Pub Date : 2021-10-04DOI: 10.33774/chemrxiv-2021-xzgst
Michael Moret, F. Grisoni, Cyrill Brunner, G. Schneider
Generative chemical language models (CLMs) can be used for de novo molecular structure generation. These CLMs learn from the structural information of known molecules to generate new ones. In this paper, we show that “hybrid” CLMs can additionally leverage the bioactivity information available for the training compounds. To computationally design ligands of phosphoinositide 3-kinase gamma (PI3Kγ), we created a large collection of virtual molecules with a generative CLM. This primary virtual compound library was further refined using a CLM-based classifier for bioactivity prediction. This second hybrid CLM was pretrained with patented molecular structures and fine-tuned with known PI3Kγ binders and non-binders by transfer learning. Several of the computer-generated molecular designs were commercially available, which allowed for fast prescreening and preliminary experimental validation. A new PI3Kγ ligand with sub-micromolar activity was identified. The results positively advocate hybrid CLMs for virtual compound screening and activity-focused molecular design in low-data situations.
{"title":"Leveraging molecular structure and bioactivity with chemical language models for drug design","authors":"Michael Moret, F. Grisoni, Cyrill Brunner, G. Schneider","doi":"10.33774/chemrxiv-2021-xzgst","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-xzgst","url":null,"abstract":"Generative chemical language models (CLMs) can be used for de novo molecular structure generation. These CLMs learn from the structural information of known molecules to generate new ones. In this paper, we show that “hybrid” CLMs can additionally leverage the bioactivity information available for the training compounds. To computationally design ligands of phosphoinositide 3-kinase gamma (PI3Kγ), we created a large collection of virtual molecules with a generative CLM. This primary virtual compound library was further refined using a CLM-based classifier for bioactivity prediction. This second hybrid CLM was pretrained with patented molecular structures and fine-tuned with known PI3Kγ binders and non-binders by transfer learning. Several of the computer-generated molecular designs were commercially available, which allowed for fast prescreening and preliminary experimental validation. A new PI3Kγ ligand with sub-micromolar activity was identified. The results positively advocate hybrid CLMs for virtual compound screening and activity-focused molecular design in low-data situations.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41379841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-10-04DOI: 10.33774/chemrxiv-2021-0b2wc
K. Gohil, M. Kazmi, Florence Williams
Neurotrophic small molecule natural products are functional analogs of signaling proteins called neurotrophins, which cause a pro-growth, pro-survival, or pro-differentiation response in neuronal cells. While these phenotypic responses are desirable to combat neurodegenerative disease progression, neurotrophin proteins possess pharmacokinetic properties that present challenges to their administration in living organisms, whether in biomedical studies or as therapeutics. Small molecules such as the cis- and trans-banglenes offer attractive alternatives to activate neurotrophic responses. We describe the synthesis and testing of banglene derivatives to establish a structure-activity response for the banglene family. Notably, during the course of our studies trans-banglene was shown to cause nerve growth factor (NGF)-potentiated neuritogenesis that was markedly stronger than the neuritogenic effects of trans-banglene alone. We demonstrate that only (–) trans-banglene is active, while its (+) enantiomer is not, and further demonstrate that select modifications on the cyclohexene ring of trans-banglene does not impair its bioactivity. Finally, to probe the relationship between (–) trans-banglene’s mechanism of ac-tion and canonical NGF signal transduction pathways, we employed kinase inhibitors targeting Pkc, Akt1/2/3 and Erk1/2, designed to inhibit NGF-induced neurotrophic signaling. Interestingly, (–) trans-banglene potentiation of NGF-induced neuri-togenesis was unaffected by the presence of these kinase inhibitors. Collectively, these results suggest a dual-mode of action for (–) trans-banglene (both neurotrophic alone and strongly potentiating of NGF activity), and an independence of its po-tentiating action on Pkc and Erk1/2 enzymatic activity.
{"title":"Structure-Activity-Relationship and Bioactivity of Neurotrophic trans-Banglene","authors":"K. Gohil, M. Kazmi, Florence Williams","doi":"10.33774/chemrxiv-2021-0b2wc","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-0b2wc","url":null,"abstract":"Neurotrophic small molecule natural products are functional analogs of signaling proteins called neurotrophins, which cause a pro-growth, pro-survival, or pro-differentiation response in neuronal cells. While these phenotypic responses are desirable to combat neurodegenerative disease progression, neurotrophin proteins possess pharmacokinetic properties that present challenges to their administration in living organisms, whether in biomedical studies or as therapeutics. Small molecules such as the cis- and trans-banglenes offer attractive alternatives to activate neurotrophic responses. We describe the synthesis and testing of banglene derivatives to establish a structure-activity response for the banglene family. Notably, during the course of our studies trans-banglene was shown to cause nerve growth factor (NGF)-potentiated neuritogenesis that was markedly stronger than the neuritogenic effects of trans-banglene alone. We demonstrate that only (–) trans-banglene is active, while its (+) enantiomer is not, and further demonstrate that select modifications on the cyclohexene ring of trans-banglene does not impair its bioactivity. Finally, to probe the relationship between (–) trans-banglene’s mechanism of ac-tion and canonical NGF signal transduction pathways, we employed kinase inhibitors targeting Pkc, Akt1/2/3 and Erk1/2, designed to inhibit NGF-induced neurotrophic signaling. Interestingly, (–) trans-banglene potentiation of NGF-induced neuri-togenesis was unaffected by the presence of these kinase inhibitors. Collectively, these results suggest a dual-mode of action for (–) trans-banglene (both neurotrophic alone and strongly potentiating of NGF activity), and an independence of its po-tentiating action on Pkc and Erk1/2 enzymatic activity.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42238041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-10-04DOI: 10.33774/chemrxiv-2021-r2nd2
C. Hoopes, Francisco García, A. Sarkar, Nicholas J Kuehl, D. Barkan, N. Collins, Chien-Hsang Hsu, Michael K. Jones, M. Schirle, Michael T. Taylor
Tryptophan (Trp) plays a variety of critical functional roles in protein biochemistry however, owing to its low natural frequency and poor nucleophilicity, the design of effective methods for both single protein bioconjugation at Trp as well as for in situ chemoproteomic profiling re-mains a challenge. Here, we report a method for covalent Trp modification that is suitable for both scenarios by invoking photo-induced electron transfer (PET) as a means of driving efficient reactivity. We have engineered biaryl N-carbamoyl pyridinium salts that possess a donor-acceptor relationship enabling optical triggering with visible light whilst simultaneously attenuating the probe’s photo-oxidation potential in order to prevent photodegradation. This probe was assayed against a small bank of eight peptides and proteins, where it was found that micromolar concentrations of probe and short irradiation times (10-60 min) with violet light enabled efficient reactivity towards surface exposed Trp residues. The carbamate transferring group can be used to transfer useful functional groups to proteins including affinity tags and click handles. DFT calculations and other mechanistic analyses reveal correlations between excited state lifetimes, relative fluorescent quantum yields, and chemical reactivity. Biotinylated and azide-functionalized pyridinium salts were used for Trp profiling in HEK293T lysates and in situ in HEK293T cells using 450 nm LED irradiation. Peptide level enrichment from live cell labelling experiments identified 290 Trp modifications, with an 82% selectivity for Trp modification over other π-amino acids; demonstrating the ability of this method to identify and quantify reactive Trp residues from live cells.
{"title":"Donor-Acceptor Pyridinium Salts for Photo-Induced Electron Transfer Driven Modification of Tryptophan in Peptides, Proteins, and Proteomes using Visible Light","authors":"C. Hoopes, Francisco García, A. Sarkar, Nicholas J Kuehl, D. Barkan, N. Collins, Chien-Hsang Hsu, Michael K. Jones, M. Schirle, Michael T. Taylor","doi":"10.33774/chemrxiv-2021-r2nd2","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-r2nd2","url":null,"abstract":"Tryptophan (Trp) plays a variety of critical functional roles in protein biochemistry however, owing to its low natural frequency and poor nucleophilicity, the design of effective methods for both single protein bioconjugation at Trp as well as for in situ chemoproteomic profiling re-mains a challenge. Here, we report a method for covalent Trp modification that is suitable for both scenarios by invoking photo-induced electron transfer (PET) as a means of driving efficient reactivity. We have engineered biaryl N-carbamoyl pyridinium salts that possess a donor-acceptor relationship enabling optical triggering with visible light whilst simultaneously attenuating the probe’s photo-oxidation potential in order to prevent photodegradation. This probe was assayed against a small bank of eight peptides and proteins, where it was found that micromolar concentrations of probe and short irradiation times (10-60 min) with violet light enabled efficient reactivity towards surface exposed Trp residues. The carbamate transferring group can be used to transfer useful functional groups to proteins including affinity tags and click handles. DFT calculations and other mechanistic analyses reveal correlations between excited state lifetimes, relative fluorescent quantum yields, and chemical reactivity. Biotinylated and azide-functionalized pyridinium salts were used for Trp profiling in HEK293T lysates and in situ in HEK293T cells using 450 nm LED irradiation. Peptide level enrichment from live cell labelling experiments identified 290 Trp modifications, with an 82% selectivity for Trp modification over other π-amino acids; demonstrating the ability of this method to identify and quantify reactive Trp residues from live cells.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43245797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-10-04DOI: 10.33774/chemrxiv-2021-5r8gf
F. Berride, Eduardo Troche-Pesqueira, R. Weiss, A. Navarro‐Vázquez, M. Cid
Disodium Cromoglycate (DSCG), a lyotropic liquid crystal in water, is shown to be an amplifier of chirality when doped with small chiral molecules. Here, we study the behaviour of the DSCG nematic phase in the presence of three aminoacids with different degrees of protonation: L-Alanine, L-Arginine·HCl and L-Arginine. The results demonstrate that the sign of the helicity of the doped nematic phase (i.e., a cholesteric phase) depends on the sign of the Helical Twisting Power of the dopant.
{"title":"Effect of the degree of protonation of amino acid dopants in Chirality amplification in DSCG Lyotropic Nematic phases.","authors":"F. Berride, Eduardo Troche-Pesqueira, R. Weiss, A. Navarro‐Vázquez, M. Cid","doi":"10.33774/chemrxiv-2021-5r8gf","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-5r8gf","url":null,"abstract":"Disodium Cromoglycate (DSCG), a lyotropic liquid crystal in water, is shown to be an amplifier of chirality when doped with small chiral molecules. Here, we study the behaviour of the DSCG nematic phase in the presence of three aminoacids with different degrees of protonation: L-Alanine, L-Arginine·HCl and L-Arginine. The results demonstrate that the sign of the helicity of the doped nematic phase (i.e., a cholesteric phase) depends on the sign of the Helical Twisting Power of the dopant.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41460596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-10-01DOI: 10.33774/chemrxiv-2021-5g682
S. S. Ling, Fabrice Saffre, Deborah L. Gater, L. Halim, A. Isakovic
Computer quiz games are introduced to improve teaching and learning in a freshman engineering chemistry course in an English-as-a-Second-Language (ESL) environment. These quiz games are developed and implemented as a supplemental and augmentative tool to enhance traditionally delivered lectures. The paper shows an increase in students’ motivation and compare the performance between students who participated in computer quiz games, a paper-based quiz or neither activity. Assessment of the effectiveness of quiz games in learning is conducted via a proposed novel chemistry achievement test, Freshman Engineering Chemistry Aptitude Test and an attitude questionnaire. The findings contribute to our understanding of the role of game-based learning in students’ achievement in chemistry and their motivation and attitudes towards learning general chemistry at a university within an ESL environment, while the computer games developed are useful in all English based Chemistry classes.
{"title":"Computer Quiz Games in General Chemistry for Engineering Majors in an English as a Second Language Environment","authors":"S. S. Ling, Fabrice Saffre, Deborah L. Gater, L. Halim, A. Isakovic","doi":"10.33774/chemrxiv-2021-5g682","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-5g682","url":null,"abstract":"Computer quiz games are introduced to improve teaching and learning in a freshman engineering chemistry course in an English-as-a-Second-Language (ESL) environment. These quiz games are developed and implemented as a supplemental and augmentative tool to enhance traditionally delivered lectures. The paper shows an increase in students’ motivation and compare the performance between students who participated in computer quiz games, a paper-based quiz or neither activity. Assessment of the effectiveness of quiz games in learning is conducted via a proposed novel chemistry achievement test, Freshman Engineering Chemistry Aptitude Test and an attitude questionnaire. The findings contribute to our understanding of the role of game-based learning in students’ achievement in chemistry and their motivation and attitudes towards learning general chemistry at a university within an ESL environment, while the computer games developed are useful in all English based Chemistry classes.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46882291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-10-01DOI: 10.33774/chemrxiv-2021-51rbh
B. Spenger, Stefan Näf, S. Manov, J. Stohner
The enantiomers of bromofluoroiodomethane (CHBrFI) were separated on a preparative scale using gas chromatography (GC). The collected single enantiomers were analysed by vibrational circular dichroism spectroscopy and polarimetry in combination with ab initio calculations to determine the respective absolute configuration.
{"title":"Absolute Configuration of Bromofluoroiodomethane after Preparative Gas Chromatographic Separation","authors":"B. Spenger, Stefan Näf, S. Manov, J. Stohner","doi":"10.33774/chemrxiv-2021-51rbh","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-51rbh","url":null,"abstract":"The enantiomers of bromofluoroiodomethane (CHBrFI) were separated on a preparative scale using gas chromatography (GC). The collected single enantiomers were analysed by vibrational circular dichroism spectroscopy and polarimetry in combination with ab initio calculations to determine the respective absolute configuration.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49191820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-10-01DOI: 10.33774/chemrxiv-2021-wdrwc
Tuomas M. A. Nurmi, J. Siitonen
We discuss the pedagogical challenges associated with the current way of introducing extraction in upper secondary school chemistry education. These challenges were identified based on a survey of upper secondary school textbooks and verified through a questionnaire study. To address the identified challenges, we introduce a simple and effective extraction experiment which focuses on building a deeper conceptual understanding of extraction processes. The operationally simple extraction experiment and the accompanying questionnaire revealed that while students have several chemical misconceptions arising from the use of superficial everyday examples, they have all the necessary knowledge for developing a deeper understanding of chemistry. Providing a suitable experimental platform for developing and re-evaluating their knowledge allows the students to reasonably independently re-conceptualize their thinking toward a more coherent view of the surrounding world and the related scientific models. Furthermore, the work analyses the challenges that can be encountered when using everyday examples in teaching, and demonstrates that student-discovered examples of chemical systems can be a powerful method for generating meaningful and relevant ways to introduce scientific phenomena in STEM education.
{"title":"Upper Secondary School and University Level Students’ Perceptions of Extractions in Context: Experiences from a Simple Laboratory Experiment","authors":"Tuomas M. A. Nurmi, J. Siitonen","doi":"10.33774/chemrxiv-2021-wdrwc","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-wdrwc","url":null,"abstract":"We discuss the pedagogical challenges associated with the current way of introducing extraction in upper secondary school chemistry education. These challenges were identified based on a survey of upper secondary school textbooks and verified through a questionnaire study. To address the identified challenges, we introduce a simple and effective extraction experiment which focuses on building a deeper conceptual understanding of extraction processes. The operationally simple extraction experiment and the accompanying questionnaire revealed that while students have several chemical misconceptions arising from the use of superficial everyday examples, they have all the necessary knowledge for developing a deeper understanding of chemistry. Providing a suitable experimental platform for developing and re-evaluating their knowledge allows the students to reasonably independently re-conceptualize their thinking toward a more coherent view of the surrounding world and the related scientific models. Furthermore, the work analyses the challenges that can be encountered when using everyday examples in teaching, and demonstrates that student-discovered examples of chemical systems can be a powerful method for generating meaningful and relevant ways to introduce scientific phenomena in STEM education.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49564826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-10-01DOI: 10.33774/chemrxiv-2021-bj119
Fabio Cortés Rodríguez, M. dal Peraro, L. Abriata
Several groups developed in the last years augmented and virtual reality (AR/VR) programs and apps to visualize 3D molecules, most rather static, limited in content, and requiring software installs, some even requiring specialized hardware. During the Covid-19 pandemic, our team launched moleculARweb (https://molecularweb.epfl.ch), a website that offers interactive content for chemistry and structural biology education through web-based AR that works on consumer devices like smartphones, tablets and laptops. The website quickly got thousands of student and teacher users, a substantial fraction of them accessing from their homes given the pandemic. Teachers have been increasingly requesting more biological macromolecules to be available in AR, a demand that we cannot satisfy individually. Therefore, to allow them to build their own material, and also to help us expedite development of activities, we built a web interface where any user can build any online AR experience in few steps starting from a PDB structure or from virtual objects/scenes exported from VMD. We here briefly describe the tool, that is accessible at https://molecularweb.epfl.ch/pages/pdb2ar.html.
{"title":"Online tools to easily build augmented reality models of biomolecules that run right on the web","authors":"Fabio Cortés Rodríguez, M. dal Peraro, L. Abriata","doi":"10.33774/chemrxiv-2021-bj119","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-bj119","url":null,"abstract":"Several groups developed in the last years augmented and virtual reality (AR/VR) programs and apps to visualize 3D molecules, most rather static, limited in content, and requiring software installs, some even requiring specialized hardware. During the Covid-19 pandemic, our team launched moleculARweb (https://molecularweb.epfl.ch), a website that offers interactive content for chemistry and structural biology education through web-based AR that works on consumer devices like smartphones, tablets and laptops. The website quickly got thousands of student and teacher users, a substantial fraction of them accessing from their homes given the pandemic. Teachers have been increasingly requesting more biological macromolecules to be available in AR, a demand that we cannot satisfy individually. Therefore, to allow them to build their own material, and also to help us expedite development of activities, we built a web interface where any user can build any online AR experience in few steps starting from a PDB structure or from virtual objects/scenes exported from VMD. We here briefly describe the tool, that is accessible at https://molecularweb.epfl.ch/pages/pdb2ar.html.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45986231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-10-01DOI: 10.33774/chemrxiv-2021-mz0tt
Tiancheng Qiu, Harvey M. Andersen, Nissa J. Larson, N. Schroeder, J. Sweedler
Free D-serine (D-Ser) is a potent co-agonist of the N-methyl-D-aspartate receptor (NMDAR) in glutamate neurotransmission and regulates NMDAR functions in the nervous system. Serine racemases convert L-serine to D-Ser and are believed to be the major source of D-Ser in animals. In Caenorhabditis elegans, a knockout of the serine racemase serr-1 results in behavioral changes, but the level of D-Ser is unaffected. By growing C. elegans on peptone-free nematode growth medium (PF-NGM), we delineated the sources of D-Ser, both exogenous from peptone in culturing media and endogenous from the serine racemase serr-1, and a potential serine/aspartate racemase candidate, Y51H7C.9, identified by sequence similarity network analysis. We also discovered a new serine dehydratase (aka serine ammonia-lyase), K01C8.1, in C. elegans. We identified the serr-1 knockout and PF-NGM culturing conditions as two independent factors that impact C. elegans locomotion behavior after off-food, both short-term and long-term, and no interactions were found between the two factors.
游离d -丝氨酸(D-Ser)是谷氨酸神经传递中n -甲基- d -天冬氨酸受体(NMDAR)的有效共激动剂，并调节NMDAR在神经系统中的功能。丝氨酸外消旋酶将l -丝氨酸转化为d -丝氨酸，被认为是动物体内d -丝氨酸的主要来源。在秀丽隐杆线虫中，丝氨酸消旋酶ser1的敲除会导致行为改变，但D-Ser的水平不受影响。通过在无蛋白胨线虫生长培养基(nf - ngm)上培养秀丽隐杆线虫，我们确定了D-Ser的来源，包括培养基中的外源蛋白胨和内源丝氨酸外消旋酶serr-1，以及一种潜在的丝氨酸/天冬氨酸外消旋酶Y51H7C。9、通过序列相似度网络分析进行识别。我们还在秀丽隐杆线虫中发现了一种新的丝氨酸脱水酶(又名丝氨酸解氨酶)K01C8.1。我们发现serr-1敲除和PF-NGM培养条件是影响秀丽隐杆线虫离食后运动行为的两个独立因素，无论是短期的还是长期的，两者之间没有相互作用。
{"title":"Identifying sources of D-serine in Caenorhabditis elegans and their impact on behavior","authors":"Tiancheng Qiu, Harvey M. Andersen, Nissa J. Larson, N. Schroeder, J. Sweedler","doi":"10.33774/chemrxiv-2021-mz0tt","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-mz0tt","url":null,"abstract":"Free D-serine (D-Ser) is a potent co-agonist of the N-methyl-D-aspartate receptor (NMDAR) in glutamate neurotransmission and regulates NMDAR functions in the nervous system. Serine racemases convert L-serine to D-Ser and are believed to be the major source of D-Ser in animals. In Caenorhabditis elegans, a knockout of the serine racemase serr-1 results in behavioral changes, but the level of D-Ser is unaffected. By growing C. elegans on peptone-free nematode growth medium (PF-NGM), we delineated the sources of D-Ser, both exogenous from peptone in culturing media and endogenous from the serine racemase serr-1, and a potential serine/aspartate racemase candidate, Y51H7C.9, identified by sequence similarity network analysis. We also discovered a new serine dehydratase (aka serine ammonia-lyase), K01C8.1, in C. elegans. We identified the serr-1 knockout and PF-NGM culturing conditions as two independent factors that impact C. elegans locomotion behavior after off-food, both short-term and long-term, and no interactions were found between the two factors.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43912342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-10-01DOI: 10.33774/chemrxiv-2021-x5mkp
S. C. Mallojjala, Rahul Sakar, Rachael W. Karugu, M. Manna, S. Mukherjee, Jennifer S. Hirschi
ABSTRACT: Experimental 13C kinetic isotope effects (KIEs) and DFT calculations are used to evaluate the mecha-nism and the origin of enantioselectivity in the C(sp2)‒H alkylative desymmetrization of cyclopentene-1,3-diones using nitroalkanes as the alkylating agent. An unusual combination of an inverse (~0.980) and a normal (~1.030) KIE is observed on the bond-forming carbon atoms of the cyclopentene-1,3-dione and nitroalkane, respectively. These data provide strong support for a mechanism involving reversible carbon-carbon bond-formation followed by rate- and enantioselectivity-determining nitro-group elimination. The theoretical free energy profile and predicted KIEs indicate that this elimination event occurs via an E1cB pathway. The origin of remote stereocontrol is evaluated by distortion-interaction and SAPT0 analyses of the enantiomeric E1cB transition states.
{"title":"Mechanism and Origin of Remote Stereocontrol in the Organocatalytic C(sp2)-H Alkylation using Nitroalkanes as Alkylating Agents","authors":"S. C. Mallojjala, Rahul Sakar, Rachael W. Karugu, M. Manna, S. Mukherjee, Jennifer S. Hirschi","doi":"10.33774/chemrxiv-2021-x5mkp","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-x5mkp","url":null,"abstract":"ABSTRACT: Experimental 13C kinetic isotope effects (KIEs) and DFT calculations are used to evaluate the mecha-nism and the origin of enantioselectivity in the C(sp2)‒H alkylative desymmetrization of cyclopentene-1,3-diones using nitroalkanes as the alkylating agent. An unusual combination of an inverse (~0.980) and a normal (~1.030) KIE is observed on the bond-forming carbon atoms of the cyclopentene-1,3-dione and nitroalkane, respectively. These data provide strong support for a mechanism involving reversible carbon-carbon bond-formation followed by rate- and enantioselectivity-determining nitro-group elimination. The theoretical free energy profile and predicted KIEs indicate that this elimination event occurs via an E1cB pathway. The origin of remote stereocontrol is evaluated by distortion-interaction and SAPT0 analyses of the enantiomeric E1cB transition states.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49368063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：