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2012 Mystery Molecule


This molecule is part of the primary immune response. Can you guess what it is?


Immunoglobulin M is the first immunoglobulin made during B cell development and is expressed (along with IgD) on the surface of naïve mature B cells. When the B cell is activated by contact with an antigen recognized by its immunoglobulin, it becomes activated and proliferates. Some of the dividing cells become plasma cells exporting IgM out of the cell. Unlike the surface IgM molecules, which are monomers, secreted IgM consists of five IgM monomers joined together. We hope that you were able to join together with family and friends during your winter holiday season.


The 2012 Nobel Prize in Chemistry was recently awarded to two American scientists for their work characterizing this molecule. Can you guess what it is?

G Protein-Coupled Receptor

This class of protein has enormous importance for the transmission of all kinds of signals from the outside of the cell to the inside. It sits inside the plasma membrane as shown with seven trans-membrane segments. Ligands as varied as neurotransmitters, cytokines and a large number of drugs act as ligands for the extracellular loops (top) which induce conformational changes releasing a G protein attached to the intracellular portion of the molecule (bottom). Robert Lefkowitz (Duke) and Brian Kobilka (Stanford) shared the prize for their pioneering work involving the beta-adrenergic receptor, including the difficult task of crystallizing the protein in both its inactive and active state.


The creator of this molecule originally thought that he had a great new drug for treating cancer but it turned out to be the first effective treatment for one of the most significant infectious diseases of the 20th century. Can you guess what it is?


Did you notice that it resembles a pyrimidine nucleoside with three nitrogens attached? More popularly known as azidothymidine (or AZT), this molecule interferes with the ability of the human immunodeficiency virus (HIV) to manufacture DNA using reverse transcriptase. Developed as a potential chemotherapeutic drug against cancer, its use in HIV infection created a dramatic turnaround in the treatment of AIDS. Now it is used in conjunction with other reverse transcriptase inhibitors and protease inhibitors. It is also used to emergently treat healthcare workers after needlestick injuries. Jerome Horwitz, a cancer researcher at Wayne State University in Michigan who created it in 1964, died last month.


The famous cyclist Lance Armstrong recently lost his championship titles because he may have used this molecule to help him win them. Can you guess what it is?


This heavily glycosylated cytokine is produced by interstitial cells in the kidney in response to low oxygen content. It travels to the bone marrow where it enhances the production of erythroid stem cells and, subsequently, the number of red blood cells. Recombinant erythropoietin is used to treat anemia, particularly in chronic renal disease (which results in defective erythropoietin production) and may also be used illegally to give athletes an unfair advantage with regard to oxygen supply for muscular contraction.


Mutations in the gene that codes for this protein have allowed humans to enjoy summer barbecuing of hot dogs and hamburgers. Can you guess what it is?

Apolipoprotein E (apo E)

At some point in the evolution of Homo sapiens, we stopped relying primarily on green leafy vegetables and began to eat meat. Mutations in the apo E gene are widely believed to have helped us adapt to this change in diet. Apo E is a component of almost all of the plasma lipoproteins and participates in lipoprotein recognition by several membrane receptors but its major role is the delivery of chylomicron remnants to the liver. Apo E is the only apolipoprotein synthesized outside of the liver and the intestines. It may help macrophages to transport cholesterol out of their cytoplasm (and avoid becoming foam cells). It also helps the nervous system to develop and a mutated apo E allele is associated with increased risk of Alzheimer's dementia. Even if you opted for the soy burger, we hope that you enjoyed your summer barbecue.


Several of the plenary sessions at this year's annual AACC meeting in Los Angeles will address the new ways that we have to know this molecule. Can you guess what it is?


Easy answer – but the plenary sessions made it clear that recent advances in our ability to sequence the genome will not easily translate into advances in diagnosis or treatment. Dr. Eric Green reviewed the history of the human genome project and forecast a "$100 genome sequencing" sometime soon but added that, without major advances in data management, the analysis may cost $100,000. Dr. Elaine Mardis showed how clinical applications are already being made with regard to cancer treatment, but the discussion of Drs. Michael Christman, Robert Cook-Deegan and Pilar Ossorio also highlighted the need to take into account other issues, including informed patient consent.


Although the patent for the production of this molecule recently expired, people may still want to call generic versions of this blockbuster drug by its more pronounceable trade name. Can you guess what it is?

Clopidogrel (Plavix ®)

When there is injury to a vessel wall, a number of substances attract platelets and cause them to aggregate – the first step in plugging the hole. Clopidogrel is metabolized in the liver to an active form of the drug (the ring with the yellow sulfur at the right is opened with a carbonyl oxygen added). This active form is an inhibitor of the platelet receptor for ADP, which diminishes platelet activation (and aggregation). Prescribed for prevention of thrombosis in patients with coronary artery disease, it is one of the most commonly used drugs in the world. The required metabolism in the liver by CYP2C19 also makes it an important drug for pharmacogenetic considerations. The patent held by Bristol-Myers Squibb expired last month and many generic versions are now available. But will we start to call it by its generic name?


April showers may have produced May flowers but they may not be visited by many honeybees because of this molecule. Can you guess what it is?


This insecticide is a neonicotinoid and it blocks the action of acetylcholine on nicotinic receptors, causing weakness and paralysis. In one sense, the effect is similar to the toxicity seen with other insecticides (such as organophosphates) but the lethal dose of imidacloprid is relatively small. Widely used since the mid-1990s, it has been implicated in the recent epidemic of honeybee "colony collapse disorders" by investigators at the Harvard School of Public Health. There is growing concern that the substance should be banned before more hives are destroyed.


Although the Affordable Care Act dominated news from the Supreme Court last month, the decision in another case involving this molecule has special importance for clinical laboratories. Can you guess what it is?


6-mercaptopurine (6MP) and azathioprine (which is converted in the body into 6MP) are inhibitors of purine synthesis used to treat neoplastic disease (such as leukemia) as well as inflammatory disease (such as vasculitis). Prometheus ®, a commercial laboratory in California, patented the use of measurement of 6MP metabolites to guide therapy in inflammatory bowel disease, and sued Mayo Clinic Laboratories ® when they offered their own version of this test. The Supreme Court ruled that because Prometheus had not discovered the metabolites nor their relationship to drug levels, they could not patent these conventional activities. This decision may have significant impact as the field of "personalized medicine" develops and organizations attempt to patent the application of a "law of nature" to a specific clinical scenario.


A shortage of this molecule last month threatened the treatment of thousands of children with leukemia. Can you guess what it is?


This folate antagonist (compare their structures) is used to treat a variety of disorders including acute lymphoblastic leukemia, the most common leukemia occurring in children. One of four U.S. companies producing the drug temporarily closed its manufacturing plant, causing a sudden shortage. The FDA had to quickly approve shipments of methotrexate from abroad. This incident exposed problems with the FDA's backlog of approvals for new applications to manufacture generic drugs of all kinds.


This molecule comes from a member of the chrysanthemum family and, although it tastes incredibly sweet, has zero calories. Can you guess what it is?

Rebaudioside A

Rebaudioside A (RebA) and stevioside are the two major glycosides of the diterpene steviol, found in the stevia plant (a member of the chrysanthemum family). Both have a glucose ester at the carbonyl atom (bottom of figure) and either two (stevioside) or three (Reb A) glucoses linked to the top of the molecule as an ester. These glycosides are hundreds of times sweeter than sucrose and are not absorbed. (They are metabolized by bacteria in the colon.) Reb A is marketed as "Truvia", the latest in a series of artificial sweeteners. We hope that your Valentine's Day was genuinely sweet.


Ryan Braun, baseball's 2011 National League Most Valuable Player, did not have enough of this molecule in his urine during a recent drug test. Can you guess what it is?


An inactive epimer of the androgen testosterone, epitestosterone differs only in the orientation of the hydrogen and hydroxyl at carbon position 17. Although its biological significance is unknown, it appears to be made along with testosterone by the testis at a ratio of 1:1. Measurement of the ratio of testosterone to epitestosterone by gas chromatography/mass spectrometry is the most commonly used method to determine whether there has been abuse of exogenous steroids by athletes. An elevated ratio (as found in Ryan Braun's case) indicates possible steroid doping. This test was the cause of Floyd Landis being stripped of the Tour de France title in 2007.