GTP Preference of d-Glycero-α-d-manno-Heptose-1-Phosphate Guanylyltransferase from Yersinia pseudotuberculosis

Abstract

d-glycero-α-d-manno-heptose-1-phosphate guanylyltransferase (HddC) is the fourth enzyme synthesizing a building component of lipopolysaccharide (LPS) of Gram-negative bacteria. Since HddC is a potential new target to develop antibiotics, the analysis of the structural and functional relationship of the complex structure will lead to a better idea to design inhibitory compounds. X-ray crystallography and biochemical experiments to elucidate the guanine preference were performed based on the multiple sequence alignment. The crystal structure of HddC from Yersinia pseudotuberculosis (YPT) complexed with guanosine 5′-(β-amino)-diphosphate (GMPPN) has been determined at 1.55 Å resolution. Meanwhile, the mutants revealed their reduced guanine affinity, instead of acquiring noticeable pyrimidine affinity. The complex crystal structure revealed that GMPPN is docked in the catalytic site with the aid of Glu80 positioning on the conserved motif EXXPLGTGGA. In the HddC family, this motif is expected to recruit nucleotides through interacting with bases. The crystal structure shows that oxygen atoms of Glu80 forming two hydrogen bonds play a critical role in interaction with two nitrogen atoms of the guanine base of GMPPN. Interestingly, the binding of GMPPN induced the formation of an oxyanion hole-like conformation on the L(S/A/G)X(S/G) motif and consequently influenced on inducing a conformational shift of the region around Ser55.

Porphyromonas gingivalis induces entero-hepatic metabolic derangements with alteration of gut microbiota in a type 2 diabetes mouse model

“…In addition, consistent with previous reports 35 , Pg treatment reduced glycogen storage in the liver of db / db mice, indicating that the treatment reduced glucose incorporation into glycogen. However, such changes in the levels of hepatic glucose metabolites could be induced by increased plasma insulin-counter regulatory hormone levels 29 , 36 , which were not extensively measured in the present study. FOXO1 mRNA expression is increased in the cultured gingival epithelial cells treated with Pg 37 .…”

“…4 e). Obese type 2 diabetes model mice extensively exhibit insulin resistance and hyperglycemia 29 , 30 . Based on the insulin tolerance test (ITT), db / db diabetic mice in both Pg- and CMC-treated groups were equally insulin resistant 31 , 32 , because of an impaired reduction in the plasma glucose levels at 30–60 min after insulin loading.…”

Exosomes derived from pioglitazone-pretreated MSCs accelerate diabetic wound healing through enhancing angiogenesis

“…In addition, recent research has reported that pioglitazone can increase cellular proliferation and promote VEGF and collagen production in MSCs. They also found that pioglitazone improved the therapeutic effects of MSCs on tendon repair [ 52 ]. In this research, our results revealed that PGZ-Exos significantly improved the biological function of HUVECs including their proliferation, migration, tube formation, and overall wound healing effects which were damaged by HG in vitro.…”

IDH1 mutant glioma is preferentially sensitive to the HDAC inhibitor panobinostat

“…One study that did include 10 IDH1 mut astrocytoma patients was inconclusive, perhaps in part because of a reliance on historical controls, and an exclusive focus on recurrent cases that had already been treated with standard therapy [ 39 ]. A recent study by others suggested that IDH1 mut gliomas were actually more resistant to HDACi [ 40 ]; however, that study used overexpression of IDH1 R132H in U87MG and U373MG glioblastoma cells. Our data demonstrate the importance of using patient-derived models, with endogenous IDH1 mut , when studying therapeutics aimed at altering the epigenome and/or chromatin.…”