Breaking News
October 16, 2018 - Health Highlights: Oct. 12, 2018
October 16, 2018 - Study holds promise for new pediatric brain tumor treatment
October 16, 2018 - Patient advocate uses MRI scans to create art and spark conversations about life with illness
October 16, 2018 - Fish oil based diets may suppress growth and spread of breast cancer cells
October 16, 2018 - Number of VHA facilities offering acupuncture has increased rapidly
October 16, 2018 - Influential Leapfrog Group jumps in to rate 5,600 surgery centers
October 16, 2018 - HIV-infected infants more likely to acquire congenital cytomegalovirus infection
October 16, 2018 - Study pinpoints new marker that can predict Crohn’s disease subtype
October 16, 2018 - Simple procedure could be efficacious intervention for failed back surgery
October 16, 2018 - New research identifies modifiable dementia risk factor in elderly people
October 16, 2018 - Zebrafish study uncovers molecular ‘brake’ that helps control eye lens development
October 16, 2018 - Overlapping copy number variations underlie autism and schizophrenia in Japanese patients
October 16, 2018 - Majority of Americans’ ancestry can be traced through existing DNA databases
October 16, 2018 - Patients coerced into mental health care less likely to perceive treatment as effective
October 16, 2018 - Interactive robot helps older people exercise and detects underlying health problems
October 16, 2018 - What you need to know about autism spectrum disorder
October 16, 2018 - Antidepressants can be used to treat Alzheimer’s disease
October 16, 2018 - Study uncovers important role of PRMT1 in dilated cardiomyopathy
October 16, 2018 - Nutritional quality of breakfast linked to cardiovascular and metabolic risk factors in children
October 16, 2018 - Study uses novel approach to investigate genetic origins of mental illnesses
October 16, 2018 - Scientists develop dual anthrax-plague vaccine
October 16, 2018 - Poor Outcomes for Hispanic Infants With Congenital Heart Dz
October 16, 2018 - Global study finds youngest in class more likely to be diagnosed with ADHD
October 16, 2018 - Researchers sequence two selfish genes in the fungus Neurospora intermedia
October 16, 2018 - Survey results highlight the need for better communication between patients and HCPs about bacterial vaginosis
October 16, 2018 - Researchers develop fibrin-targeting immunotherapy to protect against neurodegeneration
October 16, 2018 - Researchers create open access database on healthy immunity
October 16, 2018 - Rice University chemist wins big award to study small surfaces
October 16, 2018 - Study finds 43% drop in stroke rate
October 16, 2018 - Researchers identify basic relationships of cell cycle and cellular senescence in the placenta
October 16, 2018 - UA professor receives NSF grant to develop antifouling materials for medical implants
October 16, 2018 - Obesity Doubles Odds for Colon Cancer in Younger Women
October 16, 2018 - Adults with ADHD not constrained in creativity
October 16, 2018 - Raising visibility for people and students with chronic illness and disability
October 16, 2018 - Allele awarded NIH grant to develop nanoantibody therapies for treatment of sepsis
October 16, 2018 - Only 59% of young adults undergoing surgery are fluid responsive
October 16, 2018 - Research points to potential new treatment for hearing loss
October 16, 2018 - MDI Biological Laboratory receives $1.2 million SEPA grant to promote data literacy
October 16, 2018 - Vast majority of dementia cases may arise from spontaneous genetic errors
October 16, 2018 - New project aims to deliver fast, effective treatment for autoimmune rheumatic diseases
October 16, 2018 - Study identifies molecular switch that controls fate of milk-producing breast cells
October 16, 2018 - Research shows diet has little influence on precursor to gout
October 16, 2018 - “Without Dr. Shumway doing his miracle work, three generations would not be here”: A Stanford heart transplant patient’s story
October 16, 2018 - Non-invasive brain stimulation sheds light on neurobiology underlying implicit bias
October 16, 2018 - Researchers demonstrate integrated technique to control production of cell therapeutics
October 16, 2018 - Breast tomosynthesis detects 34% more tumors than traditional mammography
October 16, 2018 - Rhode Island Hospital, Brown receive $800,000 grant to keep up fight against opioid epidemic
October 16, 2018 - UVA partners with health systems in AVIA network’s Medicaid Transformation Project
October 16, 2018 - Trevena Announces Oliceridine FDA Advisory Committee Meeting Outcome
October 16, 2018 - Study reveals early warning signs of heart problems in patients with newly diagnosed lupus
October 16, 2018 - Connecting the dots of Alzheimer’s disease
October 16, 2018 - New publication offers evidence-based content for global breast imaging medical community
October 16, 2018 - ‘EinsteinVision’ that improves hand-eye coordination of surgeons introduced at Harefield Hospital
October 16, 2018 - WRAIR clinical study evaluates safety and immunogenicity of Marburg vaccine
October 16, 2018 - Ketamine can be considered as alternative to opioids for short-term pain control in ED
October 16, 2018 - Endurance exercise training beneficially alters gut microbiota composition
October 15, 2018 - FDA Approves Yutiq (fluocinolone acetonide intravitreal implant) for Chronic Non-Infectious Posterior Segment Uveitis
October 15, 2018 - Birthing Options for Full-Term Pregnancy
October 15, 2018 - Stressed, toxic, zombie cells seen for first time in Alzheimer’s
October 15, 2018 - Concussion researchers study head motion in high school football hits | News Center
October 15, 2018 - Neuropsychiatric symptoms related to earliest stages of Alzheimer’s brain pathology
October 15, 2018 - Neck collar device may help protect the brain of female high school soccer players
October 15, 2018 - Research reveals how the inner ear processes speech
October 15, 2018 - Many parents still skeptical about safety and effectiveness of flu shot, survey finds
October 15, 2018 - Payer Policies May Discourage Non-Pharma Tx for Low Back Pain
October 15, 2018 - Exercise may delay cognitive decline in people with rare Alzheimer’s disease
October 15, 2018 - Researchers modify CRISPR to reorganize genome | News Center
October 15, 2018 - Innovative brain tumor operation set to tailor to patients’ needs
October 15, 2018 - Findings offer new insight into early changes that occur during AD pathology
October 15, 2018 - Neurons regulating reproductive hormone release have different activity in epileptic mice
October 15, 2018 - More parents are concerned about taking babies swimming in public pools
October 15, 2018 - Health Tip: Know the Risk Factors for Lower Back Pain
October 15, 2018 - Study shows cigarillo flavors enhanced by high-intensity sweeteners
October 15, 2018 - Study traces hospital-acquired bloodstream infections to patients’ own bodies | News Center
October 15, 2018 - Abnormal vision in childhood can affect development of brain areas responsible for attention
October 15, 2018 - Study highlights need for increased support for alcohol-related liver disease patients
October 15, 2018 - Color-changing contact lens could help doctors to monitor eye disease medications
October 15, 2018 - Tobacco heating products cause less staining to teeth than conventional cigarettes
October 15, 2018 - Young adults who are obese can expect to lose up to 10 years in life expectancy
October 15, 2018 - Scientists uncover how proteins meet on the cell membrane
Discovery of unusual biosynthetic pathways could aid in the search for new natural products

Discovery of unusual biosynthetic pathways could aid in the search for new natural products

image_pdfDownload PDFimage_print

Bacteria are master engineers of small, biologically useful molecules. A new study in Nature Communications has revealed one of the tricks of this microbial trade: synthesizing and then later inserting a nitrogen-nitrogen bond, like a prefabricated part, into a larger molecule.

The discovery was made by a collaborative group of chemists at the University of Illinois and Harvard University. Together, they confirmed that two otherwise unrelated, bacterially-produced compounds shared an unusual set of steps in their biosynthetic pathways. Deciphering this type of biochemical process will aid in the search for other useful biological compounds.

“It’s a molecular handle or genetic handle if you wish to now go after other new molecules that people haven’t found before,” said Wilfred van der Donk, Richard E. Heckert Endowed Chair in Chemistry and Investigator of the Howard Hughes Medical Institute. “So we’re pretty excited both about what’s in the paper and also what it allows us to do going forward.”

Natural products, substances produced by living things, have provided us with antibiotics, antifungals, cancer therapies, and other important pharmaceutical and industrial compounds; continued exploration of the diverse chemical world of microbes is one of our best hopes for future drug discovery. A major focus of van der Donk’s research is the quest to identify new natural products.

Van der Donk shares that goal with a collaborative research team within the Carl R. Woese Institute for Genomic Biology (IGB), of which he is a member. The Mining Microbial Genomes research team aims to accelerate the natural product hunt using the power of next-generation genomic technologies. The tools that bacteria and other microbes use to make natural products are enzymes, specialized proteins encoded by genes. The team’s long-term research goal is to learn to read through bacterial genomes and, based on the genes each species possesses, predict what compounds they are able to make.

The team is especially interested in a class of molecules called phosphonates that has already yielded multiple useful compounds. At the outset of the present study, they wanted to understand what gene products enable a cell to form a key feature of a particular phosphonate called fosfazinomycin, a compound with antifungal properties: a chemical bond between two nitrogen atoms. Compounds with reactive nitrogen-nitrogen bonds readily react with other molecules such as DNA and proteins and as such may contribute to antimicrobial or anti-cancer activity.

“We were looking for fosfazinomycin as a group for probably a decade, because of the very unusual structure, but we didn’t know which genes” provided the enzymes to synthesize it, van der Donk explained. “We decided okay, let’s figure out how nature makes this nitrogen-nitrogen bond.”

After the group began work on the project, two publications by researchers focused on other natural products described a process of nitrogen-nitrogen bond formation in which one nitrogen atom is built into the molecule, and another is later attached–the organism is building the molecule piece by piece, like a child with a basic pack of Lego bricks.

Van der Donk’s group discovered with surprise that their molecule’s nitrogen-nitrogen bond was not being formed this way. Instead, the bacteria they studied were creating nitrogen-nitrogen bonds as part of a much smaller molecule, like a specialty Lego part, and later installing that part into the larger molecule that would become fosfazinomycin.

“We realized as we continued working that in our system, it’s done very differently,” van der Donk said. “It looked like in our case as if nature was making this nitrogen-nitrogen bond containing molecule as a prepackaged molecular entity that then later on was dumped into an existing biosynthetic pathway.”

The research project took another serendipitous turn when graduate student and co-first author Kwo-Kwang (Abraham) Wang presented the preliminary results at a conference. He was approached by Harvard chemistry graduate student Tai Ng, who along with his laboratory group led by Professor Emily Balskus was studying a natural product and promising anti-cancer agent called kinamycin. Kinamycin contains a nitrogen-nitrogen bond, and Ng’s research suggested that it also shares the prefabrication step suspected for fosfazinomycin.

“We had noticed that their molecule [is synthesized using] the same genes, but we didn’t really know how that fit in either, because they are making a completely different nitrogen-nitrogen bond containing structure that doesn’t look anything like our molecule,” van der Donk said. The two groups began to work together, coordinating experiments in which labeled molecules were fed to bacteria able to synthesize each of the two natural products, to see what intermediate molecular structures could be seamlessly introduced into the natural biosynthesis pathway within the cell.

“We would make these labeled compounds, give them to the producing organism, isolate the final product, for the Harvard group kinamycin and for us fosfazinomycin, and see whether the nitrogen-nitrogen moiety of the molecules that we were feeding to these organisms was installed into the final product,” van der Donk said. “We did that for four different compounds and every time the answer was yes, yes, yes, yes.”

Finding this improbable commonality in the way two dissimilar molecules are produced increased the researchers’ confidence in the functional roles of the genes involved. They now have a new genomic signature to add to their lexicon, something they can scan for in other bacterial genomes as they continue the search for useful natural products.

“We need to learn more about how known natural products are made. This is a great example; now that we know, we can use that knowledge. Before that, it was just a whole bunch of genes and we didn’t really know what to do with them,” van der Donk said. “By going after unknown gene clusters [we hope to be able to] see immediately from the gene cluster, this has to be a new molecule . . . could that molecule be the next antibiotic or the next anti-tumor drug?”

Source:

https://www.igb.illinois.edu/article/unusual-biosynthetic-pathway-offers-key-future-natural-product-discovery

Tagged with:

About author

Related Articles