The 2022 Nobel Prize in chemistry is shared by Drs. Carolyn R. Bertozzi, Morten Meldal, and Barry Sharpless. Dr. Bertozzi’s pioneering innovation was built upon a path paved by Dr. Sharpless. Joining Dr. Sharpless in this endeavor was Dr. Meldal. Heroes think alike! Sharpless and Meldal pioneered “click chemistry,” a method of joining molecules in a highly efficient manner with a minimal of side products. Dr. Bertozzi extended this technology to biological systems, particularly investigation of the role that certain sugars play.
Sugars are ubiquitous in our diet, as simple and complex forms. All complex sugars are eventually broken down in our body to the simplest form called glucose. Glucose is indispensable for cellular activities.
Sugars are versatile in their functions, also excellent at multi-tasking. Aside from serving as cellular fuels, sugars are also “decorators”. Before delving into how and why sugars possess such a function, a quick recap of how proteins are made by our cells. It all starts with DNA housed in the cell nucleus. Genes that encode proteins are first transcribed from DNA to messenger RNA (mRNA) followed by mRNA exiting the nucleus to the cytoplasm (the space between nucleus and cell’s outer membrane) where mRNA gets translated to the “precursor” proteins constructed by 22 types of amino acids. These precursor proteins are 2-dimensional linear structures and are useless in their current form. To function biologically, they must be folded into 3-dimensional species. Indispensable to protein 3-D folding is a modification process by attaching certain “sugars” known as “glycans” to the precursor protein surface.
Wait, sugar modifiers? Are they glucose molecules? The answer is no, they are not glucose, but related to glucose. Simply put: Glucose is the simplest sugar (also called a monosaccharide). “Glycans” is a generic term for a type of complex carbohydrate, a “polysaccharide” composed of monosaccharides linked together.) A distinction between glycans and carbohydrates is that all glycans are carbohydrates but not all carbohydrates are glycans. Examples of complex sugars include starch (found in potato) and cellulose (the tough parts of plants and vegetables indigestible by humans).
Back to proteins sugar modification: Adding glycans to precursor proteins is no easy feat. It involves “glycosylation,” a process that involves 11 different types of monosaccharides getting attached to 8 different types of amino acids, catalyzed by multiple enzymes! In my graduate school days several moons ago, I devoted many hours trying to figure out how a glycosylated protein contributes to the clustering of acetylcholine receptors essential for robust neurotransmitter acetylcholine activities at the neuro-muscular junction (where nerve endings interface with skeletal muscles).
When a glycan sugar group is added to a protein, the protein becomes a glycoprotein. Every organism under the sun has a sugar coating and more than 50% of proteins in us humans are decorated with complex sugars. Okay, we know the form, what function does sugar coating serve?
First and foremost, without proper sugar addition, the precursor proteins freshly made in our cell would not function. How? Because a functional protein needs a pre-requisite: It must be assembled into a 3-D structure via a process called protein folding. Without sugar decoration, protein folding would not be successful with two scenarios: The precursor protein either becomes folded wrongly (or mis-folded) or correctly folded but unstable. Neither scenario leads to a functional protein.
Glycans, the complex sugar, are also intimately associated with our red blood cells (RBCs). On the surface of RBCs reside different types of proteins decorated with different types of complex sugars. Such sugar coating provides a protective layer to RBCs, also serving as a cellular “barcode” that determines and distinguishes our blood type, whether Type-O, Type-A, Type-B, or Type-AB. Blood type compatibility is of utmost importance when it comes to blood transfusion. A mismatch is a matter of life or death.
Glycans also play a role in cancer by controlling how fast cancer cells grow, how extensive cancer cells metastasizes to adjacent healthy cells, and how effective cancer cells build new blood vessels to travel to tissues and organs far away from the primary tumor site. The significant contribution of Dr. Carolyn R. Bertozzi’s work on protein sugars that won her the 2022 Nobel Prize in Chemistry has paved the way to study sugars on cancer cells. A picture is worth a thousand words. To characterize sugar activities, scientists need to develop a method to visualize sugars in action. Here is how it is carried out: A chemical group is inserted to the complex sugars on the cell surface. A fluorescent dye is tagged to the chemical group. Under the microscope, where it glows indicates where sugars are localized.
There is a fancy name tag to this innovative technology: Bio-orthogonal Chemistry. Orthogonal is typically defined as two perpendicular lines that form right angles. Orthogonality in the cellular context refers to two functional groups that would interact with each other without involving other molecules that may trigger secondary (unwanted) biological activities. This very discreet aspect of bio-orthogonality ensures reliability of observations confined to sugar activity with high specificity. This remarkable tool has led to successful imaging and tracing of how sugar groups behave in several cancer types, including breast cancer and prostate cancer. Not surprisingly, new cancer drugs that target sugars is a rapidly developing field of studies. Of course “click chemistry,” independently innovated by Dr. Sharpless and Dr. Medal, played an instrumental role in the success of “bio-orthogonality” by Dr. Bertozzi. Click chemistry allows discreet interaction of two molecules in the absence of unplanned secondary effects. Congrats to the three scientists and to mankind for another achievement in broadening our understanding of nature. Looking forward to sweet success in combatting the sugar conundrum of cancer!
Dr. Nancy Liu-Sullivan holds a Ph.D. in biology and served as a senior research scientist at Memorial Sloan Kettering Cancer Center. She currently teaches biology at the College of Staten Island, City University of New York.
