Abstract
BackgroundCoxiella burnetii is Gram-negative bacterium responsible for the zoonosis Q-fever. While it has an obligate intracellular growth habit, it is able to persist for extended periods outside of a host cell and can resist environmental conditions that would be lethal to most prokaryotes. It is these extracellular bacteria that are the infectious stage encountered by eukaryotic hosts. The intracellular form has evolved to grow and replicate within acidified parasitophorous vacuoles. The outer coat of C. burnetii comprises a complex lipopolysaccharide (LPS) component that includes the unique methylated-6-deoxyhexose, virenose. Although potentially important as a biomarker for C. burnetii, the pathway for its biosynthesis remains obscure.ResultsThe 6-deoxyhexoses constitute a large family integral to the LPS of many eubacteria. It is believed that precursors of the methylated-deoxyhexoses traverse common early biosynthetic steps as nucleotide-monosaccharides. As a prelude to a full biosynthetic characterization, we present herein the results from bioinformatics-based, proteomics-supported predictions of the pathway for virenose synthesis. Alternative possibilities are considered which include both GDP-mannose and TDP-glucose as precursors.ConclusionWe propose that biosynthesis of the unique C. burnetii biomarker, virenose, involves an early pathway similar to that of other C-3’-methylated deoxysugars which then diverges depending upon the nucleotide-carrier involved. The alternatives yield either the D- or L-enantiomers of virenose. Both pathways require five enzymatic steps, beginning with either glucose-6-phosphate or mannose-6-phosphate. Our in silico results comprise a model for virenose biosynthesis that can be directly tested. Definition of this pathway should facilitate the development of therapeutic agents useful for treatment of Q fever, as well as allowing improvements in the methods for diagnosing this highly infectious disease.
Highlights
Coxiella burnetii is Gram-negative bacterium responsible for the zoonosis Q-fever
The monosaccharideprecursors are activated to one of four nucleosidediphosphate carriers (NDP); adenosine diphosphate (ADP), thymidine diphosphate (TDP), guanosine diphosphate (GDP), or uridine diphosphate (UDP) [22,25] that are exchanged in the final step by an enzyme which transfers the sugar to a lipid carrier, forming the Opolysaccharide unit
The 6-deoxyhexoses can be synthesized from D-glucose-6-phosphate which is a precursor for the biosynthesis of the TDP, CDP and UDP-sugars, or fructose-6-phosphate which is converted to mannose6-phosphate and serves as precursor of the GDP-sugars [22,23,25]
Summary
Coxiella burnetii is Gram-negative bacterium responsible for the zoonosis Q-fever While it has an obligate intracellular growth habit, it is able to persist for extended periods outside of a host cell and can resist environmental conditions that would be lethal to most prokaryotes. The outer coat of virulent phase I C. burnetii isolates, from natural sources or infections, is critical to evading the host immune system and include full-length lipopolysaccharides (LPS). It includes an O-antigen containing two unique sugars, virenose (6-deoxy-3-C-methyl-D-gulose) and dihydrohydroxystreptose (3-C-(hydroxymethyl) lyxose). The results from sequence analyses indicate that a group of LPS-biosynthetic genes, including genes that encode epimerases, dehydratases, and nucleotide-sugar glycosyltransferases, are part of the deleted segment [14,20]
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