Ferredoxin

The highly reducing ferredoxins are reduced either by using another strong reducing agent, or by using some source of energy to "boost" electrons from less reducing sources to the ferredoxin.[11]

Reactions that reduce Fd include the oxidation of aldehydes to acids like the glyceraldehyde to glycerate reaction (-580 mV), the carbon monoxide dehydrogenase reaction (-520 mV), and the 2-oxoacid:Fd Oxidoreductase reactions (-500 mV)[12][8] like the reaction carried out by pyruvate synthase.[7]

Ferredoxin can also be reduced by using NADH (-320 mV) or H
₂ (-414 mV), but these processes are coupled to the consumption of the membrane potential to power the "boosting" of electrons to the higher energy state.[6] The Rnf complex is a widespread membrane protein in bacteria that reversibly transfers electrons between NADH and ferredoxin while pumping Na⁺
or H⁺
ions across the membrane. The chemiosmotic potential of the membrane is consumed to power the unfavorable reduction of Fd
_ox by NADH. This reaction is an essential source of Fd⁻
_red in many autotrophic organisms. If the cell is growing on substrates that provide excess Fd⁻
_red, the Rnf complex can transfer these electrons to NAD⁺
and store the resultant energy in the membrane potential.[13] The energy converting hydrogenases (Ech) are a family of enzymes that reversibly couple the transfer of electrons between Fd and H
₂ while pumping H ⁺
ions across the membrane to balance the energy difference.[14]

Fd⁰
_ox + NADH + Na⁺
_outside ${\displaystyle {\ce {<=>}}}$ Fd²⁻
_red + NAD⁺
+ Na⁺
_inside

Fd⁰
_ox + H
₂ + H⁺
_outside ${\displaystyle {\ce {<=>}}}$ Fd²⁻
_red + H⁺
+ H⁺
_inside

The unfavourable reduction of Fd from a less reducing electron donor can be coupled simultaneously with the favourable reduction of an oxidising agent through an electron bifurcation reaction.[6] An example of the electron bifurcation reaction is the generation of Fd⁻
_red for nitrogen fixation in certain aerobic diazotrophs. Typically in oxidative phosphorylation the transfer of electrons from NADH to Ubiquinone(Q) is coupled to charging the proton motive force. In Azotobacter the energy released by transferring one electron from NADH to Q is used to simultaneously boost the transfer of one electron from NADH to Fd.[15][16]

Some ferredoxins have a sufficiently high redox potential that they can be directly reduced by NADPH. One such ferredoxin is adrenoxin (-274mV) which takes part in the biosynthesis of many mammalian steroids.[17] The ferredoxin Fd3 in the roots of plants that reduces nitrate and sulfite has a midpoint potential of -337mV and is also reduced by NADPH.[10]

One group of ferredoxins, originally found in chloroplast membranes, has been termed "chloroplast-type" or "plant-type" (InterPro: IPR010241). Its active center is a [Fe₂S₂] cluster, where the iron atoms are tetrahedrally coordinated both by inorganic sulfur atoms and by sulfurs of four conserved cysteine (Cys) residues.

In chloroplasts, Fe₂S₂ ferredoxins function as electron carriers in the photosynthetic electron transport chain and as electron donors to various cellular proteins, such as glutamate synthase, nitrite reductase, sulfite reductase, and the cyclase of chlorophyll biosynthesis.[22] Since the cyclase is a ferredoxin dependent enzyme this may provide a mechanism for coordination between photosynthesis and the chloroplasts need for chlorophyll by linking chlorophyll biosynthesis to the photosynthetic electron transport chain. In hydroxylating bacterial dioxygenase systems, they serve as intermediate electron-transfer carriers between reductase flavoproteins and oxygenase.

The Fe₂S₂ ferredoxin from Clostridium pasteurianum (Cp2FeFd; P07324) has been recognized as distinct protein family on the basis of its amino acid sequence, spectroscopic properties of its iron–sulfur cluster and the unique ligand swapping ability of two cysteine ligands to the [Fe₂S₂] cluster. Although the physiological role of this ferredoxin remains unclear, a strong and specific interaction of Cp2FeFd with the molybdenum-iron protein of nitrogenase has been revealed. Homologous ferredoxins from Azotobacter vinelandii (Av2FeFdI; P82802) and Aquifex aeolicus (AaFd; O66511) have been characterized. The crystal structure of AaFd has been solved. AaFd exists as a dimer. The structure of AaFd monomer is different from other Fe₂S₂ ferredoxins. The fold belongs to the α+β class, with first four β-strands and two α-helices adopting a variant of the thioredoxin fold.[23] UniProt categorizes these as the "2Fe2S Shethna-type ferredoxin" family.[24]

ferredoxin 1
Crystal structure of human ferredoxin-1 (FDX1).[25]
Identifiers
Symbol	FDX1
Alt. symbols	FDX
NCBI gene	2230
HGNC	3638
OMIM	103260
RefSeq	NM_004109
UniProt	P10109
Other data
Locus	Chr. 11 q22.3
Search for Structures Swiss-model Domains InterPro

Adrenodoxin (adrenal ferredoxin; InterPro: IPR001055), putidaredoxin, and terpredoxin make up a family of soluble Fe₂S₂ proteins that act as single electron carriers, mainly found in eukaryotic mitochondria and Pseudomonadota. The human variant of adrenodoxin is referred to as ferredoxin-1 and ferredoxin-2. In mitochondrial monooxygenase systems, adrenodoxin transfers an electron from NADPH:adrenodoxin reductase to membrane-bound cytochrome P450. In bacteria, putidaredoxin and terpredoxin transfer electrons between corresponding NADH-dependent ferredoxin reductases and soluble P450s.[26][27] The exact functions of other members of this family are not known, although Escherichia coli Fdx is shown to be involved in biogenesis of Fe–S clusters.[28] Despite low sequence similarity between adrenodoxin-type and plant-type ferredoxins, the two classes have a similar folding topology.

Ferredoxin-1 in humans participates in the synthesis of thyroid hormones. It also transfers electrons from adrenodoxin reductase to CYP11A1, a CYP450 enzyme responsible for cholesterol side chain cleavage. FDX-1 has the capability to bind to metals and proteins.[29] Ferredoxin-2 participates in heme A and iron–sulphur protein synthesis.[30]

3Fe-4S binding domain
Structural representation of an Fe3S4 ferredoxin.
Identifiers
Symbol	Fer4
Pfam	PF00037
InterPro	IPR001450
PROSITE	PDOC00176
SCOP2	5fd1 / SCOPe / SUPFAM
OPM protein	1kqf
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary PDB 1h98A:33-56 1bd6 :33-56 1bweA:33-56 1bqxA:33-56 1bc6 :33-56 7fd1A:33-56 6fd1 :33-56 6fdrA:33-56 1frx :33-56 1gaoB:33-56 1b0tA:33-56 1b0vA:33-56 1fd2 :33-56 1fdd :33-56 1fer :33-56 1axq :33-56 1g6bA:33-56 2fd2 :33-56 1ff2A:33-56 1pc5A:33-56 7fdrA:33-56 1g3oA:33-56 1ftcA:33-56 1frm :33-56 5fd1 :33-56 1a6l :33-56 1frj :33-56 1fdb :33-56 1fri :33-56 1pc4A:33-56 1f5bA:33-56 1frh :33-56 1d3wA:33-56 1frk :33-56 1f5cA:33-56 1frl :33-56 1fda :33-56 1clf :31-54 1durA:28-51 1fca :30-53 1fdn :30-53 2fdn :30-53 1xer :77-100 1h7xA:946-969 1gteA:946-969 1h7wB:946-969 1gthA:946-969 1gt8A:946-969 1gx7A:28-51 1hfeL:28-51 1blu :2-25 1rgvA:2-25 1kqfB:126-149 1kqgB:126-149 1jb0C:4-27 1k0tA:4-27 1rof :3-26 1vjw :3-26 1dwlA:2-25 2pdaA:738-763 1b0pA:738-763 1kekA:738-763 1c4cA:183-206 1c4aA:183-206 1fehA:183-206 1l0vN:142-165 1kfyN:142-165 1kf6B:142-165 1jnrB:40-63 1jnzB:40-63

A group of Fe₄S₄ ferredoxins, originally found in bacteria, has been termed "bacterial-type". Bacterial-type ferredoxins may in turn be subdivided into further groups, based on their sequence properties. Most contain at least one conserved domain, including four cysteine residues that bind to a [Fe₄S₄] cluster. In Pyrococcus furiosus Fe₄S₄ ferredoxin, one of the conserved Cys residues is substituted with aspartic acid.

During the evolution of bacterial-type ferredoxins, intrasequence gene duplication, transposition and fusion events occurred, resulting in the appearance of proteins with multiple iron–sulfur centers. In some bacterial ferredoxins, one of the duplicated domains has lost one or more of the four conserved Cys residues. These domains have either lost their iron–sulfur binding property or bind to a [Fe₃S₄] cluster instead of a [Fe₄S₄] cluster[31] and dicluster-type.[32]

3-D structures are known for a number of monocluster and dicluster bacterial-type ferredoxins. The fold belongs to the α+β class, with 2-7 α-helices and four β-strands forming a barrel-like structure, and an extruded loop containing three "proximal" Cys ligands of the iron–sulfur cluster.

High potential iron–sulfur proteins (HiPIPs) form a unique family of Fe₄S₄ ferredoxins that function in anaerobic electron transport chains. Some HiPIPs have a redox potential higher than any other known iron–sulfur protein (e.g., HiPIP from Rhodopila globiformis has a redox potential of ca. -450 mV). Several HiPIPs have so far been characterized structurally, their folds belonging to the α+β class. As in other bacterial ferredoxins, the [Fe₄S₄] unit forms a cubane-type cluster and is ligated to the protein via four Cys residues.