Structure and function of lipid A-modifying enzymes

Ann N Y Acad Sci. 2020 Jan;1459(1):19-37. doi: 10.1111/nyas.14244. Epub 2019 Sep 25.


Lipopolysaccharides are complex molecules found in the cell envelop of many Gram-negative bacteria. The toxic activity of these molecules has led to the terminology of endotoxins. They provide bacteria with structural integrity and protection from external environmental conditions, and they interact with host signaling receptors to induce host immune responses. Bacteria have evolved enzymes that act to modify lipopolysaccharides, particularly the lipid A region of the molecule, to enable the circumvention of host immune system responses. These modifications include changes to lipopolysaccharide by the addition of positively charged sugars, such as N-Ara4N, and phosphoethanolamine (pEtN). Other modifications include hydroxylation, acylation, and deacylation of fatty acyl chains. We review the two-component regulatory mechanisms for enzymes that carry out these modifications and provide details of the structures of four enzymes (PagP, PagL, pEtN transferases, and ArnT) that modify the lipid A portion of lipopolysaccharides. We focus largely on the three-dimensional structures of these enzymes, which provide an understanding of how their substrate binding and catalytic activities are mediated. A structure-function-based understanding of these enzymes provides a platform for the development of novel therapeutics to treat antibiotic resistance.

Keywords: ArnT; PagL; PagP; antibiotics; bacteria; lipid A modification; multidrug resistance; pEtN transferase; structure-function.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Acyltransferases / chemistry
  • Acyltransferases / metabolism
  • Animals
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism
  • Carboxylic Ester Hydrolases / chemistry
  • Carboxylic Ester Hydrolases / metabolism
  • Escherichia coli Proteins / chemistry
  • Escherichia coli Proteins / metabolism
  • Humans
  • Lipid A / chemistry*
  • Lipid A / metabolism*
  • Methyltransferases / chemistry
  • Methyltransferases / metabolism
  • Protein Structure, Secondary
  • Protein Structure, Tertiary


  • Bacterial Proteins
  • Escherichia coli Proteins
  • Lipid A
  • Methyltransferases
  • phosphoethanolamine methyltransferase
  • Acyltransferases
  • PagP protein, E coli
  • Carboxylic Ester Hydrolases
  • PagL protein, Salmonella typhimurium