βA1-crystallin regulates glucose metabolism and mitochondrial function in mouse retinal astrocytes by modulating PTP1B activity

AbstractβA3/A1-crystallin, a lens protein that is also expressed in astrocytes, is produced as βA3 and βA1-crystallin isoforms by leaky ribosomal scanning. In a previous human proteome high-throughput array, we found that βA3/A1-crystallin interacts with protein tyrosine phosphatase 1B (PTP1B), a key regulator of glucose metabolism. This prompted us to explore possible roles of βA3/A1-crystallin in metabolism of retinal astrocytes. We found that βA1-crystallin acts as an uncompetitive inhibitor of PTP1B, but βA3-crystallin does not. Loss of βA1-crystallin in astrocytes triggers metabolic abnormalities and inflammation. In CRISPR/cas9 gene-edited βA1-knockdown (KD) mice, but not in βA3-knockout (KO) mice, the streptozotocin (STZ)-induced diabetic retinopathy (DR)-like phenotype is exacerbated. Here, we have identified βA1-crystallin as a regulator of PTP1B; loss of this regulation may be a new mechanism by which astrocytes contribute to DR. Interestingly, proliferative diabetic retinopathy (PDR) patients showed reduced βA1-crystallin and higher levels of PTP1B in the vitreous humor.

Salmonella enterica’s “Choice”: Itaconic Acid Degradation or Bacteriocin Immunity Genes

Itaconic acid is an immunoregulatory metabolite produced by macrophages in response to pathogen invasion. It also exhibits antibacterial activity because it is an uncompetitive inhibitor of isocitrate lyase, whose activity is required for the glyoxylate shunt to be operational. Some bacteria, such as Yersinia pestis, encode enzymes that can degrade itaconic acid and therefore eliminate this metabolic inhibitor. Studies, primarily with Salmonella enterica subspecies enterica serovar Typhimurium, have demonstrated the presence of similar genes in this pathogen and the importance of these genes for the persistence of the pathogen in murine hosts. This minireview demonstrates that, based on Blast searches of 1063 complete Salmonella genome sequences, not all Salmonella serovars possess these genes. It is also shown that the growth of Salmonella isolates that do not possess these genes is sensitive to the acid under glucose-limiting conditions. Interestingly, most of the serovars without the three genes, including serovar Typhi, harbor DNA at the corresponding genomic location that encodes two open reading frames that are similar to bacteriocin immunity genes. It is hypothesized that these genes could be important for Salmonella that finds itself in strong competition with other Enterobacteriacea in the intestinal tract—for example, during inflammation.

New Leishmania donovani nucleoside hydrolase inhibitors from Brazilian flora

This study presents flavonoids as new inhibitors of the nucleoside hydrolase from Leishmania donovani (LdNH) and the first uncompetitive inhibitor described for LdNH.

Methylation of E. coli Class I Release Factors Increases the Accuracy of Translation Termination in vitro

ABSTRACTRibosomal protein synthesis (translation) is a highly accurate process. Translation termination, in particular, must be accurate to prevent truncated proteins. How this accuracy is achieved is not fully understood in all its details. Using an E. coli in vitro system, I explore novel mechanisms that contribute to the high accuracy of translation termination. By comparing the Michaelis-Menten parameters of methylated and non-methylated release factors on cognate and non-cognate codons. Post-translational methylation of a strictly conserved GGQ motif in class I release factors increases the accuracy of termination by up to 5-fold. This happens by increasing both the maximum rate of peptide release (kcat) and Michaelis-Menten constant (KM). Further, I demonstrate here that a non-methylated release factor acts like an uncompetitive inhibitor of enzyme reactions. Overall, this study shows that the methylation of class I release factors is a novel mechanism contributing to highly accurate translation termination.AbbreviationsRFrelease factorRCrelease complex

α-Glucosidase and α-Amylase Inhibitory Compounds from three African Medicinal Plants: An Enzyme Inhibition Kinetics Approach

The quest to find new lead compounds with anti-diabetic effects via the inhibition of α-glucosidase and α-amylase had led us to conduct bioassay guided isolation of three African medicinal plants which resulted in the identification of bicyclo[2.2.0]hexane-2,3,5-triol (1), 3β- O-acetyl betulinic acid (2) and 2,7-dihydroxy-4 H-1-benzopyran-4-one (3), as the bioactive compounds. The compounds demonstrated a significant (P < 0.05) inhibitory effect on α-glucosidase and α-amylase activities than acarbose. Steady state kinetic analysis revealed that compounds 1 and 2 inhibited both α-amylase and α-glucosidase in non-competitive patterns whilst compound 3 was an uncompetitive inhibitor of α-glucosidase and a non-competitive inhibitor of α-amylase. In conclusion, the study has identified three new active α-glucosidase and α-amylase inhibitory compounds that could have the potential to retard postprandial hyperglycemia.