Steven L. McKnight, Ph.D.

University of Texas Southwestern Medical Center
Dallas, TX

Metabolism has been studied by thousands of scientists and the basics of this process are very well known. Less understood is how metabolic systems cycle and interact dynamically with the environment. Also unclear is how various metabolic states enable unique growth potential, such as that of embryonic stem cells.

Dr. Steven McKnight planned to use his Pioneer Award funds to dive into uncharted territories of metabolic regulation.

He began his studies by methodically measuring the levels of hundreds of metabolites in the yeast metabolic cycle using mass spectrometry and a chemostat, a device that constantly doses chemicals into a culture vessel to maintain stable conditions.

McKnight’s Pioneer Award-supported studies have revealed a surprising level of order in metabolism. He has found that in yeast, essential cellular and metabolic events occur in synchrony with the metabolic cycle, demonstrating that key processes in a simple eukaryotic cell are compartmentalized in time. Predictable swings in nutrient consumption during continuous growth show an uncanny logic of cellular metabolism during different phases of a yeast cell’s life. McKnight reasons that these regular oscillations may be key to linking metabolism to other biological rhythms. To that end, he conjectures that synchronizing circadian, metabolic and cell division cycles may be evolution’s solution to preserving the integrity of an organism’s genome.

This work was painstaking and time-consuming, not the kind of effort typically financed by individual, investigator-initiated research, McKnight says. The Pioneer Award enabled him to lay important groundwork for unanticipated studies of the unique metabolic state of mouse embryonic stem cells. In this area, McKnight has discovered that mouse embryonic stem cells assume a special metabolic state that may enable their rapid growth compared to other, differentiated cells in an adult mouse.

The findings also reveal that mouse embryonic stem cells are critically dependent upon a single amino acid, threonine. These results imply that the cells exist in a “high-flux backbone” metabolic state resembling that of rapidly growing bacteria. McKnight discovered that the activity of the gene responsible for generating quick energy from threonine was 1,000 times higher in mouse embryonic stem cells than in any other mouse tissue measured. This gene encodes the threonine dehydrogenase (TDH) enzyme, which breaks down threonine into glycine and acetyl-CoA, two metabolites that facilitate “high-octane” metabolism.

With only one exception, all species whose genomes have been sequenced to date encode an active TDH enzyme. The exception is humans: The human genome contains three inactivating mutations in the TDH gene. McKnight speculates that human embryonic stem cells, which grow much more slowly than mouse embryonic stem cells, might benefit from receiving and expressing a repaired TDH gene. This could dramatically improve the ease of working with human embryonic stem cells, which are notoriously finicky to grow in the lab.

Tu BP, Kudlicki A, Rowicka M, McKnight SL. Logic of the yeast metabolic cycle: temporal compartmentalization of cellular processes. Science 2005;310:1152-8.

Tu BP, Mohler RE, Liu JC, Dombek KM, et al. Cyclic changes in metabolic state during the life of a yeast cell. Proc Natl Acad Sci USA. 2007;104:16886-91.

Chen Z, Odstrcil EA, Tu BP, McKnight SL. Restriction of DNA replication to the reductive phase of the metabolic cycle protects genome integrity. Science 2007;316:1916-9.

Wang J, Alexander P, Wu L, Hammer R, Cleaver O, McKnight SL. Unique dependence of mouse embryonic stem cells on threonine catabolism. Science 2009, in press.

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