TY  - JOUR
A1  - Eisenberg, Philip
A1  - Albert, Leon
A1  - Teuffel, Jonathan
A1  - Zitzow, Eric
A1  - Michaelis, Claudia
A1  - Jarick, Jane
A1  - Sehlke, Clemens
A1  - Große, Lisa
A1  - Bader, Nicole
A1  - Nunes-Alves, Ariane
A1  - Kreikemeyer, Bernd
A1  - Schindelin, Hermann
A1  - Wade, Rebecca C.
A1  - Fiedler, Tomas
T1  - The Non-phosphorylating Glyceraldehyde-3-Phosphate Dehydrogenase GapN Is a Potential New Drug Target in Streptococcus pyogenes
T2  - Frontiers in Microbiology
N2  - The strict human pathogen Streptococcus pyogenes causes infections of varying severity, ranging from self-limiting suppurative infections to life-threatening diseases like necrotizing fasciitis or streptococcal toxic shock syndrome. Here, we show that the non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase GapN is an essential enzyme for S. pyogenes. GapN converts glyceraldehyde 3-phosphate into 3-phosphoglycerate coupled to the reduction of NADP to NADPH. The knock-down of gapN by antisense peptide nucleic acids (asPNA) significantly reduces viable bacterial counts of S. pyogenes laboratory and macrolide-resistant clinical strains in vitro. As S. pyogenes lacks the oxidative part of the pentose phosphate pathway, GapN appears to be the major NADPH source for the bacterium. Accordingly, other streptococci that carry a complete pentose phosphate pathway are not prone to asPNA-based gapN knock-down. Determination of the crystal structure of the S. pyogenes GapN apo-enzyme revealed an unusual cis-peptide in proximity to the catalytic binding site. Furthermore, using a structural modeling approach, we correctly predicted competitive inhibition of S. pyogenes GapN by erythrose 4-phosphate, indicating that our structural model can be used for in silico screening of specific GapN inhibitors. In conclusion, the data provided here reveal that GapN is a potential target for antimicrobial substances that selectively kill S. pyogenes and other streptococci that lack the oxidative part of the pentose phosphate pathway.
KW  - X-ray crystallography
KW  - homology modeling
KW  - computational docking
KW  - PNA (peptide nucleic acid)
KW  - NADPH
KW  - drug target
KW  - GapN
Y1  - 2022
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/26286
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-262869
SN  - 1664-302X
VL  - 13
ER  -