Predictive reconstruction of the mitochondrial iron-sulfur cluster assembly metabolism: I. The role of the protein pair ferredoxin-ferredoxin reductase (Yah1-Axh1)

Adrenodoxin reductase homologue (Arh1) and yeast adrenodoxin homologue (Yah1) are essential Saccharomyces cerevisiae mitochondrial proteins involved in heme A biosynthesis and in iron-sulfur cluster (FeSC) assembly. Although the role of Arh1 and Yah1 in heme A biosynthesis is fairly well established, their systemic role on FeSC synthesis is not well understood. Also, while it is thought that the reductase Arh1 provides electrons for the ferredoxin Yah1, two hybrid experiments do not show interaction between the two proteins. In the first part of this article, we use structural bioinformatics methods to evaluate the possibility of interaction between Arh1 and Yah1. Using protein model building and docking algorithms, we predict a complex between Arh1 and Yah1 that is similar to that of their bovine homologues (adrenodoxin reductase-adrenodoxin reductase), suggesting that Arh1 can indeed reduce Yah1. The predicted complex allows us to suggest point mutations to either molecule that could hinder Arh1-Yah1 interaction and test the role of Arh1 as the reductase for Yah1. In the second part of this article, we investigate the physiological role of Arh1-Yah1 on FeSC assembly by deriving alternative mathematical models of the process, based on published information. Comparing the dynamical behavior of each model with that observed in reported experiments emphasizes the importance of Arh1-Yah1 providing electrons for in situ FeSC repair. Only when this mode of action of either of the two proteins in FeSC synthesis is considered can previously reported results be reproduced. (C) 2004 Wiley-Liss, Inc.