Structure and Function of Prokaryotic UDP-Glucose Pyrophosphorylase, A Drug Target Candidate

Abstract

UDP-glucose is an essential metabolite for a variety of processes in the cell physiology in all organisms. In prokaryotes, it is involved in the synthesis of trehalose, an osmoprotectant, in galactose utilization via the Leloir pathway and it plays a key role in the synthesis of the components of the bacterial envelope, particularly the lipopolysaccharide and the capsule, which represent necessary virulence factors of many bacterial pathogens. UDP-glucose is synthesized in bacteria by the prokaryotic UDP-glucose pyrophosphorylase (UGP, EC 2.7.7.9), an enzyme belonging to the family of sugar:nucleotidyl transferases. Despite the ubiquitous distribution of UGP activity in all domains of life, prokaryotic UGPs are evolutionarily unrelated to their eukaryotic counterparts. Taken together, these features make of bacterial UGP an attractive target candidate for the discovery and development of new generation antibiotics.This review summarizes the current knowledge on structure and function of bacterial UGPs, underlying their potential as drug target candidates.

Depletion of UDP-Glucose and UDP-Galactose Using a Degron System Leads to Growth Cessation of Leishmania major

“…One of the most distinctive roles of UDP-Glc and derived nucleotide sugars is the biosynthesis of polysaccharides and glycoconjugates forming the cell surface coat. In bacteria, UGP controls the biosynthesis of the most important virulence factors and is valued as antibacterial target since it is frequently essential for pathogenicity or growth [ 27 ]. Similarly, in the trypanosomatid parasites Trypanosoma brucei and Trypanosoma cruzi , which are closely related to Leishmania , biosynthesis of UDP-Glc is essential for parasite growth.…”

Crystal structure of UDP-glucose pyrophosphorylase fromYersinia pestis, a potential therapeutic target against plague

“…observed for other bacterial UGPs [ Fig. 1(a)] (Berbís et al, 2015;Thoden & Holden, 2007a). Each chain in the tetramer is structurally very similar to the others, with aligned r.m.s.d values ranging from 0.2 to 0.4 Å .…”

“…Structural studies using X-ray crystallography have revealed that many of these bacterial UGPs share a very similar three-dimensional structure in which the enzyme crystallizes as a tetramer, with each monomer consisting of a central mixed -sheet that is surrounded by -helices (Berbís et al, 2015). Efforts to screen for inhibitors of S. pneumoniae UGP identified a functional assay that has yielded initial compounds that display inhibitory activity, but to date no other inhibitors of bacterial UGPs have been reported (Zavala et al, 2017;Berbís et al, 2015). Here, we describe the first crystal structure of UGP from Y. pestis, which may be useful in efforts to develop inhibitors of this enzyme.…”

“…In fact, no recognizable sequence similarity exists between human and Y. pestis UGPs. The significant sequence differences make bacterial UGPs attractive drug targets for specifically inhibiting the pathogenic enzyme in human hosts while avoiding off-target effects (Berbís et al, 2015).…”

Phenotypic characteristics contributing to the enhanced growth ofEscherichia colibloom strains

“…The capsule synthesis regulator rcsB is implicated in the activation of ftsZ which is involved in forming the cell division apparatus in E. coli (Gervais et al ., ; Carballès et al ., ), and this might yield higher growth rates. Furthermore, the capsule core gene product GalF via its interaction with GalU, leads to increased cellular levels of uridine diphosphate (UDP)–glucose (Marolda and Valvano, ), which is a precursor for carbohydrate biosynthesis and hence may lead to the production of energy (Marolda and Valvano, ; Berbís et al ., ; Ebrecht et al ., ). Structurally, the Klebsiella capsule is thicker (160 nm) than the E. coli K1 capsule which is less than 10 nm in thickness, and the Klebsiella capsule has a denser arrangement of fine fibres compared with the E. coli K1 capsule (Amako et al ., ).…”