Disease relevance of FUM1

• Heterozygous mutations in the fumarase (FH) gene cause the tumor predisposition syndrome hereditary leiomyomatosis and renal cell cancer (MIM 605839) [1].
• Two biochemically distinct classes of fumarase in Escherichia coli [2].
• The predicted amino acid sequence of the FumC protein showed strong similarity to the E. coli FumC protein, Bacillus subtilis CitG protein, Saccharomyces cerevisiae Fum1 protein, and the mammalian fumarases [3].

High impact information on FUM1

• The single translation product of the FUM1 gene (fumarase) is processed in mitochondria before being distributed between the cytosol and mitochondria in Saccharomyces cerevisiae [4].
• All fumarase molecules synthesized in the cell are processed by the mitochondrial matrix signal peptidase; nevertheless, most of the enzyme (80 to 90%) ends up in the cytosol [4].
• The amino termini of most fumarase molecules are translocated across the mitochondrial membranes and processed [5].
• Northern and S1 nuclease analysis of fumarase transcripts in wild type yeast and in a mutant transformed with FUM1 on an episomal plasmid indicate that the gene is transcribed from multiple start sites, some of which are located inside the coding sequence [6].
• In addition, the binding of yeast fumarase, mitochondrial malate dehydrogenase, and cytosolic malate dehydrogenase to yeast inner membranes was examined [7].

Biological context of FUM1

• This plasmid contains the entire FUM1 gene with only a single base pair change (ATG-->ATC) confined to the putative second inframe translation initiation codon [8].
• Transcription of the majority of Krebs cycle enzymes was downregulated in response to mutations in fumarase [1].
• Modeling tumor predisposing FH mutations in yeast: Effects on fumarase activity, growth phenotype and gene expression profile [1].
• This transient induction was independent of the ploidy level of the cells, and coincided with induction of fumarase, a mitochondrial enzyme involved in the TCA cycle [9].
• The kinetics of continuous salting-out were similar for alcohol dehydrogenase and fumarase [10].

Anatomical context of FUM1

• A single translation product of the FUM1 gene encoding fumarase is distributed between the cytosol and mitochondria of Saccharomyces cerevisiae [5].
• The GAL10 promoter situated upstream of a promoterless FUM1 gene led to production and correct distribution of the two fumarase isoenzyme activities between cytosolic and mitochondrial subcellular fractions [11].

Associations of FUM1 with chemical compounds

• Inducible overexpression of the FUM1 gene in Saccharomyces cerevisiae: localization of fumarase and efficient fumaric acid bioconversion to L-malic acid [11].
• The expression levels of the MDH and FUM1 genes in one mutant (M20), which produced the highest amount of malate among the mutants obtained, were analyzed by Northern hybridization [12].
• On nonfermentable lactate medium, the fumarase knockout strains did not grow, whereas the mutants showed no differences, as compared to WT yeast [1].
• As a comparison, native fumarase was crystallized in the presence of the competitive inhibitor, meso-tartrate [13].
• Accumulation of fumaric acid is presumably caused by high intracellular L-malic acid concentrations and the activity of the cytosolic fumarase [14].

Regulatory relationships of FUM1

• Down-regulated enolase and up-regulated fumarase in the mutant strain seemed to play a role in the improved bioconversion of erythrose-4-phosphate to erythritol compared with the wild strain [15].

Other interactions of FUM1

• Cloning of the Saccharomyces cerevisiae FUM1 gene downstream of the strong GAL10 promoter resulted in inducible overexpression of fumarase in the yeast [11].
• A practical study is presented of the influence of cell debris and polymer recycling upon the operation of two-stage aqueous two-phase systems (ATPS) for the recovery of yeast bulk protein, pyruvate kinase and fumarase [16].
• Except for Ygr086cp, these proteins were believed to be the metabolic enzymes involved in the citric acid cycle (citrate synthase, succinyl-CoA ligase and fumarase) and the glycolysis pathway (pyruvate decarboxylase and enolase) [15].

Analytical, diagnostic and therapeutic context of FUM1

• Fumarase (fumarate hydratase, EC 4.2.1.2) from Saccharomyces cerevisiae has been purified to homogeneity by a method including acetone fractionation, DEAE ion-exchange and dye-sorbent affinity chromatography [17].

References