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The Editor’s pick selection of the most intriguing papers is highlighted in yellow.
D-AAs AND PATHOLOGIES:
Symptomatic and cognitive effects of D-amino acid oxidase inhibitors inpatients with schizophrenia: a meta-analysis of double-blind randomizedcontrolled trials
Chang CH, Hsia YD, Liu WC, Lee JH, Lin CH, Lane HYSchizophrenia 2025 (Heidelb). 11(1):73. doi: 10.1038/s41537-025-00604-2.
D-amino acid oxidase (DAAO) inhibitors have demonstrated potential therapeutic benefits for schizophreniaand cognitive impairment. This paper reports on a meta-analysis aimed to assess the symptomatic andcognitive effects of DAAO inhibitors on the treatment of schizophrenia. A total of five trials with 530participants met the inclusion criteria: 4 trials utilized sodium benzoate, while one used luvadaxistat. DAAOinhibitors showed greater improvements in cognitive functions (mainly in females).
D-AAS & PHYSIOLOGICAL ROLES:
Intestinal D-amino acids content is highly related to intestinal IgA productionupon soluble dietary fiber ingestion in mice
Matsumoto K, Noguchi A, Miyamoto F, Inoue R, Hirai H, Miwa T, Nakagawa Y, Higashimura Y
Food Chem. 2025. 12;487:144719. doi: 10.1016/j.foodchem.2025.144719.
Soluble dietary fiber (SDF) induces intestinal IgA production, mainly by intestinal bacteria producing short-chain fatty acids (SCFAs). Here. SDF feeding for 9-12 weeks induced a 4-fold increase in fecal IgA production in BALB/cA mice, and the total SCFA concentration in the cecum showed a positive correlation with fecal IgA
content, while the content of D-amino acids (D-AAs) in both cecum and colon exhibited a strongly positive correlation with the IgA content. This work suggests that D-AAs play an important role in SDF-induced intestinal IgA production.
D-amino acids: new functional insights
Pollegioni L, Kustrimovic N, Piubelli L, Rosini E, Rabattoni V, Sacchi S
FEBS J. 2025. doi: 10.1111/febs.70083.
This review focuses on novel findings that have reshaped our understanding of physiological processes related to D-amino acids across diverse organisms, from plants to humans. Beyond neurotransmission, recent studies have highlighted their role in cancer, inflammation, immune regulation, kidney disease, and diabetes. The levels of D-AAs in blood and urine could serve as early biomarkers for conditions such as Alzheimer’s disease, schizophrenia, and chronic kidney disease. The studies on D-AAs in selected diseases will allow to identify new therapeutic targets, thus offering promising opportunities for clinical applications.
Sperm metabolomics identifies freezability markers in Duroc, Landrace, and
Large White boars
Li M, Bai Y, Zhang J, Wang H, Li J, Wang W
Theriogenology. 2025. 240:117395. doi: 10.1016/j.theriogenology.2025.117395.
Cryopreservation of boar semen is widely applied in the conservation of genetic resources and animal breeding to enhance the utilization efficiency of superior boars. From six boars each from the Duroc, Landrace, and Large White breeds, categorized into poor freezability ejaculates (PFE) and good freezability ejaculates (GFE) groups, sperm metabolomic analysis was performed. A total of 1288 metabolites were identified: among the enriched pathways were the ones for: alanine, aspartate and glutamate metabolism; arginine biosynthesis; Damino
acid, pyruvate, histidine and beta-alanine metabolism; citrate cycle, pantothenate and CoA biosynthesis. Seven potential biomarkers for sperm cryopreservation were identified, among them D-ornithine and D,L-serine were tightly interconnected in a series of amino acids metabolism.
D-AAS & CHIRALITY:
Origin of homochirality in peptides: The first milestone at the origin of life
Toxvaerd S
Biosystems. 2025. 19:105479. doi: 10.1016/j.biosystems.2025.105479.
This work is based on an extensive scientific literature on Abiogenesis and focuses on the prebiotic evolution of homochiral peptides in an aqueous solution with a high concentration of amino acids and a lower water activity than in the cytosol in living organisms. The study also considered cell division in the Hot Springs environment at the interface between the crust and the Hadean Ocean.
Chirality Effects in Peptide-Based Dynamic Combinatorial Chemistry
Gable A, Pohjolainen E, Groenhof G, Cougnon FBL Chemistry. 2025. 13:e202501298. doi: 10.1002/chem.202501298.
This work investigates the effects of chirality on the formation of disulfide dynamic combinatorial libraries (DCLs) generated by short cysteine-rich peptides. The work concludes that small changes in peptide chirality can be dramatically amplified through the formation of cyclic species.
ENZYMES ACTIVE ON D-AAS:
Engineered Biocatalysts for the Asymmetric Synthesis of D-PhenylalaninesTomoiagă RB, Nagy LC, Boros K, Moisă ME, Bencze LC
ACS Catal. 2025. 18;15(9):7361-7389. doi: 10.1021/acscatal.5c00837.
This review reports on the protein engineering studies of enzymes involved in the asymmetric synthetic pathways for D-phenylalanines: D-amino acid dehydrogenases, D-amino acid transaminases, and phenylalanine ammonia-lyases are used in (chemo)enzymatic cascades, as well as engineered L-amino acid deaminases and L-amino acid oxidases.
Overexpression, Purification, and Biochemical Characterization of the vanC2 DAla- D-Ser Ligase from Enterococcus casseliflavus SSK and Its Inhibition by an Oxadiazole Derivative
Paymal SB, Barale SS, Supanekar SV, Sonawane KD, Pawar KD
ACS Omega. 2025. 10(14):14390-14402. doi: 10.1021/acsomega.5c00599
The D-alanine-D-alanine ligases (Ddl) are essential for bacterial viability. Isozymes of Ddl that utilize alternative substrates such as D-lactate or D-serine are found in vancomycin-resistant Gram-positive bacteria. Here, the vancomycin-resistant Enterococcus casseliflavus strain SSK was identified and the vanC2 type of D-Ala-D-Ser ligase (EcfDdls) was studied. The enzymatic activity was inhibited by the compound CID 45805715, a compound also showing antimicrobial activity against vancomycin-resistant E. casseliflavus strain SSK.
D-amino acid oxidase as a chemogenetic tool for spatiotemporally controlled hydrogen peroxide production: The oxygen connection
Maurer W, Zieseniss A, Priya VP, Chen Y, Bauer L, Hillemann A, Rehling P, Nanadikar MS, de Zélicourt D, Kurtcuoglu V, Katschinski DM
Br J Pharmacol. 2025. doi: 10.1111/bph.70046.
D-amino acid oxidase (DAAO) has been developed as a chemogenetic tool, to precisely manipulate redox levels in tissues and cells by generating hydrogen peroxide in the presence of D-amino acids. Here, DAAO activation was used in HEK293 cells (DAAO was targeted to both cytoplasm and mitochondrial matrix). The results demonstrate a dose-dependent increase in O consumption rate stimulating the DAAO reaction, which results in a decreased pericellular O concentration: HIF-1α protein levels were stabilised over time, reflecting
the biological cellular response to DAAO-induced hypoxia.
D-AAS & BIOTECHNOLOGY:
Optimization of D-amino acid oxidase and epoxide hydrolase through highperformance characterization for targeted cancer therapy in sustainable
biocatalysis
Yu H, Li S, Liu J, Zhao N, Liang Z, Huang L, Sun T, Zhang H
Int J Biol Macromol. 2025. 309(Pt 3):142784. doi: 10.1016/j.ijbiomac.2025.142784.
With the final aim to develop a targeted cancer therapy, enzyme characterization methods for High- Performance Rare Enzyme Characterization and Evolution System (H-PRECES) was used in this study to increase epoxide hydrolase (EH) stability and D-amino acid oxidase (DAAO) activity. Cytotoxicity assays further confirmed selective tumor cell inhibition with over 70 % cell viability retention in normal cells.
Comparison of DL-Methionine and L-Methionine levels in liver metabolism activity in commercial broilers fed a diet without antibiotic growth promoters
Andriyanto A, Taufani Sanoesi TB, Putra AA, Subangkit M, Fadholly A, Putra HY, Rotinsulu DA Vet World. 2025. 18(3):598-605. doi: 10.14202/vetworld.2025.598-605.
Methionine is an essential amino acid in broiler nutrition, playing a crucial role in growth performance and liver metabolism. This study evaluates the effects of D,L-methionine and L-methionine supplementation on liver metabolism, antioxidant activity, and growth performance in broilers raised without alternative to antibiotic growth promoters. L-Met improved growth performance, D,L-Met effectively enhanced liver metabolism and reduced oxidative stress.
Application of essential oils and D-amino acids for controlling methicillinresistant Staphylococcus aureus isolated from dairy products
Elafify M, Sadoma N.M, Wang P, Ramadan H, Bakry AM
Int J Dairy Technology. 2025. 78 (2), art. no. e70016 DOI: 10.1111/1471-0307.70016.
This study determined the prevalence of S. aureus isolated from dairy products in Egypt, also assessing the antimicrobial resistance profiling. The potential use and sensory attributes of essential oils (olive and black seed oils) along with D-amino acids as antimicrobial additives in Domiati cheese under osmotic stress were also
evaluated. The number of MRSA cells treated with 1% olive and black seed oils and 40 mM D-tryptophan was significantly reduced: natural additives improved overall acceptability and other sensory attributes of the cheese.
D-AAS IN BACTERIA:
D-Serine Can Modify the Wall Teichoic Acid of MRSA via the dlt Pathway
Wang L, Xie J, Wang Q, Wang P, Hu X, Nie T, Hou L, Yang X, Wang X, You X, Li C
Int J Mol Sci. 2025. 26(9):4110. doi: 10.3390/ijms26094110.
Methicillin-resistant Staphylococcus aureus (MRSA) infection is a serious clinical threat, and D-serine (D-Ser) was previously reported to show significant sensitization effects on β-lactams against MRSA. Quantitative PCR analysis found the elevated expression of the dlt operon with D-Ser combination, which is responsible for wall teichoic acid (WTA) modification involving D-alanine (D-Ala). This study investigates the effect of D-Ser on WTA modification through the dlt pathway, concluding that possible effects of D-Ser on MRSA virulence through WTA
modification are feasible.
D-amino acid enhanced the sensitivity of avian pathogenic Escherichia coli to tetracycline and amikacin
Wu J, Yang B, Jiang W, Yin H, Han X, Zhang L Front Vet Sci. 2025. 12:1553937. doi: 10.3389/fvets.2025.1553937.
Avian pathogenic Escherichia coli (APEC) biofilm formation has led to increased antibiotic resistance. Some Damino acids (D-AAs) have been shown to inhibit the formation of various bacterial biofilms. Here, the effects of 19 different D-AAs on clinically isolated APEC biofilm was investigated. The results show that 5 mM of D-tyrosine (D-Tyr), D-leucine (D-Leu), D-tryptophan (D-Trp), and D-methionine (D-Met) can reduce APEC formation by over 50%. Four D-AAs were selected for combination treatment with antibiotics revealing that D-Tyr enhances the sensitivity of APEC to amikacin and tetracycline, while D-Met increases the sensitivity of APEC to amikacin. The related mechanisms were also studied.
D-AAS IN PEPTIDES AND PROTEINS:
D-Amino acids are relevant components of useful peptides, as reported in:
Discovery of a potent and selective peptide inhibitor with D-amino acids
targeting the BRD4 ET domain for renal cancer therapy
Jiang N, Lou M, Wu N, Geng Y, Niu MM, Zhou Y, Zhang S Eur J Med Chem. 2025. 15;294:117767. doi: 10.1016/j.ejmech.2025.117767.
D-amino acid inhibitors targeting the ET domain of BRD4: BEP-2 show an excellent binding affinity for BRD4 (K = 0.45 nM) and inhibit the growth of 786-O cell xenograft tumors in nude mice.
Molecular Dynamics Simulations of Monomeric and Tetrameric Amyloid β(1-42) Peptides with D-Aspartic Acid Residues
Mizuno A, Nakayoshi T, Inaoka K, Shingaki A, Kurimoto E, Kato K, Oda A
Chembiochem. 2025. 25:e2500171. doi: 10.1002/cbic.202500171.
Amyloid β1-42 (Aβ1-42) peptide includes three aspartic acid (Asp) residues that can undergo stereoinversion to D-Asp in ageing tissues, a process that promotes β-sheet structure formation. This study focuses on the structures of Aβ1-42 monomers and tetramers containing D-Asp residues.
Protease Stabilizing Antimicrobial Peptide D1018M Showed Potent Antibiofilm and Anti-Intracellular Bacteria Activity Against MRSA
Zhang Z, Jiao J, Zhang J, Tan L, Dong X, Wu R, Wang Q, Wang H, Wang X
Foodborne Pathog Dis. 2025. doi: 10.1089/fpd.2024.0134.
The D-amino acid substitution peptides D1018 and D1018M show increased antimicrobial activity against Methicillin-resistant Staphylococcus aureus (MRSA) compared with L-amino acids peptides. Their bactericidal mechanisms involve cell wall destruction, membrane penetration, and genomic DNA disruption. These peptides also show increased stability against pepsin, trypsin, and cathepsin K.
A novel peptide targeting CCR7 inhibits tumor cell lymph node metastasis
Sun Y, Qian Y, Qiu L, Zhu X, Ning H, Pang L, Niu X, Liu Y, Zhou X, Chen G, Zhai W, Gao Y Cancer Immunol Immunother. 2025. 74(5):153. doi: 10.1007/s00262-025-03995-4.
Cancer cells can upregulate CC Chemokine Receptor 7 (CCR7) expression and hijack its normal functions, enabling them to migrate along the gradient of CCL19 and CCL21 toward the lymph nodes and colonies as the initial stage of distant metastasis. A CCR7 binding peptide TC6 was identified by phage display biopanning, and D-amino acids were introduced to substitute its N- and C-termini. This peptide showed higher proteolytic resistance, decreased tumor cell migration in vitro via ERK1/2 pathway and inhibited tumor growth and lymph nodes metastasis in vivo, as well as effectively restored T cells cytotoxicity in both primary tumors and lymph nodes.
Dynamic profiling of intra- and extra-containing D-amino acid exhibiting excellent stability and antibacterial activity against gram-positive bacteria
Zou J, Wang J, Gao L, Xue W, Zhu J. Zhang Y, Gou S, Liu H. Zhong C, Ni J
Eur J Medicinal Chemistry. 2025. 287, art. no. 117341 DOI: 10.1016/j.ejmech.2025.117341.
Antimicrobial peptides (AMPs) possess broad-spectrum antibacterial activity and low drug resistance. Here, a series of ultra-short lipopeptides are synthesized using D-amino acid substitution to enhance the stability of ultra-short lipopeptide C12-RRW-NH2. The ultra-short lipopeptide Lip7 (C12-rrw-NH2) with full D-amino acid
demonstrates: i) outstanding stability in protease, serum, and salt ion environments; ii) excellent antibacterial activity against Gram-positive bacteria; iii) a low propensity to develop bacterial resistance; iv) ability to rapidly depolarize the bacterial cytoplasmic membrane thus disrupting the integrity of the bacterial membrane; v) therapeutic potential in both local and systemic MRSA-infected mice models with better safety in vivo.
D-AAS AND ANALYTICAL METHODS:
Detection of D-Amino Acids in Saliva for Gastric Cancer Diagnosis Using Pt/MXene Plasmonic Nanozymes
Deng X, Wu J, Jiang ZW, Liu W, Gong X, Cao Y, Zhang P, Wang Y
Anal Chem. 20;97(19):10289-10298. doi: 10.1021/acs.analchem.5c00279.
This paper reports on the development of a non-invasive and highly sensitive method for detecting D-amino acids in saliva as a potential biomarker for early gastric cancer diagnosis. By using a novel Pt/Ti3C2Tx nanozyme probe, peroxidase-like activity and photothermal performance were enhanced under near-infrared (NIR) light irradiation. Assaying the conversion of hydrogen peroxide arising from D-AAs oxidation by D-amino acid oxidase, and the catalytic oxidation of 3,3′,5,5′-tetramethylbenzidine, D-AAs were detected using a dualmode detection platform (colorimetric and thermal signals under NIR light irradiation). The analysis was carried out on 45 clinical saliva samples
Hydrogen peroxide regulated split-type electrochemiluminescence sensing platform for non-invasive detection of gastric cancer-associated D-amino acids
Li J, Lai MC, Zhong YM, Chen YL, Wu N, Chen W, Peng HP
Anal Chim Acta. 2025. 15;1355:344010. doi: 10.1016/j.aca.2025.344010.
Similar to the aim of the previous paper, a highly sensitive and selective D-alanine (D-Ala) ECL assay strategy via a turn-off-on split-type electrochemiluminescence (ECL) platform was set up employing MnO /gold nanocluster (AuNC)-based ECL nanoswitch platform to assay hydrogen peroxide produced by the reaction of Damino acid oxidase (DAAO) on D-AAs. This ECL sensing platform achieved a linear-dependent curve in the 1×10 -1×10 mol L range, and detected D-Ala as low as 2×10 mol L .
Development of fluorescent probe for specific recognition of chiral alanine
Han Z, Chen S, Wu Y, Fan C, Liu Q, Yu X, Shu W, Chi W, Dong Q, Zeng C
Spectrochim Acta A Mol Biomol Spectrosc. 2025. 338:126155. doi: 10.1016/j.saa.2025.126155.
This study uses optical detection techniques to develop a chiral fluorescence sensor based on binaphthol (BINOL). In particular, the (R)-5 probe exhibits exclusive selectivity for D-alanine (D-Ala) among the 20 chiral amino acids, with a detection limit of 10.7 nM.
Chiral derivatization LC-TOF/MS analysis reveals presence of D-amino acids in bovine skeletal muscle tissue and the cultured cells
Yoshikuni M, Iguchi K, Otoguro Y, Sato S, Nagai H, Takemura Y, Banno A, Higuchi ., Sakamoto S, Muroya S, Matsukawa K
J Food Composition and Analysis. 2025. 144, art. no. 107722 Spectrochim Acta A Mol Biomol Spectrosc. 2025. 338:126155. doi: 10.1016/j.saa.2025.126155.
This work studies the composition and content of D/L-AAs in trapezius muscle tissue and the cultured cells of Japanese Black (JBL) and Japanese Brown (JBR) cows at slaughter and seven days post-mortem, using chiral derivatization LC-TOF/MS method. D-serine (D-Ser) and D-aspartate (D-Asp) were detected in all samples; DAsp content in JBL cells was higher than that in the muscle tissues of both cattle and JBR cells. D-Ser content in both muscle tissue and cell samples was higher in JBL than in JBR. D-threonine (D-Thr) was detected in the muscle tissue, but not in the cell cultures that contained D-Asp and D-Ser.
Separation of D-Amino Acid-Containing Tripeptide L-Asn-D-Trp-L-Phe-NH and Its Diastereomer Using Crown–Ether-Type Chiral Stationary Phase
Mijiddorj B, Kayano Y, Yamagishi H, Nakajima H, Kawamura I Separations. 2025. 12 (3), art. no. 67 DOI: 10.3390/separations12030067.
The L-Asn-D-Trp-L-Phe-NH (N(dW)F) tripeptide, derived from Aplysia kurodai, exhibits cardiac activity in invertebrates: the chirality of the tryptophan residue at the second position influences its conformation and biological characteristics. The chiral separation of N(dW)F and its diastereomer NWF was carried out using (S)-3,3′-diphenyl-1,1′-binaphthyl-20-crown-6-ether columns (CR-I(+)).
INFORMATION
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 to 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 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, 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.
https://www.d-aminoacids.com/
mailing address: info@d-aminoacids.com
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