Leucine Biosynthesis in Fungi: Entering Metabolism through the Back Door

Abstract

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 α-isopropylmalate synthase isoenzymes), LEU1 (isopropylmalate isomerase), and LEU2 (β-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 α-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

Branched chain aldehydes: production and breakdown pathways and relevance for flavour in foods

“…This scheme has extensively been reviewed for lactic acid fermentations (Yvon and Rijnen 2001;Smit et al 2005b) and alcoholic fermentations (Dickinson 2000b). The catabolism of valine, isoleucine, phenylalanine and methionine proceeds very similarly to the pathway described in this paper for leucine (suggested reviews : Kohlhaw 2003;Fernandez and Zuniga 2006).…”

Transcriptional Regulation inSaccharomyces cerevisiae: Transcription Factor Regulation and Function, Mechanisms of Initiation, and Roles of Activators and Coactivators

“…Mutations in different parts of the central region either can make Leu3 a constitutive activator or inhibit Leu3 activity independently of a-2IPM. These mutations and the ability of Leu3 to be regulated by a-IPM in mammalian cell-free extracts suggest that its activation does not require another protein (Kohlhaw 2003).…”

Effect of 21 Different Nitrogen Sources on Global Gene Expression in the YeastSaccharomyces cerevisiae

“…Transcriptional repression of genes involved in a specific biosynthetic pathway has been described in the cases of arginine (39), branched-chain amino acids (leucine, isoleucine, valine) (74), methionine (124), and lysine (10,103). In the case of leucine, repression is mediated through the inhibition of the Leu3 transcription factor (74), and the corresponding target genes have recently been identified on the whole-genome scale (13). For genes of other anabolic pathways, there appears to be no specific transcriptional control.…”