| First Author | Anderson DD | Year | 2009 |
| Journal | PLoS One | Volume | 4 |
| Issue | 6 | Pages | e5839 |
| PubMed ID | 19513116 | Mgi Jnum | J:150202 |
| Mgi Id | MGI:3849912 | Doi | 10.1371/journal.pone.0005839 |
| Citation | Anderson DD, et al. (2009) SHMT1 and SHMT2 are functionally redundant in nuclear De novo thymidylate biosynthesis. PLoS One 4(6):e5839 |
| abstractText | The three enzymes that constitute the de novo thymidylate synthesis pathway in mammals, cytoplasmic serine hydroxymethyltransferase (SHMT1), thymidylate synthase (TYMS) and dihydrofolate reductase (DHFR) undergo sumoylation and nuclear import during S-phase. In this study, we demonstrate that purified intact mouse liver nuclei convert dUMP to dTMP in the presence of NADPH and serine. Neither nuclear extracts nor intact nuclei exposed to aminomethylphosphonate, a SHMT inhibitor, exhibit thymidylate synthesis activity. Nuclei isolated from Shmt1(-/-) mouse livers retained 25% of thymidylate synthesis activity exhibited by nuclei isolated from wild type mice. This residual activity was due to the presence of a cytoplasmic/nuclear isozyme of SHMT encoded by Shmt2. Shmt2 is shown to encode two transcripts, one which encodes a protein that localizes exclusively to the mitochondria (SHMT2), and a second transcript that lacks exon 1 and encodes a protein that localizes to the cytoplasm and nucleus during S-phase (SHMT2alpha). The ability of Shmt2 to encode a cytoplasmic isozyme of SHMT may account for the viability of Shmt1(-/-) mice and provide redundancy that permitted the expansion of the human SHMT1 L474F polymorphism that impairs SHMT1 sumoylation and nuclear translocation. |
