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Inositol oxygenase

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myo-inositol oxygenase
Structure of the mouse myo-inositol oxygenase monomer, generated from 2HUO, colored by secondary structure element.
Identifiers
SymbolMIOX
Alt. symbolsALDRL6
NCBI gene55586
HGNC14522
OMIM606774
PDB2IBN
RefSeqNM_017584
UniProtQ9UGB7
Other data
EC number1.13.99.1
LocusChr. 22 q
Search for
StructuresSwiss-model
DomainsInterPro

Inositol oxygenase, also commonly referred to as myo-inositol oxygenase (MIOX), is a non-heme di-iron enzyme that oxidizes myo-inositol to glucuronic acid.[1] This enzyme is part of the only known pathway for the catabolism of inositol in humans[2] and is expressed mostly in the kidneys.[3][4] Depletion of MIOX and accumulation of polyols, such as inositol and xylitol, have been cited as contributing factors in complications associated with diabetes.[5]


Structure

The active site of the mouse MIOX enzyme highlighting the di-iron active site along with the coordinated amino acids. The Fe atom binds to the oxygens of the C1 and C6 of myo-inositol. Lys 127 helps to promote the abstraction of the hydrogen atom from the C1 carbon.

Myo-inositol oxygenase is a monomeric 33 kDa protein in both solution and crystal[6]. This class of enzyme possesses a Fe(II)/Fe(III) atomic pair at the catalytic active site which enables its unique four-electron transfer mechanism. Recent crystallization studies have elucidated the structures of the mouse MIOX [6] in 2006 followed by the human MIOX[7] in 2008.

The overall structure of the mouse MIOX is primarily helical with five alpha helices forming the core of the protein[6]. Like other di-iron oxygenases, the iron coordination centers are buried deep inside the protein presumably to protect the cell from the superoxide and radical reaction intermediates that are formed[8]. The two iron centers are coordinated by various amino acids and water molecules as shown in complex with the myo-inositol substrate. The human MIOX superimposes closely onto the mouse MIOX sharing 86% sequence identity over the the structural alignment but with some differences in the residues surrounding the active site[7]. The human enzyme is characterized by eight alpha helices and a small anti-parallel two-stranded beta sheet[7].

Interestingly, the MIOX protein fold diverges from that of other non-heme di-iron oxygenases including ribonucleotide reductase or soluble methane monooxygenase[9] . Instead, MIOX closely resembles proteins in the HD-domain superfamily which are characterized by their highly conserved metal binding strategy and based on the presence of the four His ligands on the iron center[6].

Mechanism

File:Miox-mech.gif
Key steps in the MIOX reaction. The superoxoFe(III)/Fe(III) species, formed by displacement of the terminal water on the primary Fe by dioxygen. Abstraction of the C1 hydrogen atom gives the radical species in B, followed by formation of a hydroperoxy derivative in C, breakage of the C1-C6 bond, and release of glucuronic acid.[10]

MIOX can accept D-myo-inositol as well as the less abundant chiro isomer of inositol as substrates[11]. A series of crystallization, spectroscopy and density functional theory experiments have revealed a putative mechanism (shown right) for the oxidation of myo-inositol[12] [13] [14]. ENDOR spectroscopy was used to determine that the substrate directly binds to Fe(II)/Fe(III) di-iron center of MIOX most likely through the O1 atom of myo-inositol [8]. In the mouse MIOX, this binding process was shown to be dependent on proximal amino acid residues as alanine mutants D85A and K127A were unable to turnover substrate [6]. This binding step positions the myo-inositol prior to the catalytic steps which involve attack of an iron center by diatomic oxygen followed by abstraction of a myo-inositol hydrogen atom.

A superoxide Fe(III)/Fe(III) species is formed as diatomic oxygen displaces water as a coordinating ligand on one of the Fe atoms. Next, the hydrogen atom from C1 of myo-inositol is abstracted to generate a radical that can be attacked by an oxygen radical. Release of D-glucuronic acid is achieved in the fourth step.

Biological Function

Disease Relevance.

Industrial Relevance

See also

References

  1. ^ Bollinger JM, Diao Y, Matthews ML, Xing G, Krebs C (Feb 2009). "myo-Inositol oxygenase: a radical new pathway for O(2) and C-H activation at a nonheme diiron cluster". Dalton Transactions (6): 905–14. doi:10.1039/b811885j. PMID 19173070.
  2. ^ Hankes LV, Politzer WM, Touster O, Anderson L (Oct 1969). "Myo-inositol catabolism in human pentosurics: the predominant role of the glucuronate-xylulose-pentose phosphate pathway". Annals of the New York Academy of Sciences. 165 (2): 564–76. doi:10.1111/j.1749-6632.1970.tb56424.x. PMID 5259614.
  3. ^ Reddy CC, Swan JS, Hamilton GA (Aug 1981). "myo-Inositol oxygenase from hog kidney. I. Purification and characterization of the oxygenase and of an enzyme complex containing the oxygenase and D-glucuronate reductase". The Journal of Biological Chemistry. 256 (16): 8510–8. PMID 7263666.
  4. ^ Charalampous FC (Feb 1959). "Biochemical studies on inositol. V. Purification and properties of the enzyme that cleaves inositol to D-glucuronic acid". The Journal of Biological Chemistry. 234 (2): 220–7. PMID 13630882.
  5. ^ Cohen RA, MacGregor LC, Spokes KC, Silva P, Epstein FH (Oct 1990). "Effect of myo-inositol on renal Na-K-ATPase in experimental diabetes". Metabolism. 39 (10): 1026–32. doi:10.1016/0026-0495(90)90161-5. PMID 2170818.
  6. ^ a b c d e Brown, Peter M.; Caradoc-Davies, Tom T.; Dickson, James M. J.; Cooper, Garth J. S.; Loomes, Kerry M.; Baker, Edward N. (2006-10-10). "Crystal structure of a substrate complex of myo-inositol oxygenase, a di-iron oxygenase with a key role in inositol metabolism". Proceedings of the National Academy of Sciences of the United States of America. 103 (41): 15032–15037. doi:10.1073/pnas.0605143103. ISSN 0027-8424. PMC 1622774. PMID 17012379.
  7. ^ a b c Thorsell, Ann-Gerd; Persson, Camilla; Voevodskaya, Nina; Busam, Robert D.; Hammarström, Martin; Gräslund, Susanne; Gräslund, Astrid; Hallberg, B. Martin (2008-05-30). "Structural and biophysical characterization of human myo-inositol oxygenase". The Journal of Biological Chemistry. 283 (22): 15209–15216. doi:10.1074/jbc.M800348200. ISSN 0021-9258. PMC 3258897. PMID 18364358.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ a b Kim, Sun Hee; Xing, Gang; Bollinger, J. Martin; Krebs, Carsten; Hoffman, Brian M. (2006-08-16). "Demonstration by 2H ENDOR spectroscopy that myo-inositol binds via an alkoxide bridge to the mixed-valent diiron center of myo-inositol oxygenase". Journal of the American Chemical Society. 128 (32): 10374–10375. doi:10.1021/ja063602c. ISSN 0002-7863. PMID 16895396.
  9. ^ Hirao, Hajime; Morokuma, Keiji (2009-12-02). "Insights into the (superoxo)Fe(III)Fe(III) intermediate and reaction mechanism of myo-inositol oxygenase: DFT and ONIOM(DFT:MM) study". Journal of the American Chemical Society. 131 (47): 17206–17214. doi:10.1021/ja905296w. ISSN 1520-5126. PMID 19929019.
  10. ^ Brown, Peter M.; Caradoc-Davies, Tom T.; Dickson, James M. J.; Cooper, Garth J. S.; Loomes, Kerry M.; Baker, Edward N. (2006-10-10). "Crystal structure of a substrate complex of myo-inositol oxygenase, a di-iron oxygenase with a key role in inositol metabolism". Proceedings of the National Academy of Sciences of the United States of America. 103 (41): 15032–15037. doi:10.1073/pnas.0605143103. ISSN 0027-8424. PMC 1622774. PMID 17012379.
  11. ^ Arner RJ, Prabhu KS, Thompson JT, Hildenbrandt GR, Liken AD, Reddy CC (Dec 2001). "myo-Inositol oxygenase: molecular cloning and expression of a unique enzyme that oxidizes myo-inositol and D-chiro-inositol". The Biochemical Journal. 360 (Pt 2): 313–20. doi:10.1042/0264-6021:3600313. PMC 1222231. PMID 11716759.
  12. ^ Xing, Gang; Barr, Eric W.; Diao, Yinghui; Hoffart, Lee M.; Prabhu, K. Sandeep; Arner, Ryan J.; Reddy, C. Channa; Krebs, Carsten; Bollinger, J. Martin (2006-05-02). "Oxygen activation by a mixed-valent, diiron(II/III) cluster in the glycol cleavage reaction catalyzed by myo-inositol oxygenase". Biochemistry. 45 (17): 5402–5412. doi:10.1021/bi0526276. ISSN 0006-2960. PMID 16634621.
  13. ^ Xing, Gang; Hoffart, Lee M.; Diao, Yinghui; Prabhu, K. Sandeep; Arner, Ryan J.; Reddy, C. Channa; Krebs, Carsten; Bollinger, J. Martin (2006-05-02). "A coupled dinuclear iron cluster that is perturbed by substrate binding in myo-inositol oxygenase". Biochemistry. 45 (17): 5393–5401. doi:10.1021/bi0519607. ISSN 0006-2960. PMID 16634620.
  14. ^ Xing, Gang; Diao, Yinghui; Hoffart, Lee M.; Barr, Eric W.; Prabhu, K. Sandeep; Arner, Ryan J.; Reddy, C. Channa; Krebs, Carsten; Bollinger, J. Martin (2006-04-18). "Evidence for C-H cleavage by an iron-superoxide complex in the glycol cleavage reaction catalyzed by myo-inositol oxygenase". Proceedings of the National Academy of Sciences of the United States of America. 103 (16): 6130–6135. doi:10.1073/pnas.0508473103. ISSN 0027-8424. PMC 1458843. PMID 16606846.
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