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Loss of allostery and coenzyme B12 delivery by a pathogenic mutation in adenosyltransferase

The recent issue of Biochemistry features Loss of allostery and coenzyme B12 delivery by a pathogenic mutation in adenosyltransferase, a paper co-authored by graduate student Michael Lofgren and Professor Ruma Banerjee.

ATP-dependent cob(I)alamin adenosyltransferase (ATR) is a bifunctional protein: an enzyme that catalyzes the adenosylation of cob(I)alamin and an escort that delivers the product, adenosylcobalamin (AdoCbl or coenzyme B(12)), to methylmalonyl-CoA mutase (MCM), resulting in holoenzyme formation. Failure to assemble holo-MCM leads to methylmalonic aciduria. We have previously demonstrated that only 2 equiv of AdoCbl bind per homotrimer of ATR and that binding of ATP to the vacant active site triggers ejection of 1 equiv of AdoCbl from an adjacent site. In this study, we have mimicked in the Methylobacterium extorquens ATR, a C-terminal truncation mutation, D180X, described in a patient with methylmalonic aciduria, and characterized the associated biochemical penalties. We demonstrate that while k(cat) and K(M)(Cob(I)) for D180X ATR are only modestly decreased (by 3- and 2-fold, respectively), affinity for the product, AdoCbl, is significantly diminished (400-fold), and the negative cooperativity associated with its binding is lost. We also demonstrate that the D180X mutation corrupts ATP-dependent cofactor ejection, which leads to transfer of AdoCbl from wild-type ATR to MCM. These results suggest that the pathogenicity of the corresponding human truncation mutant results from its inability to sequester AdoCbl for direct transfer to MCM. Instead, cofactor release into solution is predicted to reduce the capacity for holo-MCM formation, leading to disease.

Lofgren M, Banerjee R.

Biochemistry. 2011 Jun 28;50(25):5790-8. Epub 2011 Jun 2.

The entire paper may be read at PubMed

Georgios Skiniotis Named Pew Scholar

Professor Georgios Skiniotis has been named one of twenty-two Pew Scholars in the Biomedical Sciences by The Pew Charitable Trusts. The 2011 Pew Scholars will join a select community that includes MacArthur Fellows, recipients of the Albert Lasker Medical Research Award and three Nobel Prize winners. Research by the new class of Scholars is related to many human diseases ranging from Alzheimer’s to diabetes to ocular degeneration. The program encourages early-career scientists to advance research that leads to important medical breakthroughs and treatments.

Posted 6/15/11

Bill Smith Recipient of 2012 Distinguished Faculty Lectureship Award in Biomedical Research

William (Bill) L. Smith, Chair of the Department of Biological Chemistry has been named as the recipient of the 2012 Distinguished Faculty Lectureship Award in Biomedical Research. This award recognizes Dr. Smith’s numerous research accomplishments, his extensive contributions in mentoring and training that in addition to students, postdoctoral fellows, and visiting scholars has included the hiring and development of junior faculty, and his academic and research leadership.

The Distinguished Faculty Lectureship Award in Biomedical Research recognizes a faculty member who has made long-term contributions to biomedical research, teaching and service to the University of Michigan. The award is overseen by the Biomedical Research Council (BMRC) of the University of Michigan. The BMRC encourages biomedical research and facilitates interdisciplinary research and training across the University through it’s MRC's funding programs. The BMRC also reviews the nominations for the Distinguished Faculty Lectureship Award in Biomedical Research and the Dean's Basic Science Research Award. The BMRC members represent the Health Sciences Schools and Colleges and the Veterans Administration Medical Center.

The Distinguished Faculty Lectureship, which was first awarded in 1979 to Professor Vincent Massey, continues to be the highest honor bestowed by the Medical School upon a faculty member for research in the biomedical sciences. The recipient of this award presents a lecture, is honored at the Dean’s Award Banquet held in the Fall, and receives a $5,000 award in discretionary funds.

Bill Smith is in good company. Previous recipients of Distinguished Faculty Lectureship Award in Biomedical Research from the Department of Biological Chemistry are David Engelke (2004); Jack E. Dixon (1997); Rowena G. Matthews (1994); Irwin J. Goldstein (1988); Bernard W. Agranoff (1986); Minor J. Coon (1982); and Vincent Massey (1979).

Alex Ninfa Elected as AAM Fellow

Please join us in congratulating Alex Ninfa who has been elected as a Fellow of the American Academy of Microbiology.

The American Academy of Microbiology is the honorific leadership group within the American Society for Microbiology (ASM), the world's oldest and largest life science organization. The mission of the Academy is to recognize scientists for outstanding contributions to microbiology and provide microbiological expertise in the service of science and the public. Each elected Fellow has built an exemplary career in basic and applied research, teaching, clinical and public health, industry or government service. Election to Fellowship indicates recognition of distinction in microbiology by one's peers. Only about seventy-five microbiologists are elected to Fellowship in the American Academy of Microbiology each January. Fellows of the Academy are elected annually through a highly selective, peer-review process, based on their records of scientific achievement and original contributions that have advanced microbiology. There are now over 2,000 Fellows representing all subspecialties of microbiology, including basic and applied research, teaching, public health, industry, and government service.

Feng Wang receives Award

Feng Wang of the Ming Lei Lab has been selected to receive a ProQuest Distinguished Dissertation Award for 2010. This prestigious award is given by the University in recognition of the most exceptional scholarly work produced by doctoral students during 2010. Wang was honored at a ceremony at the Rackham Graduate School in Assembly Hall on Thursday, April 28, 2011 at 2:00 PM.

Posted 4/15/11

Krishnan Awarded Poster Prize

Swathi Krishnan, a graduate student in Ray Trievel's laboratory, was awarded a best poster prize at the ASBMB Symposium on Transcriptional Regulation, which was held on October 4th-8th at Snowbird, Utah. Swathi was one of four finalists selected from 45 posters presented at the symposium.

Minor J. Coon Symposium

The Department of Biological Chemistry hosted on July 15 a mini-symposium in honor of Emeritus Professor Minor J. Coon. The speakers included Xinxin Ding, F. P. Guengerich, Paul Hollenberg, Edward Morgan, Henry Strobel and Alfin Vaz. "Jud," as generations of devoted students have called him, was Chair of the Department from 1970 to 1990, and his work in unraveling the chemical, physical, catalytic and mechanistic properties of cytochrome P450, and in establishing its biomedical significance in steroid biosynthesis, chemical carcinogenesis and drug metabolism, led to worldwide recognition. Based on his pioneering research, he was elected to the National Academy of Science, the American Academy of Arts and Sciences, and the Institute of Medicine, and he was awarded an honorary medical degree from the Karolinska Institute in Stockholm. The lecture hall located at 3330 Medical Science I was named for Dr. Coon. To see photographs of the event visit our Photo Gallery

Jochen Schacht's research also lends more evidence to support the use of antioxidants

The world needs new antibiotics to overcome the ever increasing resistance of disease-causing bacteria — but it doesn't need the side effect that comes with some of the most powerful ones now available: hearing loss. Today, researchers report they have developed a new approach to designing antibiotics that kill even "superbugs" but spare the delicate sensory cells of the inner ear. Surprisingly, they have found that apramycin, an antibiotic already used in veterinary medicine, fits this bill -- setting the stage for testing in humans. According to the World Health Organization, about 440,000 new cases of multidrug-resistant tuberculosis emerge annually, causing at least 150,000 deaths worldwide. Aminoglycoside antibiotics, while carefully controlled in the U.S., Europe, and other developed countries are available over the counter in many developing nations, leading to overuse that makes it even easier for drug-resistant strains of many kinds of bacteria to emerge and spread.

In a paper published online in the Proceedings of the National Academy of Sciences, a team led by BioChem’s Jochen Schacht together with colleagues from Switzerland and England, show apramycin's high efficacy against bacteria, and low potential for causing hearing loss, through a broad range of tests in animals. That testing platform is now being used to evaluate other potential antibiotics that could tackle infections such as multidrug-resistant tuberculosis. The research aims to overcome a serious limitation of aminoglycoside antibiotics, a class of drugs which includes the widely used kanamycin, gentamicin and amikacin. While great at stopping bacterial infections, these drugs also cause permanent partial hearing loss in 20 percent of people who take them for a short course, and up to 100 percent of people who take them over months or years, for example to treat tuberculosis or lung infections in cystic fibrosis.

These delicate hair cells from the inner ear of mice were tested to see the effects of powerful antibiotics on structures that are crucial to hearing. At left, cells that were exposed to the antibiotic gentamycin showed signs of high levels of damaging free radicals (seen in green). But cells treated with the veterinary drug apramycin; those at right, didn't show these effects -- adding to evidence that this drug could be used to treat humans without damaging hearing.

Dr. Schacht, Director of the Kresge Hearing Research Institute, has spent decades studying why these drugs cause this "ototoxicity" — a side effect that makes doctors hesitant to prescribe them. Hearing damage has also caused patients to discontinue treatment before their antibiotic prescription is over, potentially allowing drug-resistant strains of bacteria to flourish. Further, has found that the drugs produce damaging free radicals inside the hair cells of the inner ear. Hair cells, named for the tiny sound-sensing hairs on their surface, are the linchpin of hearing -- and once destroyed, cannot be regrown. "Aminoglycosides are some of the most valuable broad-spectrum antibiotics and indispensable drugs today, but we need new options to combat drug-resistant bacteria. Importantly, we must find ways to overcome their ototoxicity," Schacht says. "Instead of the trial-and-error approach of the past, this new hypothesis-driven tactic allows us to design drugs with simultaneous attention toward both antibacterial action and impact on hair cells."

The new paper outlines a rational approach to designing drugs to combat this threat without ototoxicity, based on a theoretical framework that emerged from the work of the three laboratories and centers around the role of ribosomes, the structures inside the cell that "read" DNA and translate the genetic message into proteins. Aminoglycosides bind to the ribosomes inside bacterial cells, preventing the ability to produce proteins. But while the drugs spare most human ribosomes, they can attach to ribosomes in the mitochondria of cells, which are similar to bacterial ribosomes. Consistent with Schacht’s theories about ototoxicity, the drugs then cause the production of free radicals in such quantities that they overwhelm the hair cells' defense mechanisms -- destroying the cells and causing hearing loss.

The team's approach is to design drugs that more specifically target bacterial ribosomes over mitochondrial ribosomes, simultaneously testing the impact on hair cells as well as the ability to kill bacteria. In this way, the researchers try to avoid creating antibiotics that harm hearing. They are already using the platform employed for this study -- which involves cells from mouse ears, and tests of hearing and hair cell damage in guinea pigs -- to test other promising novel drugs synthesized based on the theoretical framework that was driving the current research. Meanwhile, the team hopes to launch a clinical trial of apramycin, an antibiotic that could prove immediately useful because multidrug-resistant TB and lung-infecting bacteria have not shown resistance to the drug yet.

The research also lends more evidence to support the use of antioxidants to protect the hearing of patients taking current aminoglycoside antibiotics. Schacht has already led a clinical trial in China that showed a major reduction in hearing loss if aspirin was given at the same time as aminoglycoside antibiotics. "This kind of protection is important, while we search for the long-term answer to drug resistance without ototoxicity," he says.

2012 NIH Merit awards

Each year the National Institutes of Health single out researchers who deserve the "provision of long-term stable support ... to foster their continued creativity and spare them the administrative burdens associated with preparation and submission of full-length research grant applications." The five-year “Method to Extend Research in Time” award mechanism, otherwise known as NIH’s prestigious MERIT awards, "allow investigators the opportunity to take greater risks, be more adventurous in their lines of inquiry or take the time to develop new techniques." Less than 5 percent of NIH-funded investigators are selected to receive MERIT awards. Among this year’s recipients of MERIT awards is BioChem’s Stephen W. Ragsdale for his NIGMS grant renewal Enzymology of the Reductive Acetyl-CoA Pathway (GM039451). Dr. Ragsdale joins BioChem’s Dr. Jerry Menon who earlier received a MERIT award for his NICHD grant Regulation of Ovarian Function by Gonadotropin (HD006656). Our congratulations go out to both.

Posted 9/12

Effects of Oxidative Stress on Caenorhabditis elegans

Accumulation of reactive oxygen species has been implicated in various diseases and aging. However, the precise physiological effects of accumulating oxidants are still largely undefined. Recently BioChem's Ursula Jakob applied a short-term peroxide stress treatment to young Caenorhabditis elegans and measured behavioral, physiological, and cellular consequences. As described in her paper, Effects of Oxidative Stress on Behavior, Physiology, and the Redox Thiol Proteome of Caenorhabditis elegans, appearing in the July 22 issue of Antioxid Redox Signal, she discovered that exposure to peroxide stress causes a number of immediate changes, including loss in mobility, decreased growth rate, and decreased cellular ATP levels. Many of these alterations, which are highly reminiscent of changes in aging animals, are reversible, suggesting the presence of effective antioxidant systems in young C. elegans. One of these antioxidant systems involves the highly abundant protein peroxiredoxin 2 (PRDX 2), whose gene deletion causes phenotypes symptomatic of chronic peroxide stress and shortens lifespan. Applying the quantitative redox proteomic technique OxICAT to oxidatively stressed wild-type and prdx 2 deletion worms, Jakob and her colleagues identified oxidation-sensitive cysteines in 40 different proteins, including proteins involved in mobility and feeding (e.g., MYO 2, LET-75), protein translation and homeostasis (e.g., EFT 1, HSP 1), and ATP regeneration (e.g., NDPK). The oxidative modification of some of these redox-sensitive cysteines may contribute to the physiological and behavioral changes observed in oxidatively stressed animals. Her entire paper may be read at ARS

More recently, Jakob has published a paper in the current issue of Cell that describes Hsp33, a type of helper protein called a stress-specific molecular chaperone. It’s function is to prevent other proteins from collapsing during stressful situations by uncoiling a long, supportive arm that wraps around them. Most molecular chaperones are active only when they are tightly folded. But Jakob’s laboratory recently discovered that certain stress-specific proteins become active as chaperones only when they partially unfold and lose some of their structure. That finding turned common assumptions about molecular chaperones on their head. Jakob comments "the way these proteins turn on makes sense, as they can very rapidly respond to conditions that unfold other proteins. But it raises several mystifying questions: How can proteins work while they are partially unfolded, and being disordered, how can they possibly bring order to other proteins?" Additional material can be read at the Jakob lab page: http://www.mcdb.lsa.umich.edu/labs/jakob/hsp33.html

Posted 3/15/12

Carol Fierke is the recipient of 2012 Repligen Award

Professor Carol Fierke is the recipient of the 2012 Repligen Award in the Chemistry of Biological Processes, in recognition of her contributions to our broad understanding of how protein and nucleic acid catalysts achieve high efficiency with rigorous control of reaction specificity. In addition to her work on catalysis, Fierke and co-workers have made a number of significant contributions to our view of metal ion homeostasis in cells. She is recognized as an international leader in devising elegant experimental approaches for probing the structure, function and biological relevance of metals as cofactors in catalysis. More specifically, she and her co-workers carried out a groundbreaking analysis of the determinants of metal affinity and specificity for carbonic anhydrase, the prototypical zinc enzyme, and then used this information to develop biosensors to make the first real-time measurement of the cellular concentration of readily exchangeable zinc ions, thereby permitting them to analyze cellular zinc homeostasis. She has also identified the biological metal cofactor and elucidated the catalytic mechanism of several other metalloenzymes, including protein farnesyltransferase, histone deacetylase and ribonuclease P. These studies have often led to unexpected conclusions that change the field. For example, she showed that the substrate for the ribozyme catalyst in ribonuclease P, which is only active as a protein/RNA complex, was actually bound by the protein subunit in contrast to previous hypotheses. Her work has also led to the novel proposal that cells may regulate enzyme activity by switching metals in the active site. More recent efforts to identify and quantify the in vivo substrates of enzymes that catalyze post-translational modifications have enhanced our understanding of the role of these modifications in biological pathways. Her ability to integrate ideas and methods from a variety of scientific disciplines to determine fundamental details about catalytic activity and cellular function is a hallmark of Professor Fierke’s work, which is important for efforts to develop enzyme inhibitors as therapeutic agents. She will present a lecture as part of a symposium at the Fall 2012 ACS National Meeting.

Dixon Elected to Royal Society

Jack E. Dixon, former Chair of the Department of Biological Chemistry, was recently named one of eight new foreign members of The Royal Society. Dixon, who is a professor at the University of California, San Diego, and the outgoing vice president and chief scientific officer of the Howard Hughes Medical Institute, was granted lifetime membership for his “elegant studies (that) have radically advanced our understanding of cell signaling and the molecular basis of pathogenesis,“ the society said in a statement. Early in his career, Dixon was a leader in research on the biosynthesis and post-translational processing of polypeptide hormones. He subsequently became a pioneer in the structure and function of the protein tyrosine phosphatases and their roles in cellular signaling, and his group found that the bacterium Yersinia pestis harbors the most active PTPase known. He is a member of the National Academy of Sciences and served as president of the American Society for Biochemistry and Molecular Biology in 1996.

Posted 9/12

Smith Recipient of NIH National Research Award

Graduate student Amber Smith has been awarded a Ruth L. Kirschstein National Research Service Award by the National Institutes of Health. The Individual Predoctoral Fellowship will provide funds for tuition, fees, health insurance, and training related expenses. Smith pursued her undergraduate work at the University of California, Santa Cruz. Under her mentor Janet Smith, her research is focused on the glutamine amidotranferases (GATs) superfamily of proteins.

Saul Roseman, dies at 90

We have learned that Dr. Saul Roseman, formerly a faculty member in our Department, died on July 2. His Ph.D. training was with Professor Karl Link at the University of Wisconsin, and he came to our Medical School in 1953 as a faculty member in Biological Chemistry and a Research Associate in the Rackham Arthritis Research Unit. He had a life-long interest in complex carbohydrates and was renowned for his studies on sialic acid. Professor Roseman moved to Johns Hopkins University in 1965 to twice become Chair of their Biology Department. He continued to have a distinguished career in research and was elected to the National Academy of Sciences in 1972, and received many other honors, including the Gairdner Foundation International Award, an NIH MERIT Award, the Rosenstiehl Award from Brandeis University, and an honorary M.D. from the University of Lund in Sweden. His trainees hold top academic and industrial research positions world-wide. More

Trievel Receives Dean's Special Recognition

Each year the Dean of the University's Medical School chooses a select number of faculty to recognize "who demonstrate exceptional accomplishment in the areas of teaching, research, clinical care and community service." This year Dean Woolliscroft selected five faculty members for his award, and BioChem's own Raymond C. Trievel Jr. is among them. Trievel earned his Doctorate at the University of Pennsylvania, and conducted his Postdoctoral Studies at the National Institutes of Health. Dr. Trievel's special interest is the chemical and structural biology of enzymes that covalently modify histones, transcription factors, and other nuclear proteins. "My current research focuses on elucidating the molecular mechanisms underlying the specificites of histone methyltransferases and demethylases and on developing new assays and reagents to characterize these enzymes."

Banerjee Elected as AAAS Fellow

Each year the Council of the American Association for the Advancement of Science (AAAS) elects members to the rank of AAAS Fellow, whose “efforts on behalf of the advancement of science or its applications are scientifically or socially distinguished.” The inductees his year include BioChem's Ruma Banerjee. This will be a busy year as Dr. Bannerjee will join the editorial board of the Journal of Biological Chemistry as an Associate Editor; she also serves on the editorial boards of Chemical Reviews and Antioxidants and Redox Signaling.

Jairam Menon receives 2010 EBS Teaching Award

Congratulations to Jairam Menon, recipient of the Medical School's Endowment for Basic Science 2010 Teaching Award for Biological Chemistry. Dr. Menon is being recognized for his many years of teaching excellence in Biol Chem 415 and the medical student M1 curriculum. On Monday, December 13, 2010, a luncheon held by the EBS to honor the awardees from basic science departments. Each honoree received a $1,000 award and an engraved plaque. Please join us in congratulating Jerry for this well-deserved recognition.

2011 Martha L. Ludwig Lectureship in Structural Biology

The Martha L. Ludwig Lectureship in Structural Biology for 2011 was Venkatraman Ramakrishnan , Ph.D. A Fellow of the Royal Society and a member of the National Academy of Sciences, he spoke on Unraveling the structure of the ribosome and its role in decoding. Dr. Venkatraman (Venki) Ramakrishnan was born in India, where he received his bachelor’s degree in physics from Baroda University. In 1971 he moved to the USA, and pursued his Ph.D. in physics from Ohio University under the direction of physicist Tomoyasu Tanaka; he recieved this degree in 1976. Between 1976–78, Dr. Ramakrishnan was a graduate student, studying biology at the University of California San Diego. In 1978, he began postdoctoral work with Peter Moore at Yale University, where he first began working on the ribosome. From 1983–95 Dr. Ramakrishnan was a staff scientist at Brookhaven National Laboratory. In 1995 he was recruited as a professor of biochemistry at the University of Utah. In 1999, he became a group leader at the MRC Laboratory of Molecular Biology in Cambridge, England, where he is currently located. Dr. Ramakrishnan received the Louis-Jeantet prize for medicine in 2007 and shared the Nobel prize for chemistry in 2009 for his work in determining the structure of the ribosome.

Engelke Lab: Mod5 protein binds to tRNA gene complexes and affects local transcriptional silencing

The tRNA gene-mediated (tgm) silencing of RNA polymerase II promoters is dependent on subnuclear clustering of the tRNA genes, but genetic analysis shows that the silencing requires additional mechanisms. We have identified proteins that bind tRNA gene transcription complexes and are required for tgm silencing but not required for gene clustering. One of the proteins, Mod5, is a tRNA modifying enzyme that adds an N6-isopentenyl adenosine modification at position 37 on a small number of tRNAs in the cytoplasm, although a subpopulation of Mod5 is also found in the nucleus. Recent publications have also shown that Mod5 has tumor suppressor characteristics in humans as well as confers drug resistance through prion-like misfolding in yeast. Here, we show that a subpopulation of Mod5 associates with tRNA gene complexes in the nucleolus. This association occurs and is required for tgm silencing regardless of whether the pre-tRNA transcripts are substrates for Mod5 modification. In addition, Mod5 is bound to nuclear pre-tRNA transcripts, although they are not substrates for the A37 modification. Lastly, we show that truncation of the tRNA transcript to remove the normal tRNA structure also alleviates silencing, suggesting that synthesis of intact pre-tRNAs is required for the silencing mechanism. These results are discussed in light of recent results showing that silencing near tRNA genes also requires chromatin modification.

Pratt-Hyatt M, Pai DA, Haeusler RA, Wozniak GG, Good PD, Miller EL, McLeod IX, Yates JR 3rd, Hopper AK, Engelke DR.

PNAS, 2013 Aug 13

PMID: 23898186

Recent Graduates

December brought a round of doctoral defenses and three of BioChem’s graduate students now proudly sport their new initials. First up was Corissa L. Lamphear whose dissertation Molecular Recognition of Substrates by Protein Farnesyltransferase and Geranylgeranyltransferanse-I was overseen by mentor Carol Fierke. Dr. Lamphear will be teaching General Chemistry here at the University of Michigan in January and continuing her work on protein prenyltransferase specificity in Dr. Fierke’s lab. Then, she plans on pursuing post-doctoral research opportunities. Next up was Valentin F. Cracan. His thesis Structure, Function and Metabolic Roles of IcmF-a Fusion Between the Radical B12 Enzyme and its G-protein Chaperone was written while in Ruma Banerjee’s lab. Dr. Cracan is headed over to Harvard’s Medical School to pursue postdoctoral studies with Dr. Vamsi Mootha. The Mootha lab combines biochemistry, genomics, and computational techniques to investigate mitochondrial disorders. Finally, Dave A. Pai, who studied with David Engelke defended his work, writing on Spatial coordination of tRNA genes. Dr. Pai plans to pursue postdoctoral research in molecular biology and nucleic acid biochemistry. Our deepest congratulations go out to them all.

Posted 12/30/11

John J. G. Tesmer joint appointment

We are pleased to announce the joint appointment of Professor John J. G. Tesmer to the department faculty, whose research into the molecular basis of G protein-coupled receptor (GPCR)-mediated signal transduction complements the ongoing strong work in the department on biochemical signaling. Dr. Tesmer also holds appointments as Professor of Pharmacology and as Research Professor in the Life Sciences Institute. More about Dr. Tesmer

Paul Weinhold Retires

Congratulations to Dr. Paul Weinhold, who earlier this month gave his final lecture in the UM medical student pre-clinical curriculum following a career spanning six decades. Dr. Roger Grekin, Professor of Internal Medicine and Associate Chief of Staff for Research and Development in the Veterans' Affairs Healthcare System was there to mark the occasion. Dr. Grekin writes, “Paul Weinhold joined the Biological Chemistry faculty in 1965 after completing a postdoctoral fellowship at Harvard. He established a highly successful laboratory at the VA Medical Center and became an internationally recognized expert in the area of phospholipid metabolism. He maintained funding from both the NIH and the VA throughout his investigative career. Paul has made major contributions to medical student teaching. He served as a laboratory instructor and then as a lecturer in the medical student Biochemistry course, and he directed the course from 1991 to 1992. When the curriculum was revised in 1992, he became the director of the Cells and Tissues sequence and served in that role for 20 years. He has given the metabolism lectures for over 30 years, and has been an important contributor to medical student education for 47 years. He won the Kaiser award, the Medical School’s highest award for excellence in teaching, in 1994. Congratulations, Paul!

A reception honoring Dr. Weinhold will be held on September 28 in Room 6311, MS1, 2-4 pm.

1/15/2012

Coxibs found to interfere with the aspirin's benefit

aspirinPainkillers of the drug class Coxibs, such as the widely used product Celebrex, seem to lower the anti-clotting action of aspirin, a new study suggests. The study, led by BioChem's Bill Smith, predicts that the cardioprotective effect of low-dose aspirin on COX-1 may be blunted when taken with coxibs. This finding could affect millions of Americans. UMHS Newsroom

Frederick L. Hoch Dies

Martha Ludwig, Fred Hoch and Tom Steitz hiking in Pontresino, Switzerland in 1968.
Photo courtesy of Joan Steitz.

Frederick L. Hoch, M.D., Professor Emeritus of Biological Chemistry and Internal Medicine, died peacefully at home on February 14, 2012. His caregiver Wendy Cooper indicated that Fred “was strong and lucid to the very end.” Dr. Hoch had retired from active faculty status on December 31, 1986.

Dr. Hoch came to the University of Michigan in 1967 as a visiting scientist in the Biophysics Research Division of the Institute of Science and Technology. He was appointed as an Associate Professor in the Department of Internal Medicine in 1968 and received a joint appointment in the Department of Biological Chemistry in 1970. He was promoted to Professor of Internal Medicine and Biological Chemistry in 1976. Dr. Hoch's career was exceptional in that he was one of the first clinicians at the Medical School to be recruited because of his outstanding biochemical training and accomplishments to represent both medical and basic science departments in the clinical and basic science curriculum for fourth year medical students. He also contributed to the teaching of residents and fellows in the Division of Nuclear Medicine, through his involvement in the Thyroid Clinic. In addition, he served as supervisor for clinicians in the Clinical Radioisotope Facility. Dr. Hoch also made significant contributions to the teaching programs of the Department of Biological Chemistry, where he served from 1972-1985 as director of the introductory biochemistry course taught to first-year medical students. Because of his expertise in the basic and clinical sciences, his presence in this course provided both a challenging blend of medical education to students and a valuable liaison between Medical School departments. Faculty who taught biochemistry with Dr. Hoch during this period remarked that he “had high standards and was very popular with students” and that he provided “sterling leadership to the medical biochemistry course……and was instrumental in implementing many innovations that could only have been carried off by a physician. He was a gentle leader but there was never any doubt as to who was boss. He was largely responsible for the good reception of the course by the students during that time.”

In addition to teaching, Dr. Hoch performed research in mammalian energy metabolism publishing a book entitled Energy Transformations in Mammals: Regulatory Mechanisms in 1971. Between 1955 and 1998 Fred authored or coauthored over 50 publications focusing largely on the effects of thyroid hormones on various biological and biochemical processes. He was an expert in the area of hyperthyroidism and hypothyroidism. Toward the end of his academic career he published several important reviews on the effects of thyroid hormones on mitochondrial lipids.

Dr. Hoch was born in Austria and immigrated to the United States from Vienna obtaining his B.S. degree from City College of New York in 1939 and his M.D. degree from New York University College of Medicine in 1943. Following an internship at Michael Reese Hospital in Chicago from 1943-44, he served as a captain in the Army Medical Corps from 1944-1946. After serving as a resident in pathology at Mt. Auburn Hospital in Cambridge, Massachusetts, he became a Research Associate at Massachusetts Institute of Technology, where he received the M.S. degree in Quantitative Biology in 1951. From 1951-53, he served as a Research Fellow in Biochemistry at Massachusetts General Hospital. In 1953 he began working in the new biophysics laboratory at Peter Bent Brigham Hospital as a junior associate in medicine at Harvard Medical School. He progressed there to assistant professor of medicine and senior associate in medicine in 1962 before moving to Michigan.

While at Harvard Fred met his future spouse, Martha L. Ludwig who at the time was a postdoctoral fellow in the Lipscomb lab. At the time Fred was a young M.D. doing research on carboxypeptidase in the laboratory of Bert Vallee. Martha was sent over to the Vallee laboratory to collect some distilled water, because in Fred’s words, “The Vallee laboratory had the purest (lowest conductivity) water in the world at that time. We collected it in a quartz bucket.” Fred continues, “I set my eyes on that woman.” They were married in 1961 and enjoyed a happy 45 year marriage until Martha’s death in November, 2006. They shared a passion for red convertible sports cars, skiing, tennis, hiking, bird-watching and cooking. In Fred’s words, “We cooked some fancy grub together.” It was during their time in Boston that Martha and Fred became friends with Tom and Joan Steitz. They hiked together in Switzerland, New Hampshire, Vermont and Minnesota. Tom recalls that “Martha and Fred introduced us to hiking in Switzerland on two trips, and I have gone on many Swiss hiking trips since.” The photograph above was taken by Joan Steitz at Pontresino, Switzerland in 1968.

Dr Hoch graciously and generously supported the endowment of the Martha L. Ludwig Professorship in Protein Structure and Function in the Medical School. The Ludwig Chair is currently held by Dr. Janet Smith.

Tom Steitz commented in a note that “Fred was a wonderful guy with a great sense of humor.” Janet and I were fortunate enough to be able to tip a few single malt scotches with Fred every few months over the last five years following Martha’s death. It was great fun. After pouring a bit of scotch Fred would, with a twinkle in his eye lift his glass and intone “Skoal!”

There is to be no memorial service for Dr. Hoch. Those who would like to make a contribution in Fred's memory, should make contributions to the Martha Ludwig Lectureship in Biological Chemistry.

William Smith, Ph.D.
Minor J. Coon Professor and Chair,
Department of Biological Chemistry
University of Michigan Medical School

Materials excerpted for the commentary above are from “A Biographical Memoir of Martha L. Ludwig” by Rowena G. Matthews, Proc. Natl. Acad. Sci. U.S.A. 2011, a memoir from the Faculty History Project of the University of Michigan (http://um2017.org/faculty-history/faculty/frederic-l-hoch-0), and personal communications from Wendy Cooper, Rowena Matthews, Charles Williams, Jud Coon, Irwin Goldstein and Tom Steitz.

Former student Pimchai Chaiyen wins award

ChaiyenThe Department of Biochemistry would like to offer our congratulations to Assoc. Prof. Dr. Pimchai Chaiyen for receiving Young Biochemist and Molecular Biologist Award 2009 from Biochemistry and Molecular Biology Section, the Science Society of Thailand. Dr. Chaiyen was a student of Dave Ballou and Vincent Massey. pfd.

Zebrafish as a model system to study retina regeneration

A major goal of Daniel Goldman’s lab is to identify strategies for restoring lost sight to those suffering from blinding eye diseases like macular degeneration and glaucoma. They use zebrafish as a model system to study retina regeneration because, unlike mammals, zebrafish can regenerate a damaged retina that culminates in restoration of visual function. The lab has found that Müller glia, the only glia in the retina, respond to retinal injury by dedifferentiating into progenitors that are able to regenerate all major retinal cell types. Their current research is focused on identifying the molecular mechanisms underlying this dedifferentiation, with the hope it will suggest new strategies for stimulating Müller glia dedifferentiation and retina regeneration in mammals. In a series of recent studies led by postdoctoral fellow Rajesh Ramachandran, the Goldman lab has shown that let-7 microRNA and Wnt signaling pathways are necessary for Müller glia dedifferentiation (Nature Cell Biol 12:1101, 2010; PNAS 108:15858, 2011). Most recently, in a paper published in the February issue of Developmental Cell with postdoctoral fellow Jin Wan as lead author, they discovered that heparin-binding epidermal-like growth factor is a Müller glia-derived factor that is necessary and sufficient for stimulating Müller glia dedifferentiation and retina regeneration. Finally, in a recent paper in the Journal of Neuroscience (J Neurosci 32:1096, 2012), graduate student Curtis Powell reports Apobec2 protein deaminases, proteins involved in DNA demethylation, are necessary for the injury-dependent reprogramming of Müller glia.

Posted 4/15/12

Feng Wang receives Award

Feng Wang of the Ming Lei Lab has been selected to receive a ProQuest Distinguished Dissertation Award for 2010. This prestigious award is given by the University in recognition of the most exceptional scholarly work produced by doctoral students during 2010. Wang will be honored at a ceremony at the Rackham Graduate School in Assembly Hall on Thursday, April 28, 2011 at 2:00 PM.

Posted 4/15/11

Visualizing molecular juggling within a B12-dependent methyltransferase complex

Catherine L. Drennan (Ph.D. BioChem '95, now HHMI Professor at MIT) and Stephen Ragsdale and Gunes Bender from our department have published in the current issue of Nature a fascinating paper, Visualizing molecular juggling within a B12-dependent methyltransferase complex. The researchers note: “Post-world war II, only one vitamin (folic acid, B9) has been deemed worthy of requiring fortification of the US food supply. Folate deficiency impedes the transfer of single carbon units from folate to another vitamin (B12), and is associated with heart disease and serious birth defects. Interestingly, this same transfer reaction is also essential for the ability of certain microorganisms to live on the greenhouse gas carbon dioxide. In this work, we use X-ray crystallography to provide the first view of how the transfer from folate to B12 occurs, revealing the requisite molecular gymnastics of the proteins involved.” Read more about this at Nature.

Posted 4/15/12

NIH scientist Marshall Nirenberg dies at 82. He deciphered the genetic code

Marshall W. Nirenberg, (Ph.D. '57) a Nobel Prize-winning NIH geneticist who deciphered the genetic code in 1961. Dr. Nirenberg and his assistant, Heinrich Matthaei, discovered how RNA transmits the "messages" that are encoded in DNA and directs how amino acids combine to make proteins. They had found the first of 64 three-letter "words" in which the instructions of life are written. Washington Post. More information about Nirenberg's work, including a video, can be found at Nobel.

As reported in last year's department Newsletter, Dr. Bernie Agranoff fondly recollected their friendship and Marshall's illustrious career. Additiional remembrances have been written by colleagues Dr. Raymond Holton and Dr. Conrad Wagner. They are available as pdf files below.

Dr. Raymond Holton's remembrances of Nirenberg. pfd here

Dr. Conrad Wagner's remembrances of Nirenberg. pfd here

Structural basis for the enhanced stability of highly fluorinated proteins

Neal Marsh from our department has published Structural basis for the enhanced stability of highly fluorinated proteins in a recent issue of Proceedings of the National Academy of Sciences. In the paper they discuss how noncanonical amino acids have proved extremely useful for modifying the properties of proteins. Among them, extensively fluorinated (fluorous) amino acids seem particularly effective in increasing protein stability; however, in the absence of structural data, the basis of this stabilizing effect remains poorly understood. To address this problem, Professor Marsh and his colleagues solved X-ray structures for three small proteins with hydrophobic cores that are packed with either fluorocarbon or hydrocarbon side chains and compared their stabilities. Although larger, the fluorinated residues are accommodated within the protein with minimal structural perturbation, because they closely match the shape of the hydrocarbon side chains that they replace. Thus, stability increases seem to be better explained by increases in buried hydrophobic surface area that accompany fluorination than by specific fluorous interactions between fluorinated side chains. This finding is illustrated by the design of a highly fluorinated protein that, by compensating for the larger volume and surface area of the fluorinated side chains, exhibits similar stability to its nonfluorinated counterpart. These structure-based observations should inform efforts to rationally modulate protein function using noncanonical amino acids. Read more about this at PNAS.

Posted 6/1/12

Ray Trievel recipient of Etter Award

Professor Ray Trievel has been named the recipient of the 2010 Etter Early Career Award from the American Crystallographic Association. He will receive this prestigious award next summer when he delivers a lecture at the ACA annual meeting in Chicago. The Etter award recognizes outstanding achievement and exceptional potential in crystallographic research demonstrated by a scientist at an early stage of their independent career. The award was established in 2002 to honor the memory of Professor Margaret C. Etter (1943-1992), who was a major contributor to the field of organic solid-state chemistry.

Rebecca Haeusler selected as a 2012 Schaefer Research Scholar

Dr. Rebecca Haeusler (BioChem '07) has been selected as a 2012 Schaefer Research Scholar at Columbia University's Diabetes and Endocrinology Research Center. This highly coveted honor is made possible through a gift from the late Dr. Ludwig Schaefer to Columbia University, and is intended to recognize outstanding work in human physiology. You can read about Becky's outstanding original discovery in the January issue of Cell Metabolism.

Posted 2/15/12

Steve Ragsdale elected as AAAS Fellow

In November, Professor Steven Ragsdale was elected as a Fellow of the American Association for the Advance of Science for his "studies of complex metalloenzymes that catalyze challenging reactions in anaerobic organisms". Election as a Fellow of AAAS is an honor bestowed upon members by their peers. Fellows are recognized for meritorious efforts to advance science or its applications. Steve will be recognized for his contributions at the Fellows Forum to be held on 20 February 2010 during the AAAS Annual Meeting in San Diego.

Daniel J. Klionsky's research into Parkinson's disease

Great progress has been made toward understanding the pathogenesis of Parkinson's disease (PD) during the past two decades, mainly as a consequence of the discovery of specific gene mutations contributing to the onset of PD. Recently, dysregulation of the autophagy pathway has been observed in the brains of PD patients and in animal models of PD, indicating the emerging role of autophagy in this disease. Indeed, autophagy is increasingly implicated in a number of pathophysiologies, including various neurodegenerative diseases. An article,The role of autophagy in Parkinson's disease, recently published by Professor Daniel J. Klionsky, in Cold Spring Harb Perspect Med will lead you through the connection between autophagy and PD by introducing the concept and physiological function of autophagy, and the proteins related to autosomal dominant and autosomal recessive PD, particularly α-synuclein and PINK1-PARKIN, as they pertain to autophagy. Read more about this at CSHPM.

Schematic model of the three main types of autophagy. The modes of autophagy differ depending on the nature of the substrate and the site of sequestration. In chaperone-mediated autophagy, the substrates contain a KFERQ-consensus motif, are unfolded by HSC70 chaperones, and translocate directly across the lysosome membrane via interaction with a LAMP-2A oligomer. There are various types of microautophagy-like processes including micropexophagy and micromitophagy, the selective degradation of peroxisomes and mitochondria, respectively. Again, sequestration occurs at the lysosome-limiting membrane, but the substrates do not have to be unfolded. Macroautophagy uses a double-membrane phagophore to sequester the cargo. Essentially any cytoplasmic component can be enwrapped by a phagophore, which expands into an autophagosome. Fusion with the lysosome allows the cargo to be degraded, and the resulting macromolecules are released into the cytosol through permeases, allowing them to be reused for anabolic processes.

Posted 5/1/12

Banerjee Lab: Autoinhibition and signaling by the switch II motif in the G-protein chaperone of a radical B12 enzyme

MeaB is an accessory GTPase protein involved in the assembly, protection, and reactivation of 5'-deoxyadenosyl cobalamin-dependent methylmalonyl-CoA mutase (MCM). Mutations in the human ortholog of MeaB result in methylmalonic aciduria, an inborn error of metabolism. G-proteins typically utilize conserved switch I and II motifs for signaling to effector proteins via conformational changes elicited by nucleotide binding and hydrolysis. Our recent discovery that MeaB utilizes an unusual switch III region for bidirectional signaling with MCM raised questions about the roles of the switch I and II motifs in MeaB. In this study, we addressed the functions of conserved switch II residues by performing alanine-scanning mutagenesis. Our results demonstrate that the GTPase activity of MeaB is autoinhibited by switch II and that this loop is important for coupling nucleotide-sensitive conformational changes in switch III to elicit the multiple chaperone functions of MeaB. Furthermore, we report the structure of MeaB·GDP crystallized in the presence of AlFx(-) to form the putative transition state analog, GDP·AlF4(-). The resulting crystal structure and its comparison with related G-proteins support the conclusion that the catalytic site of MeaB is incomplete in the absence of the GTPase-activating protein MCM and therefore unable to stabilize the transition state analog. Favoring an inactive conformation in the absence of the client MCM protein might represent a strategy for suppressing the intrinsic GTPase activity of MeaB in which the switch II loop plays an important role.

Lofgren M, Koutmos M, Banerjee R.

J Am Chem Soc. 2013 OCT 25.

PMID: 23996001

Donald Raymond awarded Rackham Fellowship

Donald Raymond, a candidate in Janet Smith's laboratory, has been awarded a Rackham Predoctoral Fellowship. One of Rackham's most prestigious fellowships, it is awarded to candidates with outstanding research and who have achieved academic excellence in their graduate career.

Interview with Ruma Banerjee

Dr. Ruma V. Banerjee, Associate Chair and Vincent Massey Collegiate Professor of Biological Chemistry, joined the ranks of The Journal of Biological Chemistry associate editors earlier this year. In December, along with BioChem's Chair and JBC Associate Editor Bill Smith, Banerjee oversaw a JBC minireview series on redox sensing and regulation. In an interview in the current issue of ASBMB Today she offers some insights on her work here at BioChem and with the journal. Read the interview at ASBMB Today.

Posted 5/15/12