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Gene Review

LEU2  -  3-isopropylmalate dehydrogenase

Saccharomyces cerevisiae S288c

Synonyms: 3-IPM-DH, Beta-IPM dehydrogenase, IMDH, YCL018W, YCL18W
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Disease relevance of LEU2

  • All are yeast centromere plasmids with the LEU2 gene for selection in yeast, and pUC19 sequences for growth in Escherichia coli [1].
  • TFIID bound to TATA elements from the adenovirus major late promoter (TATAAAA) and the yeast LEU2 promoter (TATTTAA) and formed protein-DNA complexes stable to electrophoresis only in the presence of TFIIA [2].
  • Despite this specificity, TFIID also binds with high affinity to several TATA elements that do not match the consensus TATA sequences (TATAAA and TATATA): the yeast LEU2 TATA (TATTATTTA), the simian virus 40 TATA (CTTATTTAT), and the yeast CYC1 -10 TATA (TTATACATT) all bound TFIID [3].
  • We have constructed a derivative of the bacteriophage Mu (called MudIIZZ1), which contains the lacZ gene coding for beta-galactosidase (beta Gal) and markers suited for yeast transformation (2 mu circle replication origin and LEU2) [4].
  • A 2 micron circle-based chimaeric plasmid containing the yeast LEU2 and the Herpes Simplex Virus type 1 thymidine kinase (HSV-1 TK) genes was constructed [5].

High impact information on LEU2

  • Nucleotide sequence of yeast LEU2 shows 5'-noncoding region has sequences cognate to leucine [6].
  • Recombinant DNA procedures and the yeast transformation technique were used to insert the yeast gene LEU 2 (coding for beta-isopropylmalate dehydrogenase) into the tandem array of ribosomal DNA genes of the yeast Saccharomyces cerevisiae [7].
  • Role of an upstream regulatory element in leucine repression of the Saccharomyces cerevisiae leu2 gene [8].
  • This element is located within a 280 base pair (bp) fragment which occurs 125 bp upstream of the leu2 translation initiation codon and which contains a short G + C-rich palindromic sequence [8].
  • Southern-type hybridization to DNAs isolated from the transformed yeast clones revealed that the yeast plasmid carrying the prokaryotic methylase gene, as well as the two chromosomal genes tested (his3 and leu2) were methylated, whereas the bulk of the yeast DNA remained largely unmethylated [9].

Chemical compound and disease context of LEU2


Biological context of LEU2

  • This DNA segment overlaps a larger region of DNA (40 kilobase pairs) previously identified to be around the LEU2 locus on chromosome III [Chinault, A.C. & Carbon, J. (1979) Gene 5, 111-126] and physically establishes the directionality of the cloned DNA sequences with respect to the genetic map and the centromere [12].
  • It also has six blocks of homology in common with the 5' flanking regions of two other LEU structural genes (LEU1 and LEU2) [13].
  • Genetic complementation of appropriate yeast mutants permitted the isolation of clones containing the coding sequences for GAL1, HIS3, and LEU2 from the same cDNA library [14].
  • In this study, we used two LEU2 direct-repeat assays to investigate the mechanism by which the rfa1-D228Y allele increases recombination [15].
  • The mutation mapped on chromosome III to an essential 1.5-kb open reading frame (L. S. Symington and T. D. Petes, Mol. Cell. Biol. 8:595-604, 1988), recently named NFS1 (S. G. Oliver et al., Nature [London] 357:38-46, 1992), located adjacent (centromere proximal) to LEU2 [16].

Anatomical context of LEU2

  • Antibodies to the fusion protein detect a 50-55-kDa protein in wild type yeast mitochondria but not in mitochondria of a strain in which the chromosomal MST1 gene was replaced by a copy of the same gene disrupted by insertion of the yeast LEU2 gene [17].
  • To understand how these DNA lesions are repaired in eukaryotic cells, we used mini Tn3 : : LEU2 :: LacZ transposon mutagenesis to isolate yeast mutants that were hypersensitive to bleomycin [18].
  • The methylotrophic yeast Hansenula polymorpha CBS4732 leu2 detoxifies electrophilic xenobiotics by glutathione (GSH)-dependent accumulation in vacuoles, as shown by fluorescence microscopy [19].

Associations of LEU2 with chemical compounds

  • One of the oligonucleotides (based on a LEU2 sequence) was also tested and shown to confer leucine-sensitive expression on the test promoter [20].
  • In at least one case (LEU2), Leu3 actually represses basal-level transcription when alpha-isopropylmalate is absent [21].
  • From this library, LEU2 and HIS3 cDNAs were recovered at a frequency of about 1 in 10(4) and in 12 out of 13 cases these were expressed in a galactose-dependent manner [22].
  • Finally, we found that LEU2 of Candida glabrata, encoding beta-isopropylmalate dehydrogenase and being used to construct the triple mutant, complemented some pos5 phenotypes; however, overexpression of LEU2 of S. cerevisiae did not [23].
  • The integration cassettes comprise a single selectable yeast gene adjacent to a mammalian selectable gene, either LEU2 with neo or HIS3 with hol [24].

Physical interactions of LEU2

  • We show that whole-cell extracts contained a LEU3-dependent DNA-binding activity that interacted with the 5' region of LEU2 [25].

Enzymatic interactions of LEU2

  • Southern analysis of the transformant, JPJ1, confirmed that the chromosomal copy of the RIP1 gene was deleted and replaced by the LEU2 gene [26].
  • The cloned MSL1 gene was used to construct a strain in which 1 kb of the coding sequence was deleted and substituted with the yeast LEU2 gene [27].

Regulatory relationships of LEU2


Other interactions of LEU2

  • Although the majority of genes for amino acid biosynthesis which have been examined are under general amino acid control, LEU1 and LEU2 of Saccharomyces cerevisiae respond specifically to leucine [25].
  • Basal level expression depends upon the GCN4 protein, even though LEU2 is not subject to derepression by the general amino acid control system [28].
  • Analysis of meiotic DNA extracted from the mre4 mutant cells revealed that double-strand breaks occurred at the two sites of the HIS4-LEU2 recombination hot spot, but at a frequency of about 10-20% of the wild type [29].
  • We have applied this element to analysis of the LEU2, RAD50, and CDC48 genes of Saccharomyces cerevisiae [30].
  • These markers from the yeast, Saccharomyces cerevisiae (Sc), can complement the uraA1, trp1 and leu2 mutations of Kl [31].

Analytical, diagnostic and therapeutic context of LEU2


  1. Vectors for the expression and analysis of DNA-binding proteins in yeast. Bonner, J.J. Gene (1991) [Pubmed]
  2. Isolation of the gene encoding the yeast TATA binding protein TFIID: a gene identical to the SPT15 suppressor of Ty element insertions. Hahn, S., Buratowski, S., Sharp, P.A., Guarente, L. Cell (1989) [Pubmed]
  3. Yeast TATA-binding protein TFIID binds to TATA elements with both consensus and nonconsensus DNA sequences. Hahn, S., Buratowski, S., Sharp, P.A., Guarente, L. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  4. In vivo functional characterization of a yeast nucleotide sequence: construction of a mini-Mu derivative adapted to yeast. Daignan-Fornier, B., Bolotin-Fukuhara, M. Gene (1988) [Pubmed]
  5. Amplification of plasmid copy number by thymidine kinase expression in Saccharomyces cerevisiae. Zealey, G.R., Goodey, A.R., Piggott, J.R., Watson, M.E., Cafferkey, R.C., Doel, S.M., Carter, B.L., Wheals, A.E. Mol. Gen. Genet. (1988) [Pubmed]
  6. Nucleotide sequence of yeast LEU2 shows 5'-noncoding region has sequences cognate to leucine. Andreadis, A., Hsu, Y.P., Kohlhaw, G.B., Schimmel, P. Cell (1982) [Pubmed]
  7. Unequal meiotic recombination within tandem arrays of yeast ribosomal DNA genes. Petes, T.D. Cell (1980) [Pubmed]
  8. Role of an upstream regulatory element in leucine repression of the Saccharomyces cerevisiae leu2 gene. Martinez-Arias, A., Yost, H.J., Casadaban, M.J. Nature (1984) [Pubmed]
  9. Expression of a bacterial modification methylase gene in yeast. Fehér, Z., Kiss, A., Venetianer, P. Nature (1983) [Pubmed]
  10. LEU2 directed expression of beta-galactosidase activity and phleomycin resistance in Yarrowia lipolytica. Gaillardin, C., Ribet, A.M. Curr. Genet. (1987) [Pubmed]
  11. Induction of intrachromosomal recombination in yeast by inhibition of thymidylate biosynthesis. Kunz, B.A., Taylor, G.R., Haynes, R.H. Genetics (1986) [Pubmed]
  12. Isolation of the centromere-linked CDC10 gene by complementation in yeast. Clarke, L., Carbon, J. Proc. Natl. Acad. Sci. U.S.A. (1980) [Pubmed]
  13. Structure of yeast LEU4. The 5' flanking region contains features that predict two modes of control and two productive translation starts. Beltzer, J.P., Chang, L.F., Hinkkanen, A.E., Kohlhaw, G.B. J. Biol. Chem. (1986) [Pubmed]
  14. Analysis of full-length cDNA clones carrying GAL1 of Saccharomyces cerevisiae: a model system for cDNA expression. Miyajima, A., Nakayama, N., Miyajima, I., Arai, N., Okayama, H., Arai, K. Nucleic Acids Res. (1984) [Pubmed]
  15. An allele of RFA1 suppresses RAD52-dependent double-strand break repair in Saccharomyces cerevisiae. Smith, J., Rothstein, R. Genetics (1999) [Pubmed]
  16. SPL1-1, a Saccharomyces cerevisiae mutation affecting tRNA splicing. Kolman, C., Söll, D. J. Bacteriol. (1993) [Pubmed]
  17. Characterization of a yeast nuclear gene (MST1) coding for the mitochondrial threonyl-tRNA1 synthetase. Pape, L.K., Koerner, T.J., Tzagoloff, A. J. Biol. Chem. (1985) [Pubmed]
  18. Functional mitochondria are essential for Saccharomyces cerevisiae cellular resistance to bleomycin. He, C.H., Masson, J.Y., Ramotar, D. Curr. Genet. (1996) [Pubmed]
  19. Vacuolar accumulation and extracellular extrusion of electrophilic compounds by wild-type and glutathione-deficient mutants of the methylotrophic yeast Hansenula polymorpha. Ubiyvovk, V.M., Maszewski, J., Bartosz, G., Sibirny, A.A. Cell Biol. Int. (2003) [Pubmed]
  20. LEU3 of Saccharomyces cerevisiae activates multiple genes for branched-chain amino acid biosynthesis by binding to a common decanucleotide core sequence. Friden, P., Schimmel, P. Mol. Cell. Biol. (1988) [Pubmed]
  21. The Saccharomyces cerevisiae Leu3 protein activates expression of GDH1, a key gene in nitrogen assimilation. Hu, Y., Cooper, T.G., Kohlhaw, G.B. Mol. Cell. Biol. (1995) [Pubmed]
  22. Construction of a GAL1-regulated yeast cDNA expression library and its application to the identification of genes whose overexpression causes lethality in yeast. Liu, H., Krizek, J., Bretscher, A. Genetics (1992) [Pubmed]
  23. Identification of ATP-NADH kinase isozymes and their contribution to supply of NADP(H) in Saccharomyces cerevisiae. Shi, F., Kawai, S., Mori, S., Kono, E., Murata, K. FEBS J. (2005) [Pubmed]
  24. Two vectors for the insertion of mammalian selectable genes into yeast artificial chromosome cloned DNA. Tucker, R.M., Burke, D.T. Gene (1997) [Pubmed]
  25. LEU3 of Saccharomyces cerevisiae encodes a factor for control of RNA levels of a group of leucine-specific genes. Friden, P., Schimmel, P. Mol. Cell. Biol. (1987) [Pubmed]
  26. Mutational analysis of the mitochondrial Rieske iron-sulfur protein of Saccharomyces cerevisiae. I. Construction of a RIP1 deletion strain and isolation of temperature-sensitive mutants. Beckmann, J.D., Ljungdahl, P.O., Trumpower, B.L. J. Biol. Chem. (1989) [Pubmed]
  27. Homology of yeast mitochondrial leucyl-tRNA synthetase and isoleucyl- and methionyl-tRNA synthetases of Escherichia coli. Tzagoloff, A., Akai, A., Kurkulos, M., Repetto, B. J. Biol. Chem. (1988) [Pubmed]
  28. Regulation of yeast LEU2. Total deletion of regulatory gene LEU3 unmasks GCN4-dependent basal level expression of LEU2. Brisco, P.R., Kohlhaw, G.B. J. Biol. Chem. (1990) [Pubmed]
  29. The MRE4 gene encodes a novel protein kinase homologue required for meiotic recombination in Saccharomyces cerevisiae. Leem, S.H., Ogawa, H. Nucleic Acids Res. (1992) [Pubmed]
  30. A Tn10-lacZ-kanR-URA3 gene fusion transposon for insertion mutagenesis and fusion analysis of yeast and bacterial genes. Huisman, O., Raymond, W., Froehlich, K.U., Errada, P., Kleckner, N., Botstein, D., Hoyt, M.A. Genetics (1987) [Pubmed]
  31. Low- and high-copy-number shuttle vectors for replication in the budding yeast Kluyveromyces lactis. Chen, X.J. Gene (1996) [Pubmed]
  32. Cloning and sequence analysis of the LEU2 homologue gene from Pichia anomala. De la Rosa, J.M., Pérez, J.A., Gutiérrez, F., González, J.M., Ruiz, T., Rodríguez, L. Yeast (2001) [Pubmed]
  33. Gene targeting by linear duplex DNA frequently occurs by assimilation of a single strand that is subject to preferential mismatch correction. Leung, W., Malkova, A., Haber, J.E. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  34. A short region from the LEU2 gene of Saccharomyces cerevisiae functions as an ARS in the yeast Saccharomyces exiguus Yp74L-3. Hisatomi, T., Wada, Y., Fujisaki, C., Tsuboi, M. Curr. Microbiol. (1998) [Pubmed]
  35. Use of interplasmid recombination to generate stable selectable markers for yeast transformation: application to studies of actin gene control. Hubberstey, A.V., Wildeman, A.G. Genome (1990) [Pubmed]
  36. On spontaneous mutagenesis and cell cultivation conditions. Lyubimova, K.A., Chepurnoy, A.I. Mutat. Res. (1992) [Pubmed]
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