Reference: Marobbio CM, et al. (2008) {alpha}-Isopropylmalate, a Leucine Biosynthesis Intermediate in Yeast, Is Transported by the Mitochondrial Oxalacetate Carrier. J Biol Chem 283(42):28445-53

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Abstract

In Saccharomyces cerevisiae, a-isopropylmalate (a-IPM), which is produced in mitochondria, must be exported to the cytosol where it is required for leucine biosynthesis. Recombinant and reconstituted mitochondrial oxaloacetate carrier (Oac1p) efficiently transported a-IPM besides its known substrates oxaloacetate, sulphate and malonate, in contrast to other di- and tricarboxylate transporters as well as the previously proposed a-IPM transporter. Transport was saturable with a half-saturation constant of 75 +/- 4 microM for a-IPM and 0.31 +/- 0.04 mM for ss-IPM and was inhibited by the substrates of Oac1p. Though not transported, a-ketoisocaproate, the immediate precursor of leucine in the biosynthetic pathway, inhibited Oac1p activity competitively. By contrast leucine, a-ketoisovalerate, valine and isoleucine neither inhibited nor were transported by Oac1p. Consistently with the function of Oac1p as an a-IPM transporter, cells lacking the gene for this carrier required leucine for optimal growth on fermentable carbon sources. Single deletions of other mitochondrial carrier genes or of LEU4, which is the only other enzyme that can provide the cytosol with a-IPM in addition to Oac1p, exhibited no growth defect, whereas the double mutant OAC1LEU4 did not grow at all on fermentable substrates in the absence of leucine. The lack of growth of OAC1LEU4 cells was partially restored by adding the leucine biosynthetic cytosolic intermediates a-ketoisocaproate and a-IPM to these cells as well as by complementing them with one of the two unknown human mitochondrial carriers SLC25A34 and SLC25A35. Oac1p is important for leucine biosynthesis on fermentable carbon sources catalyzing the export of a-IPM probably in exchange for oxaloacetate.

Reference Type
Journal Article
Authors
Marobbio CM, Giannuzzi G, Paradies E, Pierri CL, Palmieri F
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