Predictive reconstruction of the mitochondrial iron–sulfur cluster assembly metabolism: I. The role of the protein pair ferredoxin–ferredoxin reductase (Yah1–Arh1)

Abstract

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), 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.

Cysteine desulfurase Nfs1 and Pim1 protease control levels of Isu, the Fe-S cluster biogenesis scaffold

“…In the assembly process, a cysteine desulfurase, Nfs1, provides sulfur to Isu via the conserved cysteine located in the active site (6,7). The ferredoxin Yah1 and ferredoxin reductase Arh1 supply the required electrons (8). Yfh1, the yeast frataxin homolog, has been proposed to serve as an iron donor and/or a regulator of Nfs1 function (9-11).…”

Investigation of in Vivo Diferric Tyrosyl Radical Formation in Saccharomyces cerevisiae Rnr2 Protein

“…Our hypothesis is that these pathways will be universal. Nonetheless, the only known S. cerevisiae ferredoxin, Yah1, is localized in the mitochondria and, together with the Fre counterpart Arh1, constitutes the electron transfer chain for the mitochondrial ironsulfur cluster assembly machinery (32)(33)(34)(35). The exclusive mitochondrial localization of Yah1-Arh1 makes them unlikely to perform the role in cluster assembly in the cytoplasmically localized ␤␤Ј (20,32).…”

Biochemical Systems Theory: A Review

“…As noted earlier, the structures of systems have also been assessed with large-scale simulations and post hoc �ltering processes that distinguish acceptable from undesired structures [322,323,[370][371][372][373][374].…”

“…Alves et al applied a large-scale model screening strategy to characterizing details of the biogenesis of iron-sulfur clusters in yeast [373,374].…”

“…Alves developed a model for iron metabolism in yeast [373,374,541]. Particularly interesting in this study is the combination of dynamic modeling with the use of information regarding the molecular structure of key enzymes.…”