Mitochondrial [2Fe‐2S] ferredoxins: new functions for old dogs

Abstract

Ferredoxins (FDXs) comprise a large family of iron–sulfur proteins that shuttle electrons from NADPH and FDX reductases into diverse biological processes. This review focuses on the structure, function and specificity of mitochondrial [2Fe‐2S] FDXs that are related to bacterial FDXs due to their endosymbiotic inheritance. Their classical function in cytochrome P450‐dependent steroid transformations was identified around 1960, and is exemplified by mammalian FDX1 (aka adrenodoxin). Thirty years later the essential function in cellular Fe/S protein biogenesis was discovered for the yeast mitochondrial FDX Yah1 that is additionally crucial for the formation of haem a and ubiquinone CoQ6. In mammals, Fe/S protein biogenesis is exclusively performed by the FDX1 paralog FDX2, despite the high structural similarity of both proteins. Recently, additional and specific roles of human FDX1 in haem a and lipoyl cofactor biosyntheses were described. For lipoyl synthesis, FDX1 transfers electrons to the radical S‐adenosyl methionine‐dependent lipoyl synthase to kickstart its radical chain reaction. The high target specificity of the two mammalian FDXs is contained within small conserved sequence motifs, that upon swapping change the target selection of these electron donors.

Antitumor Activity and Mechanistic Insights of a Mitochondria-Targeting Cu(I) Complex

“…38 FDX1 (ferredoxin 1) is a small iron−sulfur protein located in the mitochondrial inner membrane, transferring electrons from NADPH to cytochromes. 39 It has also been found to reduce Cu(II) to Cu(I) and promote the lipoylation of critical enzymes in the TCA cycle, e.g., DLAT. In addition, FDX1 promotes the synthesis and stabilization of Fe−S cluster proteins, 40 which are essential components of ETC complexes.…”

Nonheme binuclear transition metal complexes with hydrosulfide and polychalcogenides

“…52,53 However, the closely related transition metal-sulfido species are found in the active sites of various important enzymes, which include nitrogenases, [54][55][56][57][58][59][60][61] A cluster and C cluster of [NiFe]-carbon monoxide dehydrogenase (CODH), [62][63][64][65] [MoCu]-CODH, [65][66][67][68] bifunctional CODH/acetyl Co-A Synthase (ACS), 69,70 [Fe-Fe]-hydrogenase, [71][72][73][74] [NiFe]-hydrogenase, 71,74 sulfite reductase [75][76][77][78][79] and aconitase, [80][81][82] as well as that of the electron transfer proteins such as ferredoxins. [83][84][85][86][87][88][89][90] Considering the versatile roles of H 2 S/HS À and S 2À in various biological processes, and the presence of metal-sulfido species in the active sites of various important enzymes, it may be considered that research directed toward the synthesis and reactivity of transition metal complexes featuring HS À and S 2À may help in the understanding and development of bioinorganic chemistry. Consequently, an appreciable number of reports describing the synthesis and characterization...…”

Rieske Oxygenases and Other Ferredoxin‐Dependent Enzymes: Electron Transfer Principles and Catalytic Capabilities

“…Adrenodoxins are also involved in the oxidation of α‐terpineol by CYP450s in Pseudomonas (CamB, often referred to as putidaredoxin), [18b] in the Fe−S cluster biosynthesis in humans, [19] and in one of the two Fe−S cluster biosynthetic pathways in Escherichia coli [20] . The adrenodoxin Fe−S cluster is typically coordinated by a four cysteine motif resembling C‐x(5)‐C‐x(2)‐C‐x(34‐36)‐C [18c] …”

“…However, there is no direct experimental proof for any of these functions yet. Members of the plant‐type Fds are typically around 10 kDa in size and coordinate Fe−S clusters with a C‐x(4)‐C‐x(2)‐C‐x(25‐30)‐C motif [13b,18c,26] . They are found in chloroplasts and cyanobacteria where they accept electrons from photosystem I which are then either reinjected in the electron transfer pathway to generate a proton gradient across the thylakoid membrane for the generation of ATP (photosynthetic cyclic electron flow), or are distributed over various other reactions (photosynthetic linear electron flow) [7,27] .…”