{"id":30593,"date":"2024-12-11T15:18:37","date_gmt":"2024-12-11T20:18:37","guid":{"rendered":"https:\/\/biology.mit.edu\/?p=30593"},"modified":"2024-12-11T16:05:30","modified_gmt":"2024-12-11T21:05:30","slug":"imperiali-lab-news-brief-combining-bioinformatics-and-biochemistry","status":"publish","type":"post","link":"https:\/\/biology.mit.edu\/imperiali-lab-news-brief-combining-bioinformatics-and-biochemistry\/","title":{"rendered":"Imperiali Lab News Brief: combining bioinformatics and biochemistry"},"content":{"rendered":"

New research from the Imperiali Lab in the Department of Biology at MIT combines bioinformatics and biochemistry to reveal critical players in assembling glycans, the large sugar molecules on bacterial cell surfaces responsible for behaviors such as evading immune responses and causing infections.<\/strong><\/p>\n

In most cases, single-celled organisms such as bacteria interact with their environment through complex chains of sugars known as glycans bound to lipids on their outer membranes. Glycans orchestrate biological responses and interactions, such as evading immune responses and causing infections.\u00a0<\/span><\/p>\n

The first step in assembling most bacterial glycans is the addition of a sugar-phosphate group onto a lipid, which is catalyzed by phosphoglycosyl transferases (PGTs) on the inner membrane. This first sugar is then further built upon by other enzymes in subsequent steps in an assembly-line-like pathway. These critical biochemical processes are challenging to explore because the proteins involved in these processes are embedded in membranes, which makes them difficult to isolate and study.\u00a0<\/span><\/p>\n

Although glycans are found in all living organisms, the sugar molecules that compose glycans are especially diverse in bacteria. There are over 30,000 known bacterial PGTs, and hundreds of sugars for them to act upon.\u00a0<\/span><\/p>\n

Research recently published in PNAS from the Imperiali Lab in the Department of Biology at MIT uses a combination of bioinformatics and biochemistry to predict clusters of \u201clike-minded\u201d PGTs and verify which sugars they will use in the first step of glycan assembly.\u00a0<\/span><\/p>\n

Defining the biochemical machinery for these assembly pathways could reveal new strategies for tackling antibiotic-resistant strains of bacteria. This comprehensive approach could also be used to develop and test inhibitors, halting the assembly pathway at this critical first step.\u00a0<\/span><\/p>\n

Exploring Sequence Similarity<\/b><\/h2>\n

First author Theo Durand, an undergraduate student from Imperial College London who studied at MIT for a year, worked in the Imperiali Lab as part of a research placement. Durand was first tasked with determining which sugars some PGTs would use in the first step of glycan assembly,<\/span> known as the sugar substrates<\/span> of the PGTs. When initially those substrate-testing experiments didn\u2019t work, Durand turned to the power of bioinformatics to develop predictive tools.\u00a0<\/span><\/p>\n

Strategically exploring the sugar substrates for PGTs is challenging due to the sheer number of PGTs and the diversity of bacteria, each with its own assorted set of glycans and glycoconjugates. To tackle this problem, Durand deployed a tool called a Sequence Similarity Network (SSN), part of a computational toolkit developed by the Enzyme Function Initiative.\u00a0<\/span><\/p>\n

According to senior author <\/span>Barbara Imperiali, Class of 1922 Professor of Biology and Chemistry<\/span><\/a>, an SSN provides a powerful way to analyze protein sequences through comparisons of the sequences of tens of thousands of proteins. In an optimized SSN, similar proteins cluster together, and, in the case of PGTs, proteins in the same cluster are likely to share the same sugar substrate.\u00a0<\/span><\/p>\n

For example, a previously uncharacterized PGT that appears in a cluster of PGTs whose first sugar substrate is FucNAc4N would also be predicted to use FucNAc4N. The researchers could then test that prediction to verify the accuracy of the SSN.\u00a0<\/span><\/p>\n

FucNAc4N is the sugar substrate for the PGT of <\/span>Fusobacterium nucleatum (F. nucleatum)<\/span><\/i>, a bacterium that is normally only present in the oral cavity but is correlated with certain cancers and endometriosis, and <\/span>Streptococcus pneumoniae<\/span><\/i>, a bacterium that causes pneumonia.\u00a0<\/span><\/p>\n

Adjusting the assay<\/b><\/h2>\n

The critical biochemical process of assembling glycans has historically been challenging to define, mainly because assembly is anchored to the interior side of the inner membrane of the bacterium. The purification process itself can be difficult, and the purified proteins don\u2019t necessarily behave in the same manner once outside their native membrane environment.<\/span><\/p>\n

To address this, the researchers modified a commercially available test to work with proteins still embedded in the membrane of the bacterium, thus saving them weeks of work to purify the proteins. They could then determine the substrate for the PGT by measuring whether there was activity. This first step in glycan assembly is chemically unique, and the test measures one of the reaction products.\u00a0<\/span><\/p>\n

For PGTs whose substrate was unknown, Durand did a deep dive into the literature to find new substrates to test. FucNAc4N, the first sugar substrate for <\/span>F. nucleatum,<\/span><\/i> was, in fact, Durand\u2019s favorite sugar \u2013 he found it in the literature and reached out to a former Imperiali Lab postdoc for the instructions and materials to make it.\u00a0<\/span><\/p>\n

\u201cI ended up down a rabbit hole where I was excited every time I found a new, weird sugar,\u201d Durand recalls with a laugh. \u201cThese bacteria are doing a bunch of really complicated things and any tools to help us understand what is actually happening is useful.\u201d\u00a0<\/span><\/p>\n

Exploring inhibitors<\/b><\/h2>\n

Imperiali noted that this research both represents a huge step forward in our understanding of bacterial PGTs and their substrates and presents a pipeline for further exploration. She\u2019s hoping to create a searchable database where other researchers can seed their own sequences into the SSN for their organisms of interest.\u00a0<\/span><\/p>\n

This pipeline could also reveal antibiotic targets in bacteria. For example, she says, the team is using this approach to explore inhibitor development.\u00a0<\/span><\/p>\n

The Imperiali lab worked with Karen Allen, a professor of Chemistry at Boston University, and graduate student Roxanne Siuda to test inhibitors, including ones for <\/span>F. nucleatum, <\/span><\/i>the bacterium correlated with certain cancers and endometriosis whose first sugar substrate is FucNAc4N. They are also hoping to obtain structures of inhibitors bound to the PGT to enable structure-guided optimization.<\/span><\/p>\n

\u201cWe were able to, using the network, discover the substrate for a PGT, verify the substrate, use it in a screen, and test an inhibitor,\u201d Imperiali says. \u201cThis is bioinformatics, biochemistry, and probe development all bundled together, and represents the best of functional genomics.\u201d <\/span><\/p>\n","protected":false},"excerpt":{"rendered":"

New research from the Imperiali Lab in the Department of Biology at MIT combines bioinformatics and biochemistry to reveal critical players in assembling glycans, the large sugar molecules on bacterial cell surfaces responsible for behaviors such as evading immune responses and causing infections. In most cases, single-celled organisms such as bacteria interact with their environment […]<\/p>\n","protected":false},"author":1783,"featured_media":30595,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[6224,6253,6212],"tags":[],"class_list":["post-30593","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-building-68-news-briefs","category-building-68-faculty-locations","category-news-briefs","placement-placement-homepage","research-area-biochemistry-biophysics-and-structural-biology","research-area-microbiology"],"acf":[],"yoast_head":"\nImperiali Lab News Brief: combining bioinformatics and biochemistry - 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\/imperiali-lab-news-brief-combining-bioinformatics-and-biochemistry\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Imperiali Lab News Brief: combining bioinformatics and biochemistry\" \/>\n<meta property=\"og:description\" content=\"New research from the Imperiali Lab in the Department of Biology at MIT combines bioinformatics and biochemistry to reveal critical players in assembling glycans, the large sugar molecules on bacterial cell surfaces responsible for behaviors such as evading immune responses and causing infections. 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