View source for Ferredoxin-thioredoxin reductase

{{Infobox protein family
| Symbol = FeThRed_A
| Name = Ferredoxin thioredoxin reductase variable alpha chain
| image = PDB 1dj7 EBI.jpg
| width = 
| caption = crystal structure of ferredoxin thioredoxin reductase
| Pfam = PF02941
| Pfam_clan =  
| InterPro = IPR004207
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 1dj7
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
{{Infobox protein family
| Symbol = FeThRed_B
| Name = Ferredoxin thioredoxin reductase catalytic beta chain
| image = PDB 1dj7 EBI.jpg
| width = 
| caption = crystal structure of ferredoxin thioredoxin reductase
| Pfam = PF02943
| Pfam_clan =  
| InterPro = IPR004209
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 1dj7
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}

'''Ferredoxin-thioredoxin reductase''' {{EC number|1.8.7.2}}, systematic name ''ferredoxin:thioredoxin disulfide oxidoreductase,'' is a [4Fe-4S] [[protein]] that plays an important role in the [[ferredoxin]]/[[thioredoxin]] regulatory chain.  It catalyzes the following reaction:

::: 2 reduced [[ferredoxin]] + [[thioredoxin]] [[disulfide]] <math>\rightleftharpoons</math> 2 oxidized ferredoxin + thioredoxin [[thiols]] + 2 H<sup>+</sup>

Ferredoxin-Thioredoxin reductase (FTR) converts an [[electron]] signal (photoreduced ferredoxin) to a [[thiol]] signal (reduced thioredoxin), regulating [[enzyme]]s by [[Redox|reduction]] of specific [[disulfide]] groups. It [[catalysis|catalyses]] the light-dependent activation of several [[photosynthesis]] [[enzymes]] and constitutes the first historical example of a thiol/disulfide exchange cascade for enzyme regulation.<ref name="pmid16245124">{{cite journal |vauthors=Buchanan B, Schurmann P, Wolosiuk R, Jacquot J | title = The ferredoxin/thioredoxin system: from discovery to molecular structures and beyond | journal = Discoveries in Photosynthesis | volume = 73 | pages = 215–222 | year = 2002 | pmid = 16245124| doi=10.1023/A:1020407432008 | issue=1–3| s2cid = 18588801 | hdl = 11336/47023 | hdl-access = free }}</ref> It is a [[heterodimer]] of subunit alpha and subunit beta. Subunit alpha is the variable subunit, and beta is the [[catalytic]] chain. The [[secondary structure|structure]] of the beta subunit has been determined and found to fold around the [[FeS]] cluster.<ref name="pmid10649999">{{cite journal |vauthors=Dai S, Schwendtmayer C, Schurmann P, Ramaswamy S, Eklund H | title = Redox signaling in chloroplasts: cleavage of disulfides by an iron-sulfur cluster | journal = Science | volume = 287 | issue = 5453 | pages = 655–8 |date=January 2000 | pmid = 10649999 | doi = 10.1126/science.287.5453.655| url = http://doc.rero.ch/record/32745/files/Shaodong_Dai-Redox_signaling_in_chloroplasts-20130731.pdf }}</ref>

==Biological Function==
Major groups of oxygen-producing, [[photosynthesis|photosynthetic]] organisms such as [[cyanobacteria]], [[algae]], [[C4 carbon fixation#C4pathway|C4]], [[C3 carbon fixation|C3]], and [[crassulacean acid metabolism]] (CAM) plants use Ferredoxin-thioredoxin reductase for [[carbon fixation]] regulation.<ref name= "Hirasawa">{{cite journal |author1=Hirasawa Masakazu |author2=Schurmann Peter |author3=Jacquot Jean-Pierre | year = 1999 | title = Oxidation-Reduction Properties of Chloroplast Thioredoxins, Ferredoxin:Thioredoxin Reductase, and Thioredoxin f-Regulated Enzymes | journal = Biochemistry | volume = 38 | issue = 16| pages = 5200–5205 | doi=10.1021/bi982783v | pmid=10213627|url=http://doc.rero.ch/record/289035/files/Hirasawa_Masakazu_-_Oxidation-Reduction_Properties_of_Chrloroplast_20170628.pdf }}</ref>  FTR, as part of a greater Ferredoxin-Thioredoxin system, allows plants to change their metabolism based on light intensity.  Specifically, the Ferredoxin-Thioredoxin system controls enzymes in the [[Calvin Cycle]] and [[Pentose phosphate pathway]] - allowing plants to balance carbohydrate synthesis and degradation based on the availability of light.<ref name="Buchanan">{{cite journal | author = Buchanan | title = Regulation of CO2 assimilation in oxygenic photosynthesis: The ferredoxin/thioredoxin system: Perspective on its discovery, present status, and future development | journal = Archives of Biochemistry and Biophysics | volume = 288 | issue = 1 | pages = 1–9 |date=July 1991 | pmid = 1910303 | doi = 10.1016/0003-9861(91)90157-E}}</ref> In the light, photosynthesis harnesses light energy and [[Organic redox reaction|reduces]] [[Ferredoxin]]. Using FTR, reduced Ferredoxin then reduces [[Thioredoxin]].  Thioredoxin, through [[Disulfide bond#Preparation and reactions|thiol/disulfide exchange]], then activates carbohydrate synthesis enzymes such as chloroplast [[fructose-1,6-bisphosphatase]], [[Sedoheptulose-bisphosphatase]], and [[phosphoribulokinase]].<ref name="Jacquot">{{cite journal |vauthors=Jacquot J, Lancelin J, Meyer Y | title = Thioredoxins: structure and function in plant cells | journal = New Phytologist | volume = 136 | issue = 4 | pages = 543–570 |date=August 1997 | jstor = 2559149 | doi=10.1046/j.1469-8137.1997.00784.x| doi-access = free }}</ref> As a result, light uses FTR to activate carbohydrate biosynthesis.  In the dark, Ferredoxin remains oxidized.  This leaves Thioredoxin inactive and allows carbohydrate breakdown to dominate metabolism.<ref name="Buchanan"/>

==Structure==
Ferredoxin-Thioredoxin Reductase is an α-β [[protein dimer|heterodimer]] of approximately 30 kDa.<ref name="Staples">{{cite journal |vauthors=Staples C, Ameyibor E, Fu W, Gardet-Salvi L, Stritt-Etter A, Schurmann P, Knaff D, Johnson M | title = The Function and Properties of the Iron-sulfur Center in Spinach Ferredoxin:Thioredoxin Reductase: A New Biological Role for Iron-Sulfur Clusters | journal = Biochemistry | volume = 35 | issue = 35 | pages = 11425–11434 |date=September 1996 | doi = 10.1021/bi961007p| pmid=8784198}}</ref> FTR structure across different plant species include a conserved catalytic β subunit and a variable α subunit. The structure of FTR from ''[[Synechocystis]]'' sp. PCC6803 has been studied in detail and resolved at 1.6 Å.<ref name="pmid10649999"/> FTR resembles a thin [[wikt:Special:Search/concave|concave]] disc, 10 Å across the center where a [[Iron-sulfur cluster|[4Fe-4S cluster]]] resides.  One side of the cluster center contains redox-active disulfide bonds that reduce Thioredoxin while the opposite docks with reduced Ferredoxin. This two sided disc structure allows FTR to simultaneously interact with Thioredoxin and Ferredoxin.<ref name="pmid10649999"/>

[[File:Ferredoxin-Thioredoxin Reductase Fe-S center with surrounding Cysteine residues.jpg|thumbnail|[4Fe-4S] cluster in the Ferredoxin-thioredoxin reductase catalytic β subunit is surrounded by several Cysteine residues.]]

The variable α subunit has an open [[Beta-barrel|β barrel]] structure made of five [[antiparallel (biochemistry)#Beta sheet|antiparallel β strands]].  Its interaction with the catalytic subunit occurs mainly with two loops between β strands. The residues in these two loops are mostly conserved and are thought to stabilize the 4Fe-4S cluster in the catalytic subunit. Structurally, the α subunit is very similar to the PsaE protein, a subunit of [[Photosystem I]], though the similarity is not seen in their sequences or functions.<ref name="pmid10649999"/>

The catalytic β subunit has a general α-helical structure with an [[Iron-sulfur cluster|[4Fe-4S center]]].  The FeS center and redox-active [[Cysteine]] residues are located within the loops of these helices. Cysteine-55, 74, 76, and 85 are coordinated to the iron atoms of the [[cubane-type cluster]].<ref name="pmid10649999"/>

==Enzymatic Mechanism==
FTR is ''unique'' among [[thioredoxin reductase]]s because it uses an Fe-S cluster [[cofactor (biochemistry)|cofactor]] rather than [[flavoprotein]]s to reduce disulfide bonds. FTR catalysis begins with its interaction with reduced Ferredoxin.  This proceeds with the attraction between FTR Lys-47 and Ferredoxin Glu-92.<ref name="Dai">{{cite journal |vauthors=Dai S, Friemann R, Glauser D, Bourqin F, Manieri W, Schurmann P, Eklund H | title = Structural snapshots along the reaction pathway of ferredoxin-thioredoxin reductase | journal = Nature | volume = 448 | pages = 92–96 |date=July 2007 | pmid = 17611542 | doi=10.1038/nature05937 | issue=7149| s2cid = 4366810 }}</ref> One electron from Ferredoxin and one electron from the Fe-S center is abstracted to break FTR's Cys-87 and Cys-57 disulfide bond, create a nucleophilic Cys-57, and oxidize the Fe-S center from [4Fe-4S]<sup>2+</sup> to [4Fe-4S]<sup>3+</sup>.<ref name="Jameson">{{cite journal |vauthors=Jameson G, Elizabeth W, Manieri W, Schurmann P, Johnson M, Huynh B | title = Spectroscopic Evidence for Site Specific Chemistry at a Unique Iron Site of the [4Fe-4S] Cluster in Ferredoxin:Thioredoxin Reductase | journal = Journal of the American Chemical Society | volume =  125| issue = 5 | pages = 1146–1147 | year = 2003 | pmid = 12553798 | doi = 10.1021/ja029338e}}</ref> The structure of this one-electron (from Ferredoxin) intermediate is contested: Staples et al. suggest Cys-87 is coordinated to a Sulfur in the Fe-S center<ref name="Staples"/> while Dai et al. argue Cys-87 is coordinated to an Iron.<ref name="pmid10649999"/>  Next, the nucleophilic Cys-57, encouraged by an adjacent [[Histidine]] residue,<ref name="Glauser">{{cite journal |vauthors=Glauser DA, Bourquin F, Manieri W, Schurmann P | title = Characterization of ferredoxin:thioredoxin reductase modified by site-directed mutagenesis | journal = The Journal of Biological Chemistry | volume = 279 | issue = 16 | pages = 16662–16669 |date=April 2004 | pmid = 14769790 | doi=10.1074/jbc.M313851200| doi-access = free }}</ref> attacks a disulfide bridge on Thioredoxin, creating a hetero-disulfide Thioredoxin intermediate.  Lastly, a newly docked Ferredoxin molecule delivers the final electron to the FeS center, reducing it to its original 2+ state, reforming the Cys-87, Cys-57 disulfide, and fully reducing thioredoxin to two [[thiol]]s.<ref name="Dai"/>

==References==
{{reflist}}
{{InterPro content|IPR004209}}
{{InterPro content|IPR004207}}

== External links ==
* {{MeshName|Ferredoxin:thioredoxin+reductase}}

{{Sulfur oxidoreductases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

[[Category:Protein domains]]
[[Category:EC 1.8.7]]