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eBriefing

The Role of Branched Chain Amino Acids in Human Disease

The Role of Branched Chain Amino Acids in Human Disease
Reported by
Kari Fischer

Posted July 20, 2020

Presented By

The Biochemical Pharmacology Discussion Group

Branched chain amino acids (BCAAs) are essential protein building blocks that are used as metabolic fuel to promote cellular growth and replication. BCAAs (leucine, isoleucine, and valine) and catabolic intermediates also serve as signaling molecules to communicate the nutritional status of the organism to the cell. Genetic loss of branched-chain a-keto acid dehydrogenase—a crucial component of BCAA catabolism—is associated with profound inborn errors of metabolism such as maple syrup urine disease and other neurological disorders. In addition, recent clinical and preclinical studies have implicated altered BCAA metabolism in multiple diseases including diabetes/metabolic syndrome, heart failure, and cancer. However, there is a lack of understanding regarding the mechanisms underlying the alterations in BCAA catabolism, how this dysfunction leads to disease, and whether aberrant BCAA metabolism is causal to or is merely a consequence of disease.

At the Branched Chain Amino Acids and Human Disease conference, held virtually on May 14, 2020, multidisciplinary scientists reviewed the fundamentals of BCAA metabolism and the contributions of BCAA dysregulation in several human diseases.

In this eBriefing, You’ll Learn:

  • What is known about BCAA metabolism in various systems
  • The existing knowledge gaps in BCAA research in human disease
  • Potential therapeutic nodes of intervention to ameliorate human diseases

Speakers

Rong Tian, MD, PhD
Rong Tian, MD, PhD

University of Washington

Christian M. Metallo, PhD
Christian M. Metallo, PhD

University of California, San Diego

Yibin Wang, PhD
Yibin Wang, PhD

UCLA

David Chuang, PhD
David Chuang, PhD

University of Texas Southwestern Medical Center

Tracy Anthony, PhD
Tracy Anthony, PhD

Rutgers University

Zoltan Arany, PhD
Zoltan Arany, PhD

University of Pennsylvania

Christopher B. Newgard, PhD
Christopher B. Newgard, PhD

Duke University Medical Center

Rachel Roth Flach, PhD
Rachel Roth Flach, PhD

Pfizer

Fundamentals of BCAA Metabolism

Speakers

Rong Tian, MD, PhD
University of Washington

Dr. Rong Tian is Director of the Mitochondria and Metabolism Center at the University of Washington. Dr. Tian has an MD from the West China University of Medical Sciences and a PhD in Pharmacology from the University of Aarhus, Denmark.  She was trained as a postdoc in Dr. Joanne Ingwall’s laboratory at Brigham and Women’s Hospital, where she studied bioenergetics of the heart using NMR spectroscopy.  Dr. Tian stayed on faculty at Harvard and rose through the ranks to associate professor when she was recruited to the University of Washington to establish the mitochondrial metabolism center. Dr. Tian’s lab is specifically interested in the molecular mechanisms regulating cell metabolism and energetics.  A long-term goal of her laboratory is to understand the role of mitochondria and metabolism in the pathogenesis of human diseases, in particular cardiovascular diseases. She has received multiple awards including the Distinguished Achievement Award of the American Heart Association Basic Science Council, the Research Achievement Award of the International Society for Heart Research, and she was elected to the American Society of Clinical Investigation.  In 2020, she assumes the position of Editor in Chief for the Journal of Molecular and Cellular Cardiology.

 

Christian M. Metallo, PhD
University of California, San Diego

Christian Metallo studies metabolism, or the biochemistry of living systems. His laboratory integrates engineering approaches with stable isotope tracing, mass spectrometry, and molecular biology tools to understand how metabolic dysregulation contributes to cancer progression, neurodegeneration, and diabetes. Christian is an Associate Professor in the Department of Bioengineering at the University of California, San Diego. He received his B.S. from the University of Pennsylvania before joining Merck Research Laboratories.  He received his Ph.D. in Chemical Engineering from the University of Wisconsin Madison and was an American Cancer Society Postdoctoral Fellow at the Massachusetts Institute of Technology. Christian was the recipient of the Biomedical Engineering Society Rita Schaffer Young Investigator Award in 2012 and a Searle Scholar Award in 2013. He received a NSF CAREER Award in 2015 and Camille and Henry Dreyfus Teacher-Scholar Award in 2017.

 

Yibin Wang, PhD
University of California, Los Angeles

Dr. Yibin Wang is currently a full Professor of Molecular Medicine in the in the Department of Anesthesiology and Perioperative Medicine at the David Geffen School of Medicine, UCLA.  Dr. Wang received his Ph.D. in molecular genetics and cell biology from the Baylor College of Medicine and postdoctoral training in neurobiology and molecular cardiology at The Scripps Research Institute and the University of California, San Diego. Dr. Wang’s research mainly focuses on genetic and molecular mechanisms of heart failure and metabolic disorders. His lab has made major advances in uncovering stress-signaling mechanisms in the pathogenesis of heart failure, and revealed the functional importance of amino acids catabolism in heart failure and metabolic disorders. He has published over 210 peer-reviewed manuscripts. Dr. Wang has received numerous awards – he was the Chinese National Expert for “Thousand Talent Plan” Visiting Professor from 2011-2016, and the recipient of Thomas Smith Memorial Lecture award at the 2016 American Heart Association Scientific Session.  He currently serves as an Associate Editor for Journal of Molecular and Cellular Cardiology, a guest Associate Editor for Circulation, and a member of the editorial board of Circulation Research and Journal of Biological Chemistry. He has authored five patents with three currently licensed. He is a scientific founder of a new biotech firm Ramino Bio, and has served as a consultant for several major pharmaceutical companies.

The Role of Branched Chain Amino Acids in Human Disease - Part 1


Rong Tian/Christian M. Metallo/Yibin Wang (University of Washington/University of California, San Diego/UCLA)

Further Readings

Metallo

Wallace M, Green CR, Roberts LS, et al

Nat Chem Biol. 2018;14(11):1021-1031

Green CR, Wallace M, Divakaruni AS, et al

Nat Chem Biol. 2016;12(1):15-21

Wang

Sun H, Olson KC, Gao C, et al.

Circulation. 2016;133(21):2038-2049

Zhou M, Shao J, Wu CY, et al

Diabetes. 2019;68(9):1730-1746

Translating BCAA Metabolism for Human Disease

Speakers

David Chuang, PhD
University of Texas Southwestern Medical Center 

Dr. David Chuang is a professor of Biochemistry at the University of Texas Southwestern Medical Center in Dallas, Texas. He received his Ph.D. from Utah State University and did postdoctoral work with Merton Utter at Case Western Reserve University in Cleveland, Ohio. He then joined the Cleveland VA Medical Center, where he teamed up with Rody Cox, M.D. to study biochemical basis of maple syrup urine disease, a severe genetic disorder in branched chain amino acid (BCAA) catabolism. In 1988, Dr. Chuang joined the Biochemistry Department faculty at UT Southwestern, where he has been ever since. His research has primarily  focused on  structure/function and clinical ramifications of the pyruvate dehydrogenase complex (PDC) and  the branched-chain α-ketoacid dehydrogenase (BCKDC) complex, both mitochondrial protein   machines, as well as their regulatory enzymes, i.e. the respective kinases and the phosphatases.  Recently, his laboratory developed a series of small-molecule inhibitors against pyruvate dehydrogenase kinase isoforms 1-4 (PDKs 1-4) and the single BCKD kinase (BDK). These specific kinase inhibitors are capable of augmenting impaired glucose and branched-chain amino acid (BCAA) fluxes, and show promise in restoring glucose and BCAA homeostasis in rodent models for diabetes/metabolic syndrome and heart failure.

Tracy Anthony, PhD
Rutgers University

Tracy G. Anthony, PhD is a professor in the department of nutritional sciences at Rutgers University. Dr. Anthony received a B.S. in human nutrition and foods from Virginia Tech, and received the M.S. and Ph.D. degrees in nutritional sciences from the University of Illinois. She completed a postdoctoral fellowship in molecular physiology at the Penn State College of Medicine in Hershey, PA. Her research program at Rutgers explores cellular responses to nutritional and environmental stress, and her lab utilizes animal models to explore mechanisms of protein homeostasis with applications toward improving metabolism, reducing disease and increasing health span. The National Institutes of Health and the United States Department of Agriculture has funded her research. She currently serves on the editorial boards for Advances in Nutrition, American Journal of Physiology - Endocrinology and Metabolism, Annual Review of Nutrition and Journal of Biological Chemistry. Dr. Anthony has won several awards including the American Society for Nutrition Peter J. Reeds Young Investigator Award for recognition of research, which focuses on the regulation of somatic growth and the unique roles of amino acids in protein metabolism. 

Zoltan Arany, PhD
University of Pennsylvania

Zoltan (Zolt) Arany, MD, PhD is Professor of Medicine and Director of the Cardiovascular Metabolism Program at the Perelman School of Medicine at the University of Pennsylvania. Dr. Arany graduated Summa Cum Laude from Harvard College. He received his Medical Degree from Harvard Medical School and his doctoral degree from the Harvard Graduate School of Arts and Sciences. After his doctoral studies, Dr. Arany completed internal medicine residency training at the Massachusetts General Hospital, followed by fellowship training in Cardiology at the Brigham and Women’s Hospital, and post-doctoral research fellowship at the Dana Farber Cancer Institute, in Boston. He joined the University of Pennsylvania as Associate Professor of Medicine in 2014. Dr. Arany’s laboratory focuses on the mechanisms that underlie metabolic pathophysiology in the cardiovascular system. He focuses on linking investigations of cardiac and vascular physiology in model organisms to clinical data and observations, and taking a multidisciplinary approach, spanning from molecular biology and numerous ‘omic approaches to model organisms and human clinical studies. Dr. Arany is a recipient of several awards including the American Heart Association Established Investigator Award in 2012, the Hal Dvorak Young Investigator Award in Translational Research, and the Inaugural Yale Calabresi Prize in 2014, given to Dr. Arany in recognition for his work on cardiovascular metabolism. He is elected to the American Society of Clinical Investigators and the Association of American Physicians. Dr. Arany has published more than 120 research papers in prominent journals such as New England Journal of Medicine, Nature, Cell, PNAS, Cell Metabolism, and Genes & Development.

The Role of Branched Chain Amino Acids in Human Disease - Part 2


David Chuang/Tracy Anthony/Zoltan Arany (University of Texas Southwestern Medical Center/Rutgers University/University of Pennsylvania)

Further Readings

Anthony

Neinast MD, Jang C, Hui S, et al

Cell Metab. 2019;29(2):417-429.e4

BCAA Metabolism and Cardiovascular Diseases

Speakers

Christopher B. Newgard, PhD
Duke University Medical Center

Christopher B. Newgard, Ph.D. is Director of the Sarah W. Stedman Nutrition and Metabolism Center, founding Director of the Duke Molecular Physiology Institute, and the W. David and Sarah W. Stedman Distinguished Professor at the Duke University Medical Center.  Prior to coming to Duke in 2002, Dr. Newgard was the Gifford O. Touchstone Jr. and Randolph G. Touchstone Distinguished Professor, Department of Biochemistry, and Co-Director of the Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas. Dr. Newgard’s research applies interdisciplinary tools for understanding of cardiometabolic disease mechanisms including gene discovery, metabolic engineering, and comprehensive metabolic analysis. Dr. Newgard has authored >350 peer-reviewed and review articles (h-index, 94), and has been the recipient of several awards, including the Outstanding Scientific Achievement (Lilly) Award from the American Diabetes Association (2001), a Merit Award from the NIH (2001),  and a Duke Medical Alumni Association Distinguished Faculty Award (2016).

 

Rachel Roth Flach, PhD
Pfizer

Rachel received her Bachelor’s degree from the University of Wisconsin-Madison in the field of Clincial Laboratory Science. Following this, Rachel was a product specialist in the diagnostics division of Abbott Laboratories. Rachel then pursued her PhD in pharmacology at Yale University in the laboratory of Anton Bennett, PhD. In 2010, Rachel joined the laboratory of Michael Czech, PhD at University of Massachusetts Medical School in Worcester, MA, for a postdoctoral fellowship. In 2015 Rachel joined Pfizer Inc in the cardiovascular group, and she now leads a laboratory in the Internal Medicine Research Unit.

The Role of Branched Chain Amino Acids in Human Disease - Part 3


Christopher B. Newgard/Rachel Roth Flach (Duke University Medical Center/Pfizer)

Further Readings

Flach

Pandey A, Patel KV, Vaduganathan M, et al

JACC Heart Fail. 2018;6(12):975-982

Sundström J, Bruze G, Ottosson J, Marcus C, Näslund I, Neovius M.

Circulation. 2017;135(17):1577-1585