The deacylase sirtuin 5 reduces malonylation in nonmitochondrial metabolic pathways in diabetic kidney disease.

Early diabetic kidney disease (DKD) is marked by dramatic metabolic reprogramming due to nutrient excess, mitochondrial dysfunction, and increased renal energy requirements from hyperfiltration. We hypothesized that changes in metabolism in DKD may be regulated by Sirtuin 5 (SIRT5), a deacylase that removes posttranslational modifications derived from acyl-coenzyme A and has been demonstrated to regulate numerous metabolic pathways. We found decreased malonylation in the kidney cortex (∼80% proximal tubules) of type 2 diabetic BKS db/db mice, associated with increased SIRT5 expression. We performed a proteomics analysis of malonylated peptides and found that proteins with significantly decreased malonylated lysines in the db/db cortex were enriched in nonmitochondrial metabolic pathways: glycolysis and peroxisomal fatty acid oxidation. To confirm relevance of these findings in human disease, we analyzed diabetic kidney transcriptomic data from a cohort of Southwestern American Indians, which revealed a tubulointerstitial-specific increase in Sirt5 expression. These data were further corroborated by immunofluorescence data of SIRT5 from nondiabetic and DKD cohorts. Furthermore, overexpression of SIRT5 in cultured human proximal tubules demonstrated increased aerobic glycolysis. Conversely, we observed reduced glycolysis with decreased SIRT5 expression. These findings suggest that SIRT5 may lead to differential nutrient partitioning and utilization in DKD. Taken together, our findings highlight a previously unrecognized role for SIRT5 in metabolic reprogramming in DKD.

[Effects of metabolites of mangrove fungus Xylaria sp. from South China Sea Coast on the activity of acetylcholinesterase in vitro].

OBJECTIVE: To investigate the effects of metabolites of mangrove fungus Xylaria sp. from South China Sea Coast, xyloketal A-D, on the activity of acetylcholinesterase (AChE) in vitro. METHODS: Activity of AChE was determined by a modified method of Ellmen. The selectivity of the compounds for AChE and butyrylcholinesterase (BuChE) was also tested and compared with that of a positive control, velnacrine. The inhibitory properties of xylokets on AChE were characterized as well. RESULTS: AChE activity was inhibited by xyloketal A-D in a dose-dependent manner, their IC50 were determined to be 29.9, 137.4, 109.3 and 425.6 micromol/L, respectively. At the same time, velnacrine and all the four compounds showed inhibitory effects on BuChE in different degree, and the inhibitory activity of xyloketals on AChE was found to be reversible and noncompetitive. CONCLUSION: Xyloketal A-D can inhibit AChE as well as BuChE activity in vitro. So xyloketal A-D were likely considered as drug candidates against Alzheimer' s disease (AD) for further development.