Carbon Chemist

Tag: Amino Acid

  • SciY launches new BioDrive tool and registration module for enhanced data management and collaboration in molecular biology research

    SciY launches new BioDrive tool and registration module for enhanced data management and collaboration in molecular biology research

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    The new Arxspan BioDrive is a tool for molecular biology that provides cross-functional research teams with a single, integrated data management platform. With Arxspan BioDrive, users have the ability to create, import, and export nucleotide and amino acid sequences in various file formats, import sequences directly from NCBI’s database, design primers using the Primer Design Tool, and maintain relationships between molecules. Additionally, users can align designed sequences with one or more sequencing files, plan cloning projects, and complete their biological workflow seamlessly.

    Molecular Biology Research: The New BioDrive by SciY

    SciY has also launched a new version of Arxspan’s Registration Module. The enhanced Registration Module provides a comprehensive solution for managing molecular biology, biology, and chemistry data all from a single platform. It features user-customizable fields, flexible parent and child naming and/or numbering, integrated chemistry drawing tools, and advanced search capabilities. The Registration Module, with its seamless integration with the new BioDrive and the Electronic Laboratory Notebook (ELN), allows users to eliminate data silos that hinder data sharing across project teams, thereby enabling a more efficient and effective completion of biological workflows.

    “We are excited to launch the new BioDrive and the new Registration Module to provide cross-functional research teams with a complete solution for managing molecular biology, biology, and chemistry data from a single platform. Our goal is to help scientists be more efficient and productive in their research by simplifying the data management process,” said Guy Desmarquets, Senior Director of Sales and Business Development, SciY.

    BioDrive and the Registration module are available now and can be accessed through Arxspan by SciY cloud-based scientific informatics solutions.

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  • Rare variants in the YKT6 gene cause new neurological disorder, study finds

    Rare variants in the YKT6 gene cause new neurological disorder, study finds

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    A recent collaborative study has discovered rare variants in the YKT6 gene as the cause of a new neurological disorder characterized by developmental delays along with severe progressive liver disease and a potential risk for liver cancer. The study, published in Genetics in Medicine, was led by Dr. Hugo Bellen, Distinguished Service Professor at Baylor College of Medicine and Principal Investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, and Dr. Wendy Chung, the Chief of the Department of Pediatrics at Boston Children’s Hospital. 

    “It is known that the YKT6 gene plays important roles in many intracellular vesicular trafficking events in the cells but this is the first time it has been linked to a genetically inherited disorder,” Dr. Bellen said. “This study, using patient samples and fruit flies, provides a solid experimental foundation for future studies to better understand this new disease and to develop therapies.”

    YKT6 gene variants disrupt brain development and sometimes, liver function

    In collaboration with Dr. Mythily Ganapathi at Columbia University Irving Medical Center, Drs. Paula Hertel and Davut Pehlivan at Texas Children’s Hospital and Dr. James Lupski at Baylor College of Medicine, and by using the GeneMatcher tool and Baylor Genetics clinical diagnostics laboratory, this team of researchers and clinicians found three unrelated individuals with missense (analogous to misspellings in a word) variants in both copies of the YKT6 gene. 

    All three individuals had early onset of disease (four to six months of age) with failure to thrive. Two of them had an identical missense variant because of which the tyrosine amino acid at position 185 was changed to cysteine (Tyr185Cys). On the other hand, the third child carried a variant that caused the same amino acid change but in a different location (Tyr64Cys) of the YKT6 protein. Interestingly, in addition to developmental delays and neurological defects which were observed in all three children, only the two individuals with the Tyr185Cys variant had liver dysfunction and a potential risk for developing liver cancer.

    Interestingly, both individuals with the Tyr185Cys variant belong to the Syrian/Saint Thomas Christians of Kerala, India, a group currently estimated to be comprised of about 5 million individuals worldwide. Our genetic lineage analysis suggests this variant likely originated from a common ancestor before the community split.”


    Dr. Mythily Ganapathi at Columbia University Irving Medical Center 

    YKT6 gene variants impair autophagy

    To assess how YKT6 variants result in the observed disease pathologies, the Bellen team studied the fruit fly version of this gene which is quite similar to its human counterpart.

    “We found that the fly version of this protein is expressed in the fat body and brain which are analogous to the human liver and central nervous system respectively,” Dr. Mengqi Ma, one of the first authors and a postdoctoral fellow in the Bellen lab, said. “Moreover, fly strains with loss of function mutations in this gene were lethal.”

    Further, they observed that Ykt6 mutant flies expressing the normal fly version of the Ykt6 gene flies had an average lifespan. However, transgenic flies expressing the fly versions of the disease variants were less effective in restoring lifespan and other symptoms. While Ykt6 mutant flies expressing Tyr65Cys (equal to human Tyr64Cys) had normal lifespan and locomotion, those expressing Tyr186Cys (equal to human Tyr185Cys) had severely reduced lifespan and locomotor defects. “Our results showed that the fly Ykt6 Tyr186Cys cause more severe defects than Tyr65Cys,” Dr. Ma added, “suggesting that the corresponding human YKT6 Tyr185Cys is a more severe variant than Tyr64Cys.”

    To understand why these variants behaved differently, they delved deeper into their biology.

    YKT6 belongs to the SNARE family of proteins that regulate the flow of protein traffic to various compartments within the cell. In mammalian cells, YKT6 mediates the fusion of two cellular organelles – the autophagosomes and lysosomes to form autolysosomes – within which ‘used’ cellular proteins, lipids, and other molecules are degraded and recycled back for future use. This process called autophagy is critical for the proper function and health of the cells.

    The team found that the loss of fly Ykt6 led to an abnormal accumulation of proteins involved in autophagosome formation and autophagic cargo receptor, indicating a block in the autophagy pathway. Further studies revealed that just like lethality and other defects, fly Tyr186Cys (equal to human Tyr185Cys) was less efficient in reverting the symptoms compared to a normal copy of the Ykt6 gene. Furthermore, they observed that while autophagy initiation was normal, the steps involved in the breakdown of cellular waste were impaired in the absence of Ykt6.

    “Based on our findings, we recommend the YKT6 gene as a candidate for carrier screening in the Syrian/Saint Thomas Christian community of Kerala,” Dr. Mythily Ganapathi said.

    “Our work suggests children diagnosed with YKT6 liver disease will also need to be screened for hepatocellular carcinoma,” Dr. Paula Hertel said.

    “In summary, we have discovered YKT6 variants as the cause of a novel developmental disorder affecting brain function and in certain cases, also liver function, providing us valuable insights into a new genetic disease. However, additional studies with more patients will be needed to precisely understand the pathogenesis and to identify potential therapeutic targets for this condition,” Dr. Bellen added.

    Source:

    Texas Children’s Hospital

    Journal reference:

    Ma, M., et al. (2024). Homozygous missense variants in YKT6 result in loss of function and are associated with developmental delay, with or without severe infantile liver disease and risk for hepatocellular carcinoma. Genetics in Medicine. doi.org/10.1016/j.gim.2024.101125.

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  • Gut bacteria and tryptophan diet can play a protective role against pathogenic E. coli

    Gut bacteria and tryptophan diet can play a protective role against pathogenic E. coli

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    Gut bacteria and a diet rich in the amino acid tryptophan can play a protective role against pathogenic E. coli, which can cause severe stomach upset, cramps, fever, intestinal bleeding and renal failure, according to a study published March 13 in Nature.

    The research reveals how dietary tryptophan – an amino acid found mostly in animal products, nuts, seeds, whole grains and legumes – can be broken down by gut bacteria into small molecules called metabolites. It turns out a few of these metabolites can bind to a receptor on gut epithelial (surface) cells, triggering a pathway that ultimately reduces the production of proteins that E. coli use to attach to the gut lining where they cause infection. When E. coli fail to attach and colonize the gut, the pathogen benignly moves through and passes out of the body.

    The research describes a previously unknown role in the gut for a receptor, DRD2. DRD2 has otherwise been known as a dopamine (neurotransmitter) receptor in the central and peripheral nervous systems.

    It’s actually two completely different areas that this receptor could play a role in, which was not appreciated prior to our findings. We essentially think that DRD2 is moonlighting in the gut as a microbial metabolite sensor, and then its downstream effect is to help protect against infection.”


    Pamela Chang, associate professor of immunology in the College of Veterinary Medicine and of chemical biology in the College of Arts and Sciences

    Samantha Scott, a postdoctoral researcher in Chang’s lab, is first author of the study, “Dopamine Receptor D2 Confers Colonization Resistance via Microbial Metabolites.”

    Now that Chang, Scott and colleagues have identified a specific pathway to help prevent E. coli infection, they may now begin studying the DRD2 receptor and components of its downstream pathway for therapeutic targets.

    In the study, the researchers used mice infected with Citrobacter rodentium, a bacterium that closely resembles E. coli, since certain pathogenic E. coli don’t infect mice. Through experiments, the researchers identified that there was less pathogen and inflammation (a sign of an active immune system and infection) after mice were fed a tryptophan-supplemented diet. Then, to show that gut bacteria were having an effect, they gave the mice antibiotics to deplete microbes in the gut, and found that the mice were infected by C. rodentium in spite of eating a tryptophan diet, confirming that protection from tryptophan was dependent on the gut bacteria.

    Then, using mass spectrometry, they ran a screen to find the chemical identities of tryptophan metabolites in a gut sample, and identified three such metabolites that were significantly increased when given a tryptophan diet. Again, based on pathogen levels and inflammation, when these three metabolites alone were fed to the mice, they had the same protective effect as giving the mice a full tryptophan diet.

    Switching gears, the researchers used bioinformatics to find which proteins (and receptors) might bind to the tryptophan metabolites, and from a long list they identified three related receptors within the same family of dopamine receptors. Using a human intestinal cell line in the lab, they were able to isolate receptor DRD2 as the one that had the protective effect against infection in the presence of tryptophan metabolites.

    Having identified the metabolites and the receptor, they analyzed the downstream pathway of DRD2 in human gut epithelial cells. Ultimately, they found that when the DRD2 pathway was activated, the host’s ability to produce an actin regulatory protein was compromised. C. rodentium (and E. coli) require actin to attach themselves to gut epithelial cells, where they colonize and inject virulence factors and toxins into the cells that cause symptoms. But without actin polymerization they can’t attach and the pathogen passes through and clears.

    The experiments revealed a new role of dopamine receptor DRD2 in the gut that controls actin proteins and affects a previously unknown pathway for preventing a pathogenic bacteria’s ability to colonize the gut. 

    Jingjing Fu, a former postdoctoral researcher in Chang’s lab, is a co-author.

    The study was supported by the Arnold and Mabel Beckman Foundation, a President’s Council of Cornell Women Affinito-Stewart Grant, the National Institutes of Health and a Cornell Institute of Host-Microbe Interactions and Disease Postdoctoral Fellowship. 

    Source:

    Journal reference:

    Scott, S. A., et al. (2024). Dopamine receptor D2 confers colonization resistance via microbial metabolites. Nature. doi.org/10.1038/s41586-024-07179-5

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  • Tryptophan digestion by gut microbiome spurs arthritis inflammation

    Tryptophan digestion by gut microbiome spurs arthritis inflammation

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    A University of Colorado Department of Medicine faculty member says she and her colleagues have identified the means in which bacteria in the digestive system can break down tryptophan in the diet into an inflammatory chemical that primes the immune system towards arthritis.

    The research was co-authored by Kristine Kuhn, MD, PhD, Scoville Endowed Chair and head of the CU Division of Rheumatology. Several of her division colleagues collaborated on the paper, which was published in February in the Journal of Clinical Investigation.

    Tryptophan is an essential amino acid found in many protein-rich foods, including meats, fish, dairy products, and certain seeds and nuts. It has many uses in the body, including helping in the production of proteins, muscles, enzymes, and neurotransmitters – the nervous system’s chemical messengers. The body doesn’t make it; we get it from our diet.

    Many people think of tryptophan as the ingredient in turkey that supposedly makes us sleepy after a Thanksgiving feast. In fact, researchers say that although tryptophan plays a role in helping to regulate the sleep cycle, the amount that’s in turkey probably isn’t a significant cause of post-dinner drowsiness.

    Cause and effect

    Kuhn and her associates set out to learn how a substance that often is a force for good in the body is converted into a pathway to inflammatory diseases such as rheumatoid arthritis, which affects about 1% of the population. It can cause painful swelling of the hands and feet, and joint deformities if left untreated.

    It’s been known that the microbiome – the bacteria in our gut – can break down tryptophan into byproducts. Some of those byproducts are anti-inflammatory, but we’ve also associated some inflammatory causes of those products. We’re the first to highlight which products are contributing to inflammation, and how they are doing that.”


    Kristine Kuhn, MD, PhD, Scoville Endowed Chair and Head of the CU Division of Rheumatology

    She says the new research “builds upon some observations we had in patients with spondyloarthritis – not quite rheumatoid arthritis, but a closely related condition – where we found that changes in the microbiome were associated with increased production of these products called indoles, which are what bacteria make from tryptophan.” Similar changes were observed in arthritis studies involving mice, she says.

    “We put mice on antibiotics to wipe out their microbiome, and they didn’t get arthritis, and they didn’t have indole,” she says. “So we said, OK, what if they do have a microbiome and we put them on a diet with little tryptophan? The microbiome can’t break down tryptophan into indole, and the mice didn’t get arthritis. So two different ways, we showed that it’s tryptophan that’s broken down by the microbiome into indole.”

    Inflammatory flags

    So how does that work? “We found that when indole is present, the mice start to develop autoreactive T-cells that are more inflammatory. They have less of those regulatory T-cells that help maintain balance in the immune system, and they start to develop antibodies that are more pathogenic. We found that the antibodies had flags for being more inflammatory when indole was present.”

    The paper concludes that “blockade of indole generation may present a unique therapeutic pathway” for rheumatoid arthritis and spondyloarthritis. That’s all about finding the right path for the body’s tryptophan, Kuhn says.

    “If tryptophan hits our body’s cells, it tends to go get broken down into anti-inflammatory products versus when it hits the bacterial cells and goes more inflammatory. The ways we think about how this could lead to therapies are: How do you keep that balance tipped so that tryptophan goes towards that anti-inflammatory pathway? How can you manipulate intestinal bacteria to tip that balance? That’s where we’re interested in going in the future.”

    Does Kuhn’s research suggest we should be eating differently? “I get asked that a lot,” she says. “A diet that’s rich in plant-based fibers and lean meats – this whole Mediterranean diet – seems to push the microbiome into a healthier state, so that you are getting the anti-inflammatory properties of tryptophan, whereas the typical western diet seems to go more toward the inflammatory pathway.”

    As for other ways to protect against arthritis, Kuhn says that through research by her Division of Rheumatology colleagues, “we have started to understand the at-risk stage, where we can actually identify people who are likely to progress to rheumatoid arthritis within the next few years based on blood markers. There’s some data that suggests we could intervene during that period and prevent disease, but we’re not quite sure yet what are the right ways to intervene.”

    Source:

    University of Colorado Anschutz Medical Campus

    Journal reference:

    Seymour, B. J., et al. (2024). Microbiota-dependent indole production stimulates the development of collagen-induced arthritis in mice. The Journal of Clinical Investigation. doi.org/10.1172/JCI167671.

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  • Discovery of novel enzyme family holds potential for antibiotic development

    Discovery of novel enzyme family holds potential for antibiotic development

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    Researchers at Umeå University in Sweden, led by Professor Felipe Cava, have identified a new family of enzymes that creates a unique type of cross-linking between the building blocks of bacterial cell walls. This discovery could help develop new antibiotics against infectious diseases.

    Bacterial cell walls form mesh-like structures, shielding cells from rupturing under high internal pressure and safeguarding against external threats. The cell wall is comprised of sugar and amino acid molecules interconnected by various types of cross-links. These cross-links play a crucial role in providing strength and stability to the cell wall, while also enabling bacteria to adapt to diverse environments and stressors.

    In a groundbreaking study recently published in the esteemed journal Nature Communications, researchers from Umeå University and international institutions have unveiled a novel family of enzymes responsible for generating a unique cross-linkage between L-alanine and meso-diaminopimelic acid. These amino acids are integral components of the peptide chains constituting the cell wall of numerous bacterial species. Termed LD1,3-transpeptidase, this enzyme has been identified across various groups of alpha and beta proteobacteria, including opportunistic pathogens such as Burkholderia and Achromobacter.

    The researchers utilized Gluconobacter oxydans, a model organism employed in vinegar production, to identify the novel LD1,3-transpeptidase enzyme and elucidate its three-dimensional structure. They have demonstrated that this enzyme possesses unique characteristics distinguishing it from other known enzymes involved in cell wall cross-linkage. These distinctive properties enable the enzyme to utilize various substrates and execute diverse reactions, critical for maintaining the cell wall’s integrity. Specifically, their findings indicate that cells lacking these cross-links exhibit heightened sensitivity to β-lactam antibiotics, underscoring the potential of LD1,3-transpeptidases as promising targets for therapeutic interventions, particularly those aimed at enhancing antibiotic effectiveness.

    The principal investigator of the study is Felipe Cava, Professor of Infection Biology at Umeå University and Director of the Umeå Hypoxic Research Facility. With extensive expertise in bacterial cell wall research and its implications in bacterial survival and disease progression, Professor Cava has spearheaded investigations into this field for a significant duration.

    The bacterial cell wall stands as one of the most remarkable structures, yet much remains to be uncovered about its diversity and dynamics. Through the identification and characterization of novel enzyme families like LD1,3-transpeptidase, we not only expand our understanding of bacterial biology but also discover fresh targets for developing antibiotics to combat infectious diseases.”


    Felipe Cava

    The study was funded by, among others, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Kempe Foundations.

    Source:

    Journal reference:

    Espaillat, A., et al. (2024). A distinctive family of L,D-transpeptidases catalyzing L-Ala-mDAP crosslinks in Alpha- and Betaproteobacteria. Nature Communications. doi.org/10.1038/s41467-024-45620-5.

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