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  • richardmitnick 12:51 pm on October 19, 2018 Permalink | Reply
    Tags: , , , , RNA studies,   

    From Science Magazine: “Chemists find a recipe that may have jump-started life on Earth’ 

    AAAS
    From Science Magazine

    1
    New research spells out the simple chemical steps that may have launched the RNA World. Mark Garlick/Science Source

    Oct. 18, 2018
    Robert F. Service

    In the molecular dance that gave birth to life on Earth, RNA appears to be a central player. But the origins of the molecule, which can store genetic information as DNA does and speed chemical reactions as proteins do, remain a mystery. Now, a team of researchers has shown for the first time that a set of simple starting materials, which were likely present on early Earth, can produce all four of RNA’s chemical building blocks.

    Those building blocks—cytosine, uracil, adenine, and guanine—have previously been re-created in the lab from other starting materials. In 2009, chemists led by John Sutherland at the University of Cambridge in the United Kingdom devised a set of five compounds likely present on early Earth that could give rise to cytosine and uracil, collectively known as pyrimidines. Then, 2 years ago, researchers led by Thomas Carell, a chemist at Ludwig Maximilian University in Munich, Germany, reported that his team had an equally easy way to form adenine and guanine [Nature], the building blocks known as purines. But the two sets of chemical reactions were different. No one knew how the conditions for making both pairs of building blocks could have occurred in the same place at the same time.

    Now, Carell says he may have the answer. On Tuesday, at the Origins of Life Workshop here, he reported that he and his colleagues have come up with a simple set of reactions that could have given rise to all four RNA bases.

    Carell’s story starts with only six molecular building blocks—oxygen, nitrogen, methane, ammonia, water, and hydrogen cyanide, all of which would have been present on early Earth. Other research groups had shown that these molecules could react to form somewhat more complex compounds than the ones Carell used.

    To make the pyrimidines, Carell started with compounds called cyanoacetylene and hydroxylamine, which react to form compounds called amino-isoxazoles. These, in turn, react with another simple molecule, urea, to form compounds that then react with a sugar called ribose to make one last set of intermediate compounds.

    Finally, in the presence of sulfur-containing compounds called thiols and trace amounts of iron or nickel salts, these intermediates transform into the pyrimidines cytosine and uracil. As a bonus, this last reaction is triggered when the metals in the salts harbor extra positive charges, which is precisely what occurs in the final step in a similar molecular cascade that produces the purines, adenine and guanine. Even better, the step that leads to all four nucleotides works in one pot, Carell says, offering for the first time a plausible explanation of how all of RNA’s building blocks could have arisen side by side.

    “It looks pretty good to me,” says Steven Benner, a chemist with the Foundation for Applied Molecular Evolution in Alachua, Florida. The process provides a simple way to produce all four bases under conditions consistent with those believed present on early Earth, he says.

    The process doesn’t solve all of RNA’s mysteries. For example, another chemical step still needs to “activate” each of RNA’s four building blocks to link them into the long chains that form genetic material and carry out chemical reactions. But making RNA under conditions like those present on early Earth now appears within reach.

    See the full article here .


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    • stewarthoughblog 11:31 pm on October 19, 2018 Permalink | Reply

      Some interesting science here, but mostly wildly speculative naturalism. The “molecular dance” is a myth, like Darwin’s “warm little ponds,” Oparin-Haldane primordial soup or Miller-Urey test tube goo. There are no naturalistic processes capable of any appreciable assembly of abiotic chemicals at any level that approach the basic, elemental level of assembly required for the origin of life.

      RNA, in particular, is an intermediate molecule that is easily mutated, easily contaminated, highly reactive, composed of homochiral AGCU that does not develop naturalistically and does not function at any level that produces metabolic processes or reproduce.

      The intelligently designed, highly orchestrated lab experiments are biogeochemically irrelevant to primordial Earth conditions and do no demonstrate any significant achievement relative to the origin of life.

      Like

  • richardmitnick 1:22 pm on August 7, 2018 Permalink | Reply
    Tags: Catching the dance of antibiotics and ribosomes at room temperature, , , , RNA studies, , ,   

    From SLAC National Accelerator Lab: “Catching the dance of antibiotics and ribosomes at room temperature” 

    From SLAC National Accelerator Lab

    August 6, 2018
    Ali Sundermier

    1
    Hasan DeMirci refers to ribosomes as the 3D printers of the human body because they synthesize proteins, which are essential to life. (Dawn Harmer/SLAC National Accelerator Laboratory)

    2
    Interns in DeMirci’s lab help grow ribosome crystals. Once grown and suspended in a special chemical solution called “mother liquor,” the crystals are imaged at the LCLS to uncover how they interact with antibiotics. (Dawn Harmer/SLAC National Accelerator Laboratory)

    Antibiotics have been a pillar of modern medicine since the 1940s. Streptomycin, which belongs to a class of antibiotics called aminoglycosides, was the first hint of light in the millennia-long search for a treatment for tuberculosis, which remains one of the deadliest infectious diseases in human history.

    Today, aminoglycosides are the most commonly prescribed antibiotics in the world due to their low cost and high effectiveness in tackling a broad spectrum of bacterial infections. But they also bring along side effects that can have lifelong impacts. Depending on the dosage and the particular antibiotic, an estimated 10 to 20 percent of patients who take aminoglycosides suffer kidney damage and 20 to 60 percent end up with irreversible hearing loss.

    Now researchers at the Department of Energy’s SLAC National Accelerator Laboratory have developed a new imaging technique to better understand the mechanisms that lead to hearing loss when aminoglycosides are introduced to the body. Using the lab’s Linac Coherent Light Source (LCLS) X-ray laser and Stanford Synchrotron Lightsource (SSRL), SLAC researchers, in collaboration with researchers at Stanford University, were able to observe interactions between the drugs and bacterial ribosomes at both extremely low and room temperatures, revealing never-before-seen details.

    SLAC LCLS

    SLAC/SSRL

    They also demonstrated how small modifications to the antibiotics can lead to dramatic changes in ribosome shape that eliminate hearing loss. The research could lead to a better understanding of which parts of a drug molecule cause unwanted reactions in the body, which will enable the development of more effective antibiotics with fewer side effects.

    The group was led by research associate and senior author Hasan DeMirci. Their results were published in Nucleic Acids Research.

    3D printing proteins

    Hasan DeMirci refers to ribosomes – tiny molecular machines made up of tangles of RNA and proteins clumped together and intricately wired like ramen noodles in soup – as “the 3D printers of the human body.” The ribosomes synthesize proteins using the genetic information contained in DNA, “building our bodies from the ground up.”

    3
    Ribosomes (shown here) are tiny molecular machines made up of tangles of RNA and proteins clumped together and intricately wired like ramen noodles in soup. (Hasan DeMirci/SLAC National Accelerator Laboratory)

    “While one subunit of the ribosome, its brain, deciphers and translates the genetic code, the other, its hands, links together amino acids to form proteins,” DeMirci said.

    Unlike viruses, which have to leech off hosts to survive, bacteria have their own ribosomes, which is where antibiotics come into play. Bacterial ribosomes are the targets of many antibiotics. So-called “cidal” antibiotics like aminoglycosides function by attacking the brains of bacterial ribosomes, causing them to make mistakes and fill the cells with protein-like garbage molecules.

    “It’s like a house with a lot of hoarded junk,” DeMirci says. “There’s no going back. From that point the bacteria just die.”

    The problem with this strategy is that human cells contain energy-producing factories called mitochondria that have their very own ribosomes – and since those ribosomes are dangerously similar to those found in bacteria, they’re also vulnerable to antibiotic attack.

    “We’re killing the bacteria, but the same drug gets into our mitochondria and destroys the ribosomes there,” DeMirci says. “Now we cannot produce those enzymes that power us. You take an antibiotic and you start losing your hearing, your kidney fails.”

    Insights into molecular machinery

    DeMirci has a strong interest in aminoglycosides because he can use them to gain insight into the molecular machinery of the ribosome.

    “What I really want to know is what those drugs can teach us about how ribosomes decipher the genetic code,” DeMirci said. “Drugs give us an opportunity to stop that process at different stages to understand how each and every step is catalyzed by the ribosome.”

    To better understand this process, he struck up a collaboration with Anthony Ricci, a biophysicist and professor of medicine at Stanford who focuses on the inner ear. In previous research, Ricci found that aminoglycosides infiltrate specialized channels to target the sensory cells essential to hearing.

    “You can think of it as a roach motel,” Ricci says. “The drugs can get in but they can’t get out. They start to build up, binding to the ribosomes and altering protein synthesis. This puts a huge metabolic load on the sensory cells, which eventually leads to their deaths.”

    A major goal of Ricci’s lab has been to design and develop new aminoglycosides that kill bacteria but cannot squeeze through the channel. In order to do this, the researchers need to understand exactly how the aminoglycosides interact with the ribosomes so they can modify parts of the drug without weakening its bacteria-killing properties.

    Defrosting interactions

    The best way to reach this understanding, researchers have found, is through a technique called X-ray crystallography. In X-ray crystallography, researchers use the patterns formed when a beam of X-rays scatters off a crystal sample to form a 3D model of how its atoms and molecules are arranged. This technique allows researchers to observe how a drug binds to a ribosome.

    While the key interactions in these processes happen at body temperature, around 37 degrees Celsius, X-ray crystallography usually has to be done at extremely low, or cryogenic, temperatures, around minus 180 degrees Celsius. This leads to gaps in the data, obscuring tiny details that could greatly inform future experiments.

    “Our bodies are warm, so the important biology is happening at body temperature,” DeMirci said, “but in crystallography everything is frozen. When you cool these processes down, you miss out on thermal fluctuations, tiny movements that could change your understanding of how the drugs and ribosomes are behaving.”

    In order to design better antibiotics, they need to get as close a view as they can of this interaction happening under physiological conditions. At the LCLS, using a technique called serial femtosecond crystallography, DeMirci is able to catch the intricate waltz of the drugs and ribosomes at room temperature. Rather than freeze the ribosome crystals, the researchers suspend them in ‘mother liquor,’ a special chemical solution they were grown in that keeps them stable, so they are “swimming happily, still wiggling and fluctuating,” he says.

    The crystals travel from a reservoir to the interaction region through a single capillary, like a garden hose. Once in the interaction region, the crystals are zapped with a beam of X-rays from the LCLS, which scatters off of them into a detector and provides the researchers with patterns they can use to build detailed 3D models of the ribosome before and after they’ve bound with the drugs. They then use these models to piece together a simulation of the interaction.

    4
    At LCLS, crystallized ribosomes travel through a capillary into the interaction region, where they are zapped with a beam of X-rays. The X-rays scatter off the crystals into a detector, providing the researchers with patterns they can use to build detailed 3D models of interactions between the drug and ribosome. (Greg Stewart/SLAC National Accelerator Laboratory)

    Uncovering hidden wiggles

    To demonstrate their technique, the researchers imaged modified and unmodified drugs binding to ribosomes at both cryogenic and room temperatures to see if they could catch any differences. They found that the drug molecules were less flexible at cryogenic temperatures: Tiny wiggles essential to a better understanding of their interactions with ribosomes were frozen in place.

    “Despite the fact that we’ve recorded hundreds of thousands of structures of ribosomal interactions, less than a handful of new-generation drugs have been designed based on these cryogenic structures,” DeMirci said. “That’s because every small interaction makes a huge difference, even a single hydrogen bond.”

    With the images taken at room temperature, Ricci’s group identified a site where the drug could be modified without altering its effectiveness.

    “We now have some idea that when the drug binds with the ribosome, a global change occurs in the ribosome that might actually be important for the function of the antibiotic and the sensitivity of the ribosome,” Ricci said.

    Refining the jigsaw pieces

    In the next phase of experiments, DeMirci hopes to design a setup in which the antibiotics aren’t introduced until the last second before the ribosome is imaged so that they can watch as it binds to the ribosome, rather than just taking images before and after.

    Up to this point, Ricci said, his group had been doing drug synthesis with very little information or insight into how the antibiotic interacts with the ribosome.

    “What this paper and overall collaboration allow is a direct investigation of the drug-ribosome interaction,” he said. “It’s like having more defined pieces to the jigsaw puzzle. You don’t have to guess about what’s happening.”

    Developing antibiotics that can fight off drug-resistant bacteria with minimal side effects is essential because the rise of antibiotic resistant strains is currently the biggest threat to modern medicine, DeMirci said.

    “Every year more than a million people die from tuberculosis and nearly half a million are HIV positive,” he said. “People don’t usually die from HIV or cancer, they die because their immune system is suppressed and they can’t fight off bacterial infections. That’s when you need antibiotics. But what if you don’t have one that’s effective against the resistant strains? That’s exactly what’s happening right now. This research can help us make informed decisions when designing the next generation of drugs.”

    The research team included scientists from LCLS; SSRL; SLAC’s Biosciences Division; the Stanford PULSE Institute; and the Stanford School of Medicine.

    See the full article here .


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    Please help promote STEM in your local schools.

    Stem Education Coalition

    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.

     
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