{"id":13097,"date":"2019-11-06T13:01:48","date_gmt":"2019-11-06T18:01:48","guid":{"rendered":"https:\/\/biology.mit.edu\/?page_id=13097"},"modified":"2022-01-23T19:51:52","modified_gmt":"2022-01-24T00:51:52","slug":"news-brief-mysterious-metabolite-ppapp","status":"publish","type":"page","link":"https:\/\/biology.mit.edu\/news\/news-brief-mysterious-metabolite-ppapp\/","title":{"rendered":"News Brief: New toxin impedes bacterial growth"},"content":{"rendered":"<p><img loading=\"lazy\" decoding=\"async\" class=\" wp-image-13107 aligncenter\" src=\"https:\/\/biology.mit.edu\/wp-content\/uploads\/2019\/10\/ppApp7-300x144.jpg\" alt=\"\" width=\"1008\" height=\"484\" srcset=\"https:\/\/biology.mit.edu\/wp-content\/uploads\/2019\/10\/ppApp7-300x144.jpg 300w, https:\/\/biology.mit.edu\/wp-content\/uploads\/2019\/10\/ppApp7-768x368.jpg 768w, https:\/\/biology.mit.edu\/wp-content\/uploads\/2019\/10\/ppApp7-391x187.jpg 391w, https:\/\/biology.mit.edu\/wp-content\/uploads\/2019\/10\/ppApp7-598x286.jpg 598w, https:\/\/biology.mit.edu\/wp-content\/uploads\/2019\/10\/ppApp7-420x201.jpg 420w\" sizes=\"(max-width: 1008px) 100vw, 1008px\" \/><\/p>\n<h2><strong>Researchers discover a new toxin that impedes bacterial growth<\/strong><\/h2>\n<h3>Raleigh McElvery<\/h3>\n<p>&nbsp;<\/p>\n<p>An international research collaboration has discovered a new toxin, which bacteria inject into their neighboring cells to hinder growth and compete for limited resources. Their findings <a href=\"https:\/\/www.nature.com\/articles\/s41586-019-1735-9\" target=\"_blank\" rel=\"noopener noreferrer\">were published<\/a> on November 6 in <em>Nature<\/em>.<\/p>\n<p>At McMaster University in Ontario, Canada, co-senior author John Whitney and his team were studying a secretion system that allows bacteria to deliver these deleterious molecules, when they came across a new toxin. This toxin was an enzyme, and one they had never seen before. Based on their structural analyses, it looked a lot like the enzymes that synthesize guanosine tetra- and penta-phosphate, collectively known as \u201c(p)ppGpp.\u201d (p)ppGpp is a signaling molecule that helps bacteria safely dial down their growth rate in response to starvation. Suspecting the toxin might produce (p)ppGpp in recipient cells and ultimately impact their growth, the McMaster team shared their findings with <a href=\"https:\/\/biology.mit.edu\/profile\/michael-t-laub\/\">Michael Laub<\/a>, a professor of biology at MIT and a Howard Hughes Medical Institute investigator.<\/p>\n<figure id=\"attachment_13115\" aria-describedby=\"caption-attachment-13115\" style=\"width: 397px\" class=\"wp-caption alignleft\"><img loading=\"lazy\" decoding=\"async\" class=\" wp-image-13115\" src=\"https:\/\/biology.mit.edu\/wp-content\/uploads\/2019\/10\/Pseudomonas-232x300.jpg\" alt=\"\" width=\"397\" height=\"513\" srcset=\"https:\/\/biology.mit.edu\/wp-content\/uploads\/2019\/10\/Pseudomonas-232x300.jpg 232w, https:\/\/biology.mit.edu\/wp-content\/uploads\/2019\/10\/Pseudomonas-768x995.jpg 768w, https:\/\/biology.mit.edu\/wp-content\/uploads\/2019\/10\/Pseudomonas-791x1024.jpg 791w, https:\/\/biology.mit.edu\/wp-content\/uploads\/2019\/10\/Pseudomonas-144x187.jpg 144w, https:\/\/biology.mit.edu\/wp-content\/uploads\/2019\/10\/Pseudomonas-221x286.jpg 221w, https:\/\/biology.mit.edu\/wp-content\/uploads\/2019\/10\/Pseudomonas-212x275.jpg 212w, https:\/\/biology.mit.edu\/wp-content\/uploads\/2019\/10\/Pseudomonas.jpg 800w\" sizes=\"(max-width: 397px) 100vw, 397px\" \/><figcaption id=\"caption-attachment-13115\" class=\"wp-caption-text\">Researchers identified Tas1 in Pseudomonas aeruginosa bacteria. Credit: U.S. Centers for Disease Control and Prevention &#8211; Medical Illustrator.<\/figcaption><\/figure>\n<p>Boyuan Wang, a postdoc in the <a href=\"https:\/\/www.laublab.mit.edu\/\" target=\"_blank\" rel=\"noopener noreferrer\">Laub lab<\/a> who specializes in (p)ppGpp synthesis, examined the unknown enzyme&#8217;s activity to\u00a0determine its product. He soon realized that, rather than making (p)ppGpp, this enzyme was instead producing related molecules, adenosine tetraphosphate and adenosine pentaphosphate, collectively referred to as (p)ppApp. Somehow, (p)ppApp production was hindering growth.<\/p>\n<p>\u201cScientists have known about (p)ppApp for decades, but it\u00a0hadn&#8217;t been shown to have a physiological role in organisms until now,\u201d says Wang, a co-first author. Researchers had previously speculated that (p)ppApp was merely a non-specific product generated during (p)ppGpp synthesis, so it was surprising to find an enzyme that made it specifically.<\/p>\n<p>The researchers named their enzyme Tas1, and determined that it uses the cell\u2019s main energy currency, ATP, and its precursor, ADP, to produce (p)ppApp. In fact, one molecule of Tas1 was enough to consume 180,000 molecules of ATP per minute \u2014 two orders of magnitude faster than the fastest known (p)ppGpp synthetases work to make (p)ppGpp. Using metabolomic analyses, the MIT group showed that this exceptional rate of (p)ppApp production requires so much energy that there\u2019s not enough left to carry out essential cellular processes, effectively killing the bacterium.<\/p>\n<p>\u201cBacteria can inject only one Tas1 molecule at a time, and yet the toxin has such a powerful impact on its target, depleting the ATP supply in a matter of minutes,\u201d Wang says. \u201cThe secretion system is kind of like a miniaturized intercontinental ballistic missile in terms of its structure and impact, except it functions \u2018intercompartmentally\u2019 between two bacteria.\u201d<\/p>\n<p>\u201cIt\u2019s amazing that the first (p)ppApp synthase ever discovered actually serves as a novel, and quite clever, means of killing another cell,\u201d says Laub, a co-senior author. \u201cFindings like these really highlight the diversity of mechanisms that bacteria use to inhibit each other\u2019s growth.\u201d<\/p>\n<p>Tas1, the researchers believe, may augment other known toxins that bacteria inject into one another to hinder cell growth, including those that work in the cytoplasm or target the cell envelope.<\/p>\n<p>As a biochemist, Wang is excited by the prospect of using Tas1 as a tool in future experiments to deplete ATP, and probe the networks of metabolic regulation within bacteria and higher organisms.<\/p>\n<p>\u201cIt\u2019s fascinating to uncover the strategies nature uses to repurpose proteins,\u201d Wang says. \u201cBefore this study, we wouldn\u2019t have considered the possibility that a member of this protein family could be used as a deadly toxin.\u201d<\/p>\n<h5>Image: Tas1, a newly discovered enzyme, has a similar structure to the widespread bacterial Rel proteins that produce (p)ppGpp to promote survival during starvation. Tas1 alters its specificity to quickly produce large amounts of (p)ppApp, serving as a toxin in <em>Pseudomonas aeruginosa<\/em> and killing competing bacteria. Credit: Boyuan Wang.<\/h5>\n<p><strong>Citation:<br \/>\n<\/strong>&#8220;An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp&#8221;<br \/>\n<i>Nature, <\/i>online November 6, 2019, DOI: <a href=\"https:\/\/www.nature.com\/articles\/s41586-019-1735-9\" target=\"_blank\" rel=\"noopener noreferrer\">10.1038\/s41586-019-1735-9<\/a><br \/>\nShehryar Ahmad, Boyuan Wang, Matthew D. Walker, Hiu-Ki R. Tran, Peter J. Stogios, Alexei Savchenko, Robert A. Grant, Andrew G. McArthur, Michael T.\u00a0 Laub, and John C. Whitney<\/p>\n<h5>Posted: 10.7.19<\/h5>\n","protected":false},"excerpt":{"rendered":"<p>Researchers discover a new toxin that impedes bacterial growth Raleigh McElvery &nbsp; An international research collaboration has discovered a new toxin, which bacteria inject into their neighboring cells to hinder growth and compete for limited resources. Their findings were published on November 6 in Nature. At McMaster University in Ontario, Canada, co-senior author John Whitney [&hellip;]<\/p>\n","protected":false},"author":16,"featured_media":0,"parent":83,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":""},"class_list":["post-13097","page","type-page","status-publish","hentry"],"acf":[],"yoast_head":"\n<title>News Brief: New toxin impedes bacterial growth - MIT Department of Biology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/biology.mit.edu\/news\/news-brief-mysterious-metabolite-ppapp\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"News Brief: New toxin impedes bacterial growth\" \/>\n<meta property=\"og:description\" content=\"Researchers discover a new toxin that impedes bacterial growth Raleigh McElvery &nbsp; An international research collaboration has discovered a new toxin, which bacteria inject into their neighboring cells to hinder growth and compete for limited resources. Their findings were published on November 6 in Nature. 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