Amino Acids最新文献

{"title":"Comprehensive analysis of peripheral blood free amino acids in MASLD: the impact of glycine-serine-threonine metabolism","authors":"Masaaki Mino,&nbsp;Eiji Kakazu,&nbsp;Akitoshi Sano,&nbsp;Mio Tsuruoka,&nbsp;Hiroko Matsubara,&nbsp;Keisuke Kakisaka,&nbsp;Takayuki Kogure,&nbsp;Katsunori Sekine,&nbsp;Yoshihiko Aoki,&nbsp;Masatoshi Imamura,&nbsp;Michitaka Matsuda,&nbsp;Taiji Yamazoe,&nbsp;Taizo Mori,&nbsp;Sachiyo Yoshio,&nbsp;Jun Inoue,&nbsp;Atsushi Masamune,&nbsp;Tatsuya Kanto","doi":"10.1007/s00726-024-03433-2","DOIUrl":"10.1007/s00726-024-03433-2","url":null,"abstract":"<div><p>Little is known about how blood free amino acids (FAAs) change in metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to identify the imbalance of FAAs in MASLD and explore its correction as a potential therapeutic target. We analyzed plasma FAAs data from 23,036 individuals with steatosis information from a biobank in Japan, and 310 patients with MASLD were enrolled. According to diagnostic criteria for steatotic liver disease (SLD) or cardiometabolic criteria (CC), we divided the subjects into five groups: MASLD, metabolic dysfunction and alcohol-associated liver disease (MetALD), CC-SLD-, CC + SLD-, and CC-SLD + . Twenty FAAs were compared among these groups and among MASLD patients with pathological information. Among the 20 FAAs, the levels of 16 FAAs increased in CC + SLD- according to the number of matches with CC items associated with insulin resistance (IR). Steatosis enhanced most of these changes but serine (Ser) and threonine (Thr) were unaffected. Glycine (Gly), Ser and Thr were significantly decreased in patients according to steatosis grade. We investigated the association between these FAAs imbalances and pathogenesis using MASLD mouse models. In mice fed a high-fat, fructose, and cholesterol (FFC) diet, metabolomics and RNA sequencing analyses indicated that abnormality in Gly, Ser, and Thr metabolism in the liver was associated with mitochondrial dysfunction and enhanced glycolysis via pyruvate. High-Gly, Ser, and Thr diet ameliorated pathogenesis of MASLD in leptin-deficient mice. Most FAAs increase due to cardiometabolic abnormalities, particularly IR. However, interventions targeting the metabolism of Gly, Ser, and Thr have the potential to improve MASLD.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"57 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00726-024-03433-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of D-amino acid metabolic enzyme deficiency on cancer development—diffuse large B-cell lymphoma onset and gene expression analyses in DASPO-knockout mice","authors":"Yusuke Nakade,&nbsp;Yasunori Iwata,&nbsp;Kenichi Harada,&nbsp;Yasuharu Sato,&nbsp;Masashi Mita,&nbsp;Kenji Hamase,&nbsp;Ryuichi Konno,&nbsp;Mayo Hayashi,&nbsp;Taku Kobayashi,&nbsp;Yuta Yamamura,&nbsp;Tadashi Toyama,&nbsp;Atsushi Tajima,&nbsp;Takashi Wada","doi":"10.1007/s00726-024-03426-1","DOIUrl":"10.1007/s00726-024-03426-1","url":null,"abstract":"<div><p>The relationship between D-AA metabolic enzymes and cancer development remains unclear. We aimed to investigate this relationship using mice deficient in D-AA-related metabolic enzymes. We examined mice lacking these enzymes for approximately 900 days and the effects of altered D-AA metabolism on cancer development based on lifespan, pathological findings, and gene expression. The lifespan of female <i>DASPO</i> -knockout (<i>DASPO</i>^{<i>−/−</i>}) mice was shorter than that of the other group mice; furthermore, these mice showed tumor-like masses in the liver, spleen, and small intestine. A pathological diagnosis of diffuse large B-cell lymphoma (DLBCL) was made. RNA sequencing of the liver samples showed specific alterations in the expression of 71 genes in <i>DASPO</i>^{<i>−/−</i>} mice compared with that in wild-type B6 mice; <i>RGS 1</i>, <i>MTSS1</i>, and <i>SMARCD 1</i> were identified as DLBCL-related genes. Patients with DLBCL exhibiting low <i>DASPO</i> expression demonstrated a shorter survival period than those showing high expression. However, the role of <i>DASPO</i> in DLBCL development is unclear. Therefore, future research should focus on B cells. <i>DASPO</i> may serve as novel biomarkers and therapeutic targets in cancer.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"57 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00726-024-03426-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dipeptides in CSF and plasma: diagnostic and therapeutic potential in neurological diseases","authors":"Katharina Küper,&nbsp;Gernot Poschet,&nbsp;Julia Rossmann,&nbsp;Sven F. Garbade,&nbsp;Alexander Spiegelhalter,&nbsp;Dan Wen,&nbsp;Georg F. Hoffmann,&nbsp;Claus P. Schmitt,&nbsp;Thomas Opladen,&nbsp;Verena Peters","doi":"10.1007/s00726-024-03434-1","DOIUrl":"10.1007/s00726-024-03434-1","url":null,"abstract":"<div><p>Dipeptides (DPs), composed of two amino acids (AAs), hold significant therapeutic potential but remain underexplored. Given the crucial role of AAs in central nervous system (CNS) function, this study investigated the presence of DPs in cerebrospinal fluid (CSF) and their correlation with corresponding AAs, potentially indicating their role as AA donors. Plasma and CSF samples were collected from 43 children with neurological or metabolic conditions of unknown origin, including 23 with epilepsy. A panel of 33 DPs was quantified using UPLC-MS/MS. Out of 33 DPs, 18 were detectable in CSF and 20 in plasma, displaying high inter-individual variance. Gly-Asp, Gly-Pro, and Ala-Glu were consistently found in all CSF samples, while only Gly-Asp was universally detectable in plasma. Anserine and carnosine were prominent in CSF and plasma, respectively, with no other histidine-containing DPs observed. Generally, DP concentrations were higher in plasma than in CSF; however, anserine and Gly-Pro had similar concentrations in both fluids. Significant correlations were observed between specific DPs and their corresponding AAs in CSF (Gly-Glu, Gly-Pro and Ser-Gln) and plasma (Glu-Glu and Glu-Ser). Notably, patients with epilepsy had elevated medium anserine concentrations in CSF. This study is the first to demonstrate the presence of numerous DPs in CSF and plasma. Further research is needed to determine if DP patterns can support the diagnosis of neurological diseases and whether DP administration can modulate amino acid availability in the brain, potentially offering new therapeutic options, such as for defects in the amino acid transporter.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"57 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00726-024-03434-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Free amino acids accelerate the time-dependent inactivation of rat liver nucleotide pyrophosphatase/phosphodiesterase Enpp3 elicited by EDTA","authors":"Ana Romero,&nbsp;Guadalupe Cumplido-Laso,&nbsp;Ascensión Fernández,&nbsp;Javier Moreno,&nbsp;José Canales,&nbsp;Rui Ferreira,&nbsp;Juan López-Gómez,&nbsp;João Meireles Ribeiro,&nbsp;María Jesús Costas,&nbsp;José Carlos Cameselle","doi":"10.1007/s00726-024-03431-4","DOIUrl":"10.1007/s00726-024-03431-4","url":null,"abstract":"<div><p>Nucleotide-pyrophosphatases/phosphodiesterases (NPP/PDE) are membrane or secreted Zn²⁺-metallohydrolases of nucleoside-5´-monophosphate derivatives. They hydrolyze, for instance, ATP and 4-nitrophenyl-dTMP, and belong to the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family that contains seven members (ENPP1-ENPP7). Earlier we had shown that an NPP/PDE activity solubilized and partially purified from rat liver membranes is inactivated by EDTA in a time-dependent fashion, an effect enhanced by glycine and blocked by the 4-nitrophenyl-dTMP. Here, we extended this observation to other free amino acids. Activity assays started after different incubation lengths with EDTA provided first-order, apparent inactivation constants (k_i(ap)). With the exception of cysteine (a strong inhibitor) and histidine (itself evoking a time-dependent inactivation), free amino acids themselves did not affect activity but increased k_i(ap). The results are compatible with a conformational change of NPP/PDE evoked by interaction with free amino acids. The enzyme preparation was analyzed to identify what ENPP family members were present. First, the hydrolytic activity on 2´,3´-cGAMP was assayed because until very recently ENPP1 was the only mammalian enzyme known to display it. 2´,3´-cGAMP hydrolase activity was clearly detected, but mass spectrometry data obtained by LC-MS/MS gave evidence that only rat Enpp3, Enpp4 and Enpp5 were present with low abundance. This finding coincided in time with a recent publication claiming that mouse Enpp3 hydrolyzes 2´,3´-cGAMP, and that Enpp1 and Enpp3 account for all the 2´,3´-cGAMP hydrolase activity in mice. So, our results are confirmatory of Enpp3 activity towards 2´,3´-cGAMP. Finally, the effect of amino acids could be relevant to NPP/PDE actions dependent on protein-protein interactions, like the known insulin-related effects of ENPP1 and possibly ENPP3.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"57 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00726-024-03431-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The application and prospects of antimicrobial peptides in antiviral therapy","authors":"Fei Yang,&nbsp;Yunqi Ma","doi":"10.1007/s00726-024-03427-0","DOIUrl":"10.1007/s00726-024-03427-0","url":null,"abstract":"<div><p>Antimicrobial peptides (AMPs) have broad-spectrum antimicrobial activity, enabling them to rapidly detect and eliminate targets. In addition, many AMPs are natural peptides, making them promising candidates for therapeutic drugs. This review discusses the basic properties and mechanisms of action of AMPs, highlighting their ability to disrupt microbial membranes and modulate host immune responses. It also reviews the current state of research into using AMPs against various viral infections, focusing on their therapeutic potential against viruses that contribute to the global health crisis. Despite promising developments, therapies based on AMPs still face challenges such as stability, toxicity, and production costs. In this text, we will discuss these challenges and the latest technological advances aimed at overcoming them. The combination of nanotechnology and bioengineering approaches offers new ways to enhance the delivery, efficacy, and safety of AMPs. We emphasize the importance of further research to fully exploit the potential of AMPs in antiviral therapy, advocating a multifaceted approach that includes optimizing clinical use and exploring synergies with existing antiviral drugs.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00726-024-03427-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142762024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of enantiomerically enriched β-substituted analogs of (S)-α-alanine containing 1-phenyl-1H-1,2,3-triazole groups","authors":"Artavazd S. Poghosyan,&nbsp;Emma A. Khachatryan,&nbsp;Anna F. Mkrtchyan,&nbsp;Volodya Mirzoyan,&nbsp;Anahit M. Hovhannisyan,&nbsp;Karapet R. Ghazaryan,&nbsp;Ela V. Minasyan,&nbsp;Peter Langer,&nbsp;Ashot S. Saghyan","doi":"10.1007/s00726-024-03430-5","DOIUrl":"10.1007/s00726-024-03430-5","url":null,"abstract":"<div><p>A synthesis of new enantiomerically enriched derivatives of (S)-α-aminopropionic acid, containing in the β-position 1,2,3-triazole groups coupled with a o-, m- and p-substituted phenyl residue, was developed based on Cu(I) catalyzed [3 + 2] cycloaddition of azides with alkynes. As the starting materials was used the square-planar Ni(II)complex of the Schiff base of propargylglycine with the chiral auxiliary BPB (Benzylprolylbenzophenone) and 1,4-substituted phenyl azides. The assignment of the (S)-absolute configuration of the α-carbon atom of the amino acid residue of the main diastereomeric complexes of the cycloaddition products was carried out on the basis of positive Cotton effects in the region of 480–580 nm of the circular dichroism spectra. The target amino acids were isolated from acid hydrolysates of diastereomeric complexes using ion-exchange demineralization and crystallization from aqueous ethanol. Additional confirmation of the absolute configuration and determination of the enantiomeric purity of the target amino acids were carried out by chiral HPLC analysis. As a result, seven new non-proteinogenic (S)-α-amino acids, containing in the β-position a 1,2,3-triazole moiety, were synthesized.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00726-024-03430-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142761860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple strategies of HSP antimicrobial peptide optimization to enhance antimicrobial activity","authors":"Xiaozhong Cheng,&nbsp;Yonghuang Zhang,&nbsp;Yan Zhang,&nbsp;Yajun Chen,&nbsp;Jianli Chen,&nbsp;Wei Wang,&nbsp;Guilan Zhu","doi":"10.1007/s00726-024-03428-z","DOIUrl":"10.1007/s00726-024-03428-z","url":null,"abstract":"<div><p>Antimicrobial peptides (AMPs) have caught the attention of researchers over the last couple of years due to their unique membrane lytic mechanism for combating antibiotic resistance, which differs from the molecular targets of traditional antibiotics. Although natural AMPs exhibit potential antimicrobial activity against a wide range of microorganisms, some drawbacks, such as toxicity, low antibacterial activity, and high production costs limit their clinical application. To enhance the antimicrobial activity of a series of HSP peptides derived from the natural peptide HSP-1, this study optimized them using a variety of strategies, including net charge, hydrophobic moment, hydrophobicity, and helicity. Optimizing the antimicrobial action of HSP peptides depended mostly on net charge, hydrophobic moment, and hydrophobicity rather than helicity. HSP-M4 may be designed to combat microbial infections because the antimicrobial activity and cytotoxicity assays showed that they exhibited low cytotoxicity and prominent antimicrobial activity, respectively.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00726-024-03428-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered amino acid levels in young hypopituitarism: impact of NAFLD and insulin resistance","authors":"Yuwen Zhang,&nbsp;Jiting Qiu,&nbsp;Shouyue Sun,&nbsp;Xuqian Fang","doi":"10.1007/s00726-024-03429-y","DOIUrl":"10.1007/s00726-024-03429-y","url":null,"abstract":"<div><p>Elevated concentrations of amino acids (AAs) are commonly observed in patients with nonalcoholic fatty liver disease (NAFLD). Individuals with hypopituitarism (HP) are at a heightened risk of developing NAFLD due to factors such as visceral obesity, increased insulin resistance (IR), and disturbances in lipid metabolism. However, the changes in AAs concentrations associated with HP remain poorly understood. Therefore, our study aimed to investigate whether individuals with HP, who were not receiving growth hormone replacement therapy (GHRT), exhibited altered AAs compared to controls (CTs), and whether these AAs were associated with IR, the presence of NAFLD, and the Metabolic Syndrome (MetS) score. The AAs profiles of 133 young males with HP (age: 24.5 ± 5.9; 57 with NAFLD and 76 without NAFLD) and 90 age and BMI-matched CTs were analyzed using untargeted metabolomics. The results revealed that most AAs were found to be elevated in subjects with HPs compared to CTs. Glutamate, glutamine, norleucine, and branched-chain amino acids (BCAAs) (leucine and valine) were correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), with glutamate and norleucine showing independent linkage. Glutamate and proline levels were specifically associated with MetS score, while alanine and proline linked to NAFLD. Given that elevated glutamate and BCAAs levels have higher prevalence of NAFLD, we hypothesized that the changes in AAs observed in HPs may be attributed to the impact of NAFLD and IR.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00726-024-03429-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142691868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The reverse transsulfuration pathway affects the colonic microbiota and contributes to colitis in mice","authors":"Alain P. Gobert,&nbsp;Yvonne L. Latour,&nbsp;Kara M. McNamara,&nbsp;Caroline V. Hawkins,&nbsp;Kamery J. Williams,&nbsp;Mohammad Asim,&nbsp;Daniel P. Barry,&nbsp;Margaret M. Allaman,&nbsp;Alberto G. Delgado,&nbsp;Ginger L. Milne,&nbsp;Shilin Zhao,&nbsp;M. Blanca Piazuelo,&nbsp;M. Kay Washington,&nbsp;Lori A. Coburn,&nbsp;Keith T. Wilson","doi":"10.1007/s00726-024-03423-4","DOIUrl":"10.1007/s00726-024-03423-4","url":null,"abstract":"<div><p>Cystathionine γ-lyase (CTH) is a critical enzyme in the reverse transsulfuration pathway, the major route for the metabolism of sulfur-containing amino acids, notably converting cystathionine to cysteine. We reported that CTH supports gastritis induced by the pathogen <i>Helicobacter pylori</i>. Herein our aim was to investigate the role of CTH in colonic inflammation. First, we found that CTH is induced in the colon mucosa in mice with dextran sulfate sodium-induced colitis. Expression of CTH was completely absent in the colon of <i>Cth</i>^–/– mice. We observed that clinical and histological parameters are ameliorated in <i>Cth</i>-deficient mice compared to wild-type animals. However, <i>Cth</i> deletion had no effect on tumorigenesis and the level of dysplasia in mice treated with azoxymethane-DSS, as a reliable model of colitis-associated carcinogenesis. Mechanistically, we determined that the deletion of the gene <i>Slc7a11</i> encoding for solute carrier family 7 member 11, the transporter of the anionic form of cysteine, does not affect DSS colitis. Lastly, we found that the richness and diversity of the fecal microbiota were significantly increased in <i>Cth</i>^–/– mice compared to both WT and <i>Slc7a11</i>^–/– mice. In conclusion, our data suggest that the enzyme CTH represents a target for clinical intervention in patients with inflammatory bowel disease, potentially by beneficially reshaping the composition of the gut microbiota.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00726-024-03423-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-activity relationship of amino acid analogs to probe the binding pocket of sodium-coupled neutral amino acid transporter SNAT2","authors":"Sebastian Jakobsen,&nbsp;Maria Pedersen,&nbsp;Carsten Uhd Nielsen","doi":"10.1007/s00726-024-03424-3","DOIUrl":"10.1007/s00726-024-03424-3","url":null,"abstract":"<div><p>The sodium-coupled neutral amino acid transporter SNAT2 (SLC38A2) has been shown to have important physiological functions and is implicated in various diseases like cancer. However, few compounds targeting this transporter have been identified and little is known about the structural requirements for SNAT2 binding. In this study, the aim was to establish the basic structure-activity relationship for SNAT2 using amino acid analogs. These analogs were first studied for their ability to inhibit SNAT2-mediated ³H-glycine uptake in hyperosmotically treated PC-3 cells. Then to identify substrates a FLIPR membrane potential assay and o-phthalaldehyde derivatization of intracellular amino with subsequent quantification using HPLC-Fl was used. The results showed that ester derivatives of the C-terminus maintained SNAT2 affinity, suggesting that the negative charge was less important. On the other hand, the positive charge at the N-terminus of the substrate and the ability to donate at least two hydrogen bonds to the binding site appeared important for SNAT2 recognition of the amine. Side chain charged amino acids generally had no affinity for SNAT2, but their non-charged derivatives were able to inhibit SNAT2-mediated ³H-glycine uptake, while also showing that amino acids of a notable length still had affinity for SNAT2. Several amino acid analogs appeared to be novel substrates of SNAT2, while γ-benzyl L-glutamate seemed to be inefficiently translocated by SNAT2. Elaborating on this structure could lead to the discovery of non-translocated inhibitors of SNAT2. Thus, the present study provides valuable insights into the basic structural binding requirements for SNAT2 and can aid the future discovery of compounds that target SNAT2.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00726-024-03424-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}