Ferric-chelate reductase

ferric-chelate reductase
Identifiers
EC no.	1.16.1.7
CAS no.	122097-10-3
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

In enzymology, a ferric-chelate reductase (EC 1.16.1.7) is an enzyme that catalyzes the chemical reaction

2 Fe(II) + NAD⁺${\displaystyle \rightleftharpoons }$ 2 Fe(III) + NADH + H⁺

Thus, the two substrates of this enzyme are Fe(II) and NAD⁺, whereas its 3 products are Fe(III), NADH, and H⁺.

Nomenclature

This enzyme belongs to the family of oxidoreductases, specifically those oxidizing metal ion with NAD⁺ or NADP⁺ as acceptor. The systematic name of this enzyme class is Fe(II):NAD⁺ oxidoreductase. Other names in common use include:

• ferric chelate reductase
• iron chelate reductase
• NADH:Fe³⁺-EDTA reductase
• NADH₂:Fe³⁺ oxidoreductase

Prokaryotes

Most studied ferric reductases in bacteria are either specific for a ferric iron complex or non-specific flavin ferric reductases, with the latter being more common in bacteria. ^[1] Both reductase forms are suitable complimentary soluble pathways for the efficient extraction of iron via siderophores. ^[1]

Bacterial soluble flavin reductase in E. coli

Non-specific bacterial flavin reductase has been well researched within E. coli , which is the NAD(P)H: flavin oxidoreductase (Fre). ^[1] In E. coli, NAD(P)H is reduced to either free FAD or riboflavin, which is known to reduce ferric iron to ferrous iron intracellularly. Fre is also structurally similar to ferredoxin-NADP⁺ reductase (Fpr), and bids flavin cofactor to reduce ferredoxin and siderophore bound ferric iron. ^[2] Despite these hypothesized structural commonalities, not much is known regarding this enzymatic structure overall.

Bacterial flavin reductase in Paracoccus denitrificans

Paracoccus denitrificans contains two enzymes which aid in iron reduction - ferric reductase A and B (FerA and FerB). ^[3] FerA binds to oxidized flavins (FMN and FAD). ^[3] Unlike the many structural unknowns surrounding Fre, the crystal structure of FerA is well defined (see Fig. 6 in Sedlácek et. al., 2016). FerA consists of two protein subunits, with three alpha-helices and ten beta-sheets total. ^[3]

Archaeal soluble flavin reductase in Archaeoglobus fulgidus

Archaeoglobus fulgidus has been shown to have a similar ferric reductase (FeR) to the NAD(P)H:flavin oxidoreductase family. ^[1] FeR is archaea specific and reduces external, synthetic ferric iron complexes and Fe(III)-citrate with NAD(P)H and bound flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN) cofactor. ^[4]

Eukaryotes

Soluble ferric reductase in yeast

Ferric reductases are present in some unicellular eukaryotes, including pathogenic yeast which utilize ferric reductases during infection of a host. ^{[5] [6]} Contrary to archaea and bacteria, soluble ferric reductases are much more rare in fungi, with more research necessary to determine just how widespread soluble ferric reductase are amongst fungi. ^[1] These soluble ferric reductases in fungi are known to operate extracellularly, as fungi are capable of excreting them to reduce iron in the environment. ^[1] This mechanism of ferric reductase excretion allows the labilization of iron in the environment, and typically happens concurrently with fungal siderophore pathways and iron reduction on cellular surfaces, which occur with membrane-bound ferric reductases. ^[1]

Membrane-bound ferric reductase in yeast

Membrane-bound ferric reductases are fore more common in yeast cells relative to soluble ferric reductases. These reductases utilize NAD(P)H, falvin, and heme b cofactors in order to move reducing agents across their membranes to an extracellular Fe(III) source. ^{[5] [6]} After this, the reduced Fe(II) may be re-oxidized and rebound to be transported across the membrane again via both Cu-dependent ferroxidase and Fe(III) transport proteins. ^{[6] [7]} Alternatively, ferrous, unchelated iron can be transported via low-affinity proteins, however, this mechanism is less common than the former. ^[6]

Membrane-bound ferric reductase in Arabidopsis

Most plants contain ferric-chelate reductase in order to uptake iron from the environment. Arabidopsis is capable of increasing the activity of ferric-chelate reductase, which is located in the membranes of root epidermal cells, in environments with limited iron availability. ^[8] Additionally, it is hypothesized that the activity of this reductase stimulates iron release from organic compounds within the soils, releasing it for biological uptake. ^[9] The crystalline structure of this enzyme in Arabidopsis has not yet been well constrained, however, it is hypothesized that, due to its similar functions, its structure is likely similar to ferric-chelate reductases in both yeast and human phagocytic NADPH oxidase gp91phox. ^{[10] [11]}

References

1. Cain TJ, Smith AT (May 2021). "Ferric iron reductases and their contribution to unicellular ferrous iron uptake". Journal of Inorganic Biochemistry. 218: 111407. doi:10.1016/j.jinorgbio.2021.111407. PMC   8035299 . PMID   33684686.
2. Yeom J, Jeon CO, Madsen EL, Park W (March 2009). "Ferredoxin-NADP+ reductase from Pseudomonas putida functions as a ferric reductase". Journal of Bacteriology. 191 (5): 1472–1479. doi:10.1128/JB.01473-08. PMC   2648195 . PMID   19114475.
3. Sedláček V, Klumpler T, Marek J, Kučera I (2016-07-01). "Biochemical properties and crystal structure of the flavin reductase FerA from Paracoccus denitrificans". Microbiological Research. 188–189: 9–22. doi:10.1016/j.micres.2016.04.006. PMID   27296958.
4. Vadas A, Monbouquette HG, Johnson E, Schröder I (December 1999). "Identification and characterization of a novel ferric reductase from the hyperthermophilic Archaeon Archaeoglobus fulgidus". The Journal of Biological Chemistry. 274 (51): 36715–36721. doi: 10.1074/jbc.274.51.36715 . PMID   10593977.
5. Saikia S, Oliveira D, Hu G, Kronstad J (February 2014). Deepe GS (ed.). "Role of ferric reductases in iron acquisition and virulence in the fungal pathogen Cryptococcus neoformans". Infection and Immunity. 82 (2): 839–850. doi:10.1128/IAI.01357-13. PMC   3911385 . PMID   24478097.
6. Martínez-Pastor MT, Puig S (October 2020). "Adaptation to iron deficiency in human pathogenic fungi". Biochimica et Biophysica Acta. Molecular Cell Research. 1867 (10): 118797. doi:10.1016/j.bbamcr.2020.118797. PMID   32663505. S2CID   220527792.
7. Singh A, Kaur N, Kosman DJ (September 2007). "The metalloreductase Fre6p in Fe-efflux from the yeast vacuole". The Journal of Biological Chemistry. 282 (39): 28619–28626. doi: 10.1074/jbc.M703398200 . PMID   17681937.
8. Robinson NJ, Procter CM, Connolly EL, Guerinot ML (February 1999). "A ferric-chelate reductase for iron uptake from soils". Nature. 397 (6721): 694–697. Bibcode:1999Natur.397..694R. doi:10.1038/17800. PMID   10067892. S2CID   204991448.
9. Eide D (1998). "The Molecular Biology of Iron and Zinc Uptake in Saccharomyces cerevisiae". Metal Ions in Gene Regulation. Boston, MA: Springer US. pp. 342–371. doi:10.1007/978-1-4615-5993-1_13. ISBN   978-1-4613-7745-0.
10. Dancis A, Klausner RD, Hinnebusch AG, Barriocanal JG (May 1990). "Genetic evidence that ferric reductase is required for iron uptake in Saccharomyces cerevisiae". Molecular and Cellular Biology. 10 (5): 2294–2301. doi:10.1128/mcb.10.5.2294. PMC   360576 . PMID   2183029.
11. Chanock SJ, el Benna J, Smith RM, Babior BM (October 1994). "The respiratory burst oxidase". The Journal of Biological Chemistry. 269 (40): 24519–24522. doi:10.1016/s0021-9258(17)31418-7. PMID   7929117.

Further reading

• Askerlund P, Larsson C, Widell S (1988). "Localization of donor and acceptor sites of NADH dehydrogenase activities using inside-out and right-side-out plasma membrane vesicles from plants". FEBS Lett. 239: 23–28. doi:10.1016/0014-5793(88)80538-6. S2CID   51767403.
• Freitas MP (March 2006). "MIA-QSAR modelling of anti-HIV-1 activities of some 2-amino-6-arylsulfonylbenzonitriles and their thio and sulfinyl congeners". Organic & Biomolecular Chemistry. 4 (6): 1154–1159. doi:10.1039/b516396j. PMID   16525561.
• Buckhout TJ, Hrubec TC (1986). "Pyridine nucleotide-dependent ferricyanide reduction associated with isolated plasma membranes of maize (Zea mays L.) roots". Protoplasma. 135 (2–3): 144–154. doi:10.1007/BF01277007. S2CID   19281109.
• Sandelius AS, Barr R, Crane FL, Morre DJ (1986). "Redox reactions of plasma membranes isolated from soybean hypocotyls by phase partition". Plant Sci. 48: 1–10. doi:10.1016/0168-9452(87)90062-8.