Structure and mechanism of TagA, a novel membrane-associated glycosyltransferase that produces wall teichoic acids in pathogenic bacteria

• Published in: PLoS pathogens Vol. 15; no. 4; p. e1007723
• Main Authors: Kattke, Michele D, Gosschalk, Jason E, Martinez, Orlando E, Kumar, Garima, Gale, Robert T, Cascio, Duilio, Sawaya, Michael R, Philips, Martin, Brown, Eric D, Clubb, Robert T
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.04.2019; Public Library of Science (PLoS)
• Subjects: Acids; Amides; Antibiotics; Bacteria; Bacterial physiology; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; BASIC BIOLOGICAL SCIENCES; Beta lactam antibiotics; Beta lactamases; Biochemistry; Biology and Life Sciences; Biosynthesis; Catalysis; Catalytic Domain; Cell membranes; Cell Wall - metabolism; Chemistry; Copolymers; Crystal structure; Crystallography, X-Ray; Dimers; Drug development; Enzymatic activity; Enzyme activity; Enzyme structure; Enzymes; Genomics; Glycerol; Glycopolymers; Glycosyltransferase; Glycosyltransferases; Gram-positive bacteria; Imipenem; Lactams; Lipids; Lipoproteins - chemistry; Lipoproteins - metabolism; Localization; Methicillin; Microorganisms; Models, Molecular; Novels; Pathogenic microorganisms; Phosphates; Physical Sciences; Polymers; Polysaccharides; Protein Multimerization; Protein Structure, Tertiary; Proteins; Proteomics; Saccharides; Staphylococcus aureus; Staphylococcus aureus - enzymology; Staphylococcus aureus infections; Staphylococcus infections; Substrates; Supervision; Surface active agents; Teichoic acids; Teichoic Acids - metabolism; β-Lactam antibiotics; Los Angeles California; Ontario Canada; California; United States > US
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007723

Staphylococcus aureus and other bacterial pathogens affix wall teichoic acids (WTAs) to their surface. These highly abundant anionic glycopolymers have critical functions in bacterial physiology and their susceptibility to β-lactam antibiotics. The membrane-associated TagA glycosyltransferase (GT) catalyzes the first-committed step in WTA biosynthesis and is a founding member of the WecB/TagA/CpsF GT family, more than 6,000 enzymes that synthesize a range of extracellular polysaccharides through a poorly understood mechanism. Crystal structures of TagA from T. italicus in its apo- and UDP-bound states reveal a novel GT fold, and coupled with biochemical and cellular data define the mechanism of catalysis. We propose that enzyme activity is regulated by interactions with the bilayer, which trigger a structural change that facilitates proper active site formation and recognition of the enzyme's lipid-linked substrate. These findings inform upon the molecular basis of WecB/TagA/CpsF activity and could guide the development of new anti-microbial drugs.