SUMMARY PARAGRAPH for SHM2
SHM2 encodes the cytosolic isoform of serine hydroxymethyltransferase (SHMT) (2), an enzyme which reversibly converts serine to the products glycine and 5,10 methylene tetrahydrofolate (CH2-THF). CH2-THF serves as a one-carbon donor for reactions leading into purine, pyrimidine, amino acid, and lipid biosynthesis (1). Shm2p is responsible for about 95% of the total cellular SHMT activity, with the mitochondrial isoform Shm1p contributing the remainder; in serine-rich conditions, Shm2p is the major source of one-carbon units and glycine produced from serine (2, 1).
SHM2 transcription is repressed by adenine, and this repression is regulated by the transcription factors Bas1p and Pho2p (3). Transcription of SHM2, along with that of other genes involved in one-carbon metabolism, is also repressed under conditions of glycine limitation (4, 5), and this regulatory effect requires Bas1p but is at least partially independent of Pho2p (4). Transcription is induced in a Bas1p-independent manner during methionine limitation (4).
Although the shm2 null mutation confers no apparent phenotype (2), shm2 exhibits a triple synthetic lethal genetic interaction with srp40 and ade3 null mutations (6). Genetic interaction with ADE3 is expected, since Ade3p is also involved in synthesis of tetrahydrofolate compounds, and in fact in some genetic backgrounds, the shm2 ade3 double mutant is inviable (7). However, in a genetic background in which the shm2 ade3 double mutant is viable, a triple srp40 shm2 ade3 null mutant is inviable, which is surprising since there is no obvious connection between these two cytoplasmic biosynthetic enzymes and Srp40p, a nucleolar protein involved in ribosome assembly. Furthermore, a catalytically inactive mutant version of SHM2 can rescue the lethality, suggesting that Shm2p may have an additional non-catalytic function (6). The observation that overproduction of the catalytically inactive mutant Shm2p causes a dramatic increase in cell size also suggests that Shm2p may have a function in addition to its SHMT enzymatic activity (6).
Shm1p and Shm2p have similarity to other SHMTs, which are conserved from bacteria to humans (2, 8). Mutation of an isoform of SHMT in C. elegans has a maternal effect lethal phenotype (8), and the human ortholog of Shm2p, SHMT1 (OMIM) is implicated in Smith-Magenis syndrome.
Last updated: 2008-01-29