By David A. Cruz Walma, DPhil in Biomedical Sciences

Nothing ruins your morning appetite faster than the stench of spoiled milk as you open the refrigerator door to prepare breakfast. Yet, a fresh glass of cold milk, a heaping scoop of colourful ice cream, or a hearty tub of fruit-filled yogurt are sure to satisfy even the pickiest palates. How do these mouthwatering delicacies become inedible, and potentially poisonous, soups of primordial sludge? Milk and other dairy products are packed with proteins — think of the “Got Milk” ads showing athletes with milk moustaches. While these proteins help us become star athletes “like Mike” and build muscle after hard workouts, they are also responsible for the insulting smells and tastes associated with expired dairy. More specifically, the evildoers are groups of enzymes called “proteases” and “lipases.” In dairy products, proteases break down proteins to produce a lip-puckering bitter taste, and lipases break down fats to produce gag-inducing flavours. In case spoiled dairy isn’t horrific enough, imagine if mutations caused these proteases and lipases to work at an even faster rate — your milk would spoil before you return home from the grocery store! In contrast, imagine the possibilities if we could slow or even stop the function of these enzymes – milk that never curdles, ice cream with no expiration date, the ability to finish drinking the eggnog you left on your nightstand the evening prior! This ability to hijack a protein and modify its function requires a thorough understanding of how the protein behaves, both alone and with other interacting proteins.

Turning away from your glass of milk, the human body contains thousands of enzymes, each reacting with their own set of molecules to carry out millions of important biological reactions. My work focuses on a group of enzymes called “E3 ubiquitin ligases” or “E3s” which are well-known for their roles in targeted protein degradation. E3s act by tagging specific target proteins with a small molecule called “ubiquitin.” In most cases, the body will degrade any proteins labelled with ubiquitin, though other events can also occur as a result of ubiquitin-labelling. Imagine a quality assurance officer at Ben and Jerry’s ice cream factory ensuring each tub of ice cream meets the company’s strict standards. If a tub fails the quality assurance test, it is labeled for recycling and does not reach the supermarket shelves. E3 ubiquitin ligases are the body’s quality assurance officers — they ensure mutated and/or malfunctioning proteins are destroyed and recycled by the body.

Think back to the mutated enzymes wreaking havoc on your dairy products. In human disease, E3 ligases can be similarly mutated and no longer serve their critical roles. For example, when the E3 ubiquitin ligase CUL7 is mutated in humans, the result is a low birth weight dwarfism called “3M syndrome.” Comparable to modifying enzymes to prevent milk spoilage, scientists are hijacking E3 ligases using small molecules to create “targeted protein degraders” — E3 ligases that target specific proteins for degradation. As an example, one group of modified E3 ligases in clinical trials can target misfolded tau proteins for degradation and shows promise for slowing the progression of Alzheimer’s disease. These targeted protein degraders are an exciting and promising new avenue for treatment in several human diseases.

This is a brief digest of my work in Professor Alex Bullock’s group as a DPhil student in St. Edmund Hall. Our lab team strives to understand how E3 ligases interact with other molecules and function in the human body. We re-create specific mutations in E3 ligases that cause human disease and characterise how such mutations alter the actions of the E3s. Using this understanding, we modify E3 activity to treat human disease. Though our group will not be the ones to create the everlasting vanilla sundae, the therapeutic agents produced by our team may help provide children with musculoskeletal developmental diseases the opportunity to enjoy heaping scoops of ice cream on hot summer days.