Putting enzymes on pause: structural prediction and biochemical characterization of Alternaria Alternata Cdc14 phosphatase for antifungal inhibitor design
Elaab Tsegaye
Since the United Nations World Food Program’s (WFP) creation in 1963, hunger has never reached such devastating highs (World Food Program USA, 2024). Up to 350 million people globally endure the harshest forms of famine, with each statistic representing real individuals suffering from the grave impacts of acute hunger, including wasting, stunting, underweight conditions, and micronutrient deficiencies (World Health Organization, 2022). Malnourished mothers have malnourished newborns, perpetuating a cycle of hunger across generations, and these children face stunted physical and cognitive development, which propagates into long-term neurodevelopmental, cognitive, behavioural and mental health impairments (Kirolos et al., 2022). Farmers struggle to produce sufficient food to sustain their families and communities. It is expected that the issue of global food insecurity will continue rising exponentially as population size also escalates (United Nations, 2024). One of the most significant reasons why farmers struggle to produce enough food is that crops are afflicted by fungi, bacteria, viruses, insects, and other pathogens that drastically reduce yields. For example, in the 1840s, a plant infection caused the Irish potato famine (wassanalampech, 2024). The Great Famine began in 1845 when Phytophthora infestans , a destructive plant disease, spread rapidly throughout Ireland. The infestation led to the destruction of half of the potato crop that year, with over a million people dying of starvation, as well as forcing the mass migration of several million natives (History.com Editors, 2017). To this day, no effective treatment exists, and this consequently leads to ‘potato blight’ - a disease that causes the rotting of potatoes and results in $6 billion in damages per year (Keithly, 2000). This is just one of many crop diseases that pose persistent threats to our global food supply. Alternaria alternata is another fungal pathogen that can cause disease in a wide range of crops, including potatoes, apples, pears, and citrus fruits. It primarily leads to black rot, characterized by dark, decayed spots on fruit, and a significant decrease in crop yield. In the late 19th and early 20th centuries, early blight caused by A. alternata became a substantial problem for tomato and potato farmers in the United States (Schmey et al., 2024). The disease typically manifests during warm and humid seasons, resulting in a drastic reduction in yield. Historical accounts from agricultural extension services often highlighted the struggle of managing early blight, which led to significant research into resistant varieties and improved fungicide treatments. However, this approach was unsuccessful, as there is no known fungicide to combat this pathogenic fungus. A new antifungal target, Gene X, was discovered in a genetic screen and found in pathogenic fungi. Gene X is required for the fungal infection of wheat by F. graminearum , corn by F. graminearum , and rice by M. oryzae (Mocciaro and Schiebel, 2010). When a plant is a carrier of Gene X and becomes infected, it can become decoloured due to the damage to its chlorophyll, leading to stunted growth and ultimately the
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