Bioactivity-guided identification of botanical inhibitors of ketohexokinase

The excessive consumption of added sugars is epidemiologically associated with rising prevalence of obesity, metabolic syndrome, and cardiovascular diseases in the United States. As a major constituent of added sugars, fructose has been shown to cause a variety of adverse metabolic effects, such as impaired insulin sensitivity, hypertriglyceridemia, and oxidative stress. Recent studies have shown that ketohexokinase isoform C (KHKC) is the key enzyme responsible in fructose metabolism that drive's fructose's adverse effects. The primary objective of this study was to identify botanicals with inhibitory activity against KHKC. Extracts from 406 botanicals were screened initially at 50 µg/mL for their inhibitory activity using a cell free, recombinant human KHKC assay. Dose response evaluations were conducted on botanical extracts that inhibited KHKC by ≥30%. Angelica archangelica, Garcinia mangostana, Petroselinum crispum, and Scutellaria baicalensis were the top four botanical candidiates identified with inhibitory activity against KHKC and prevented fructose-induced ATP depletion and elevation in triglyceride and uric acid production.