Leucine biosynthesis in fungi: entering metabolism through the back door.
After exploring evolutionary aspects of branched-chain amino acid biosynthesis, the review focuses on the extended leucine biosynthetic pathway as it operates in Saccharomyces cerevisiae. First, the genes and enzymes specific for the leucine pathway are considered: LEU4 and LEU9 (encoding the alpha-isopropylmalate synthase isoenzymes), LEU1 (isopropylmalate isomerase), and LEU2 (beta-isopropylmalate dehydrogenase). Emphasis is given to the unusual distribution of the branched-chain amino acid pathway enzymes between mitochondrial matrix and cytosol, on the newly defined role of Leu5p, and on regulatory mechanisms governing gene expression and enzyme activity, including new evidence for the metabolic importance of the regulation of alpha-isopropylmalate synthase by coenzyme A. Next, structure-function relationships of the transcriptional regulator Leu3p are addressed, defining its dual role as activator and repressor and discussing evidence in support of the self-masking model. Recent data pointing at a more extended Leu3p regulon are discussed. An overview of the layered controls of the extended leucine pathway is provided that includes a description of the newly recognized roles of Ilv5p and Bat1p in maintaining mitochondrial integrity. Finally, branched-chain amino acid biosynthesis and its regulation in other fungi are summarized, the question of leucine as metabolic signal is addressed, and possible directions of future research in this area are outlined.
Kohlhaw
Gunter B
GB
Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA. kohlhaw@purdue.edu
D015079:2-Isopropylmalate Synthase / Q000235:genetics* / Q000378:metabolism*; D050539:3-Isopropylmalate Dehydrogenase; D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D005075:Biological Evolution; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005658:Fungi / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D007930:Leucine / Q000096:biosynthesis*; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins
C109421:DLEU1 lncRNA, human; D004268:DNA-Binding Proteins; C063667:LEU3 protein, S cerevisiae; D011506:Proteins; D062085:RNA, Long Noncoding; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D000429:Alcohol Oxidoreductases; D050539:3-Isopropylmalate Dehydrogenase; D015079:2-Isopropylmalate Synthase; C080062:LEU4 protein, S cerevisiae; D007930:Leucine