June 30, 2016 § Leave a comment
Seven milliliters of a king cobra’s venom can kill 20 people. But what exactly is in the snake’s venom? Researchers have pursued that question for decades.
Now, in a paper published in the journal Molecular & Cellular Proteomics, a team of researchers reveals a detailed account of the proteins in the venom of king cobras. “I believe this study to be one of the most complete and precise catalogues of proteins in a venom yet obtained,” states Neil Kelleher at Northwestern University, one of the study’s senior investigators.
Snake venoms always have intrigued scientists, because they “have a rich diversity of biological activities,” says Kelleher’s collaborator Gilberto Domont at Universidade Federal do Rio de Janeiro in Brazil. Among other things, venoms contain various proteases, lipases, nerve growth factors and enzyme inhibitors. Besides understanding how venoms function, researchers want to develop better antidotes to snake venom and identify molecules from venom that can be exploited as drugs, such as painkillers, anticlotting medications and blood pressure treatments. Domont points to captopril, a drug now commonly used to treat high blood pressure and heart failure. It was derived from a molecule found in the venom of a poisonous Brazilian viper.
Although the venom of the king cobra, the largest venomous snake in the world, which can stretch up to 13 feet, has been analyzed previously, questions persist about the venom. How do the sequences of the toxins evolutionarily vary? How do some post-translational modifications on proteins make the venom lethal? But to answer these questions, researchers need a proper count of the proteins in king cobra venom.
The advent of proteomics has allowed scientists to survey the rich diversity of proteins in a given sample. There are different approaches that rely on mass spectrometry to carry out proteomic analyses. One approach is called top-down proteomics. It allows researchers to look at proteins as whole, intact entities. In the more conventional approach, called bottom-up proteomics, proteins are cut into bite-sized fragments for analysis.
In bottom-up proteomics, researchers have to use computer algorithms to stitch back together protein fragments identified by mass spectrometry. Top-down proteomics avoids this problem. Its biggest advantage is that it can capture variations within the proteins as well as post-translational modifications.
Kelleher’s group is one of the leaders in developing top-down proteomics, so that’s what the investigators decided to use to analyze king cobra venom. Domont, Kelleher, Domont’s graduate student Rafael Melani and colleagues obtained venom from two Malaysian king cobras held at the Kentucky Reptile Zoo. They analyzed the venom by top-down proteomics in two modes, denatured and native. In the denatured mode, the protein complexes were taken apart; in the native mode, the venom was kept as is so the protein complexes remained intact.
The investigators identified 113 proteins in king cobra venom as well as their post-translational modifications. To date, only 17 proteins had been known in king cobra venom.
August 13, 2013 § Leave a comment
Wild Types is taking a summer break! Check back at the end of the month for new posts.
March 25, 2013 § 1 Comment
Jon Lorsch, a professor at Johns Hopkins University, will be the next director of the National Institute of General Medical Sciences. He’ll arrive at the institute in Bethesda, Md., this summer.
Lorsch, an active member of the American Society for Biochemistry and Molecular Biology’s mentoring committee, will oversee a $2.4 billion budget that supports primarily fundamental research and scientific workforce training.
“With his reputation of being a broad-minded and visionary thinker with strong management skills, I am confident that Jon will lead NIH’s basic science flagship to keep the U.S. at the forefront of biomedical research,” Francis S. Collins, director of the National Institutes of Health, said in a statement announcing the appointment on March 25.
Lorsch will take the NIGMS reins from Judith H. Greenberg. Greenberg has served as the acting director of the institute since July 2011, when Jeremy Berg stepped down, after holding the director position for eight years, to become the University of Pittsburgh’s associate senior vice-chancellor of science strategy and planning.
Berg, who now is also president of the ASBMB, said he was pleased with the appointment: “Jon is a great choice. He is an outstanding scientist with ideas spanning many disciplines and with great teaching and training experience. He also led the curriculum reform efforts at Johns Hopkins and balanced clinical and basic perspectives very well.”
Berg continued: “He is very personable and is a good listener but is not at all afraid of tough issues. Jon is one of a small group of people whom I frequently reached out to when I was NIGMS director for his perspectives and advice. NIGMS will be in good hands.”
Lorsch holds a Ph.D. in biochemistry from Harvard University and completed a postdoctoral stint at Stanford University. His group at Hopkins developed a fully reconstituted yeast translation initiation system, which the group used to understand the molecular mechanisms of the process by which the genetic blueprint in cells gets turned into working protein machines.
According to a Hopkins bio, Lorsch is thought to be the black sheep in his family “because, out of five males, he is the only one without a degree from Harvard Business School.”
January 24, 2013 § Leave a comment
November 19, 2012 § Leave a comment
Clinical depression, also known as major depressive disorder, robs its victims of interest and pleasure, sleep, appetite and concentration. Clinically depressed people also suffer from excessive fatigue and dark thoughts. The illness is a major cause of disability, suicide and physical problems. However, a diagnosis for the illness is based on psychiatric reviews, which can be subjective. In a paper in Molecular & Cellular Proteomics, Chinese researchers described a test that could objectively diagnose the illness.
Depression is a complex mental disorder that involves multiple factors. The disease diagnosis is subjective because it can present a number of different symptoms and the exact causes for it are not understood. “Despite overwhelming efforts to identify the biomarkers for MDD, there were still no empirical laboratory tests available to diagnose MDD,” says Peng Xie of Chongqing Medical University who was the senior author on the MCP paper, adding that the current subjective diagnosis process has a considerable error rate.
The researchers decided to analyze urine, a sample that can be collected easily, for metabolites that could act as markers for depression. By using nuclear magnetic resonance spectroscopy, they were able to identify five molecules in urine that together seemed to sort out people who suffered from depression from those who didn’t.
The molecules were malonate, formate, N-methylnicotinamide, m-hydroxyphenylacetate and alanine. Malonate and formate are primarily involved in energy metabolism, m-hydroxyphenylacetate has a role in gut microbial metabolism and N-methylnicotinamide N-methylnicotinamide affects tryptophan-nicotinic acid metabolism. Alanine is one of the 20 amino acids used to make proteins. Xie says, “Based on the previous clinical and basic studies, we suggest that disturbances of these metabolic pathyways are implicated in the development of MDD.”
Xie says the researchers zoomed in on a few metabolites as markers because, in clinical practice, it is not convenient or economically feasible to simultaneously measure a large number of metabolites for diagnosis. The current work is a proof-of-concept and opens up more avenues of investigation. Xie says for one, the researchers would like to collect urine samples from depression patients and healthy controls from more ethnically diverse populations to further validate the diagnostic performance of the five metabolites. They also would like to dig deeper in to the underlying metabolic pathways of these five molecules to see if they can uncover how these biochemical pathways play into the disease.
November 12, 2012 § Leave a comment