofouling activity shown by the P-GO-DAA membrane was associated to the properties of D-tyrosine in inhibiting biofilm formation during the bacterial adhesion experiments.



  • Reactive oxygen species as a double-edged sword: The role of oxidative enzymes in antitumor therapy

Rosini E, Pollegioni L. 
Biofactors. 2022 Mar;48(2):384-399. doi: 10.1002/biof.1789.

Over the years, a number of approaches have been developed to manage cancer, such as chemotherapy using low-molecular-mass molecules and radiotherapy. On this side, enzymes able to produce reactive oxygen species (ROS) in tumors are of main relevance, such as the flavoenzyme D-amino acid oxidase acting on D-amino acids. Anticancer therapeutic approaches based on oxidase-based ROS production have been revised here.





  • A D-peptide ligand of neuropeptide Y receptor Y1 serves as nanocarrier traversing of the blood brain barrier and targets glioma

Yanying Li, Yuanbo Pan, Yinjie Wang, Zhenqi Jiang, Ozioma U. Akakuru, Mingli Li, Xianyun Zhang, Bo Yuan, Jie Xing, Lijia Luo, Dan Larhammar, Aiguo Wu, Juan Li,
Nano Today, Volume 44, 2022, 101465, ISSN 1748-0132,

Strategies for drug transport across the blood-brain barrier (BBB) are an important component in development of CNS drug therapies. In this work, a D-amino acid ligand of the neuropeptide Y (NPY) receptor Y1 has been described. The D[Asn28, Pro30, Trp32]- DNPY (25−36) (termed DAPT) shows a theoretical 2.5-fold higher number of hydrogen bonds interacting with the receptor than the corresponding peptide with L-amino acids (LAPT). The authors demonstrated that DAPT exhibits significantly higher ability than LAPT to serve as nanocarrier across the BBB and specifically targets gliomas. Using DAPT nanomicelles loaded with IRDye780, excellent photothermal therapeutic and photoacoustic cancer imaging were reported.



  • Design of D-Amino Acids SARS-CoV-2 Main Protease Inhibitors Using the Cationic Peptide from Rattlesnake Venom as a Scaffold

Eberle R.J., Gering I., Tusche M., Ostermann P.N., Müller L., Adams O., Schaal H., Olivier D.S., Amaral M.S., Arni R.K., Willbold D., Coronado M.A. 
Pharmaceuticals 2022, 15, 540.

The C30 endopeptidase (3C-like protease; 3CLpro) is essential for the life cycle of SARS-CoV-2 since it plays a pivotal role in viral replication and transcription: it represents a promising drug target. Crotamine is a small cationic peptide from the venom of the rattlesnake Crotalus durissus terrificus. Crotamine derivative L-peptides (L-CDP) that inhibit the 3CL protease in the low µM range were examined for their sensitivity to proteolytic degradation in comparison to their D-enantiomers form. The D-peptides can impair SARS-CoV-2 replication in vivo, probably targeting the viral protease 3CLpro.





  • Stereospecific recognition and rapid determination of D-amino acids in human serum based on luminescent metal–organic frameworks 

Qingju Liu, Saixue Tang, Hui Wang, Ping Han
New Journal of Chemistry, Issue 17, 2022

A novel luminescent terbium-based metal–organic framework (Tb-MOF) based biosensing system with excellent performance for stereoselective detection of D-amino acids was developed. D-Amino acid oxidase catalyzes stereospecific oxidative deamination of D-AAs, producing H2O2, which quenches the fluorescence of Tb-MOF. D-AAs were detected with excellent efficiency: i) linear working range was 0.5–100 μM for D-Ala and 0.5–5 μM for D-Pro; ii) limit of detection for D-Ala and D-Pro was 0.09 μM and 0.14 μM, respectively; iii) detection was performed within 30 min with high selectivity and long-term stability. This system was successfully applied in D-AA detection in human serum with good recovery.



  • Construction of an enzyme-based all-fiber SPR biosensor for detection of enantiomers

Zhuoyue Zhou, Zhao Yang, Li Xia, Houjin Zhang
Biosensors and Bioelectronics, Volume 198, 2022, 113836,

This work combined the fiber optic SPR with an enzyme-substrate recognition mechanism to set up a direct-assay-type chiral amino acid biosensor. Rasamsonia emersonii D-amino acid oxidase (ReDAAO), characterized by a wide substrate spectrum and high stability, was immobilized on the graphene oxide and gold nanorods composites (GO-AuNRs). Such a biosensor can distinguish two amino acid enantiomers at the same concentration and achieved specific detection of D-amino acids with a linear range from 0.0005 to 30 mM. At higher D-AA percentage a good linear relationship between the D/(D + L)-AA ratio and SPR spectral shift was obtained.





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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