Premium
Metabolic Specialization of Mouse Embryonic Stem Cells
Author(s) -
McKnight Steven Lanier
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.87.1
Subject(s) - biochemistry , metabolism , biology , embryonic stem cell , purine metabolism , enzyme , metabolic pathway , citric acid cycle , threonine , methyltransferase , chemistry , gene , methylation , serine
The cell doubling time of mouse embryonic stem (ES) cells is shorter than that of even the most aggressively growing cancer cells. To investigate whether mouse ES cells might exist in a unique metabolic state supportive of rapid growth, organic extracts were prepared and analyzed by mass spectrometry. Upon comparison of mouse ES cells with differentiating embryoid bodies, such assays revealed profound differences in the abundance of metabolites associated with one‐carbon metabolism. It was also noted that the abundance of both threonine and acetyl‐CoA changed markedly as ES cells differentiate into embryoid bodies. These differences in metabolite abundance were traced to the copious, ES cell‐specific expression of the gene encoding threonine dehydrogenase (TDH). TDH gene expression was observed to be 1,000‐fold higher in ES cells than any of 7 tissues assayed from adult mice. The TDH enzyme catalyzes the mitochondrial breakdown of threonine into glycine and acetyl‐CoA. Glycine is further catabolized by mitochondrial enzymes associated with the glycine cleavage system to foster the charging (methylation) of tetrahydrofolate, a key intermediate in purine synthesis. The acetyl‐CoA produced from TDH‐mediated breakdown of threonine can be fed into the TCA cycle, used as a building block for the synthesis of lipids and sterols, or deployed as a substrate for protein acetylation. This TDH‐dependent metabolic pathway is prototypic of rapidly growing microbial organisms, and is a component of what has been termed the high flux backbone of microbial metabolism. Nutritional, pharmacologic and genetic approaches have been used to confirm the unique dependency of mouse ES cells on threonine consumption as a metabolic fuel. This research was supported by a program project grant funded by The National Cancer Institute and philanthropic contributions from an anonymous donor.