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4  structures 323  species 1  interaction 465  sequences 12  architectures

Family: MIOX (PF05153)

Summary: Myo-inositol oxygenase

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Domain of unknown function". More...

Domain of unknown function Edit Wikipedia article

A domain of unknown function (DUF) is a protein domain that has no characterised function. These families have been collected together in the Pfam database using the prefix DUF followed by a number, with examples being DUF2992 and DUF1220. There are now over 3,000 DUF families within the Pfam database representing over 20% of known families.[1]


The DUF naming scheme was introduced by Chris Ponting, through the addition of DUF1 and DUF2 to the SMART database.[2] These two domains were found to be widely distributed in bacterial signaling proteins. Subsequently, the functions of these domains were identified and they have since been renamed as the GGDEF domain and EAL domain respectively.


Structural genomics programmes have attempted to understand the function of DUFs through structure determination. The structures of over 250 DUF families have been solved.[3] This work showed that about two thirds of DUF families had a structure similar to a previously solved one and therefore likely to be divergent members of existing protein superfamilies, whereas about one third possessed a novel protein fold.

Frequency and conservation

Protein domains and DUFs in different domains of life. Left: Annotated domains. Right: domains of unknown function. Not all overlaps shown.[4]

More than 20% of all protein domains were annotated as DUFs in 2013. About 2,700 DUFs are found in bacteria compared with just over 1,500 in eukaryotes. Over 800 DUFs are shared between bacteria and eukaryotes, and about 300 of these are also present in archaea. A total of 2,786 bacterial Pfam domains even occur in animals, including 320 DUFs.[4]

Role in biology

Many DUFs are highly conserved, indicating an important role in biology. However, many such DUFs are not essential, hence their biological role often remains unknown. For instance, DUF143 is present in most bacteria and eukaryotic genomes.[5] However, when it was deleted in Escherichia coli no obvious phenotype was detected. Later it was shown that the proteins that contain DUF143, are ribosomal silencing factors that block the assembly of the two ribosomal subunits.[5] While this function is not essential, it helps the cells to adapt to low nutrient conditions by shutting down protein biosynthesis. As a result, these proteins and the DUF only become relevant when the cells starve.[5] It is thus believed that many DUFs (or proteins of unknown function, PUFs) are only required under certain conditions.

Essential DUFs (eDUFs)

Goodacre et al. identified 238 DUFs in 355 essential proteins (in 16 model bacterial species), most of which represent single-domain proteins, clearly establishing the biological essentiality of DUFs. These DUFs are called "essential DUFs" or eDUFs.[4]

External links


  1. ^ Bateman A, Coggill P, Finn RD (October 2010). "DUFs: families in search of function". Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 66 (Pt 10): 1148–52. doi:10.1107/S1744309110001685. PMC 2954198. PMID 20944204. 
  2. ^ Schultz J, Milpetz F, Bork P, Ponting CP (May 1998). "SMART, a simple modular architecture research tool: identification of signaling domains". Proc. Natl. Acad. Sci. U.S.A. 95 (11): 5857–64. doi:10.1073/pnas.95.11.5857. PMC 34487. PMID 9600884. 
  3. ^ Jaroszewski L, Li Z, Krishna SS, et al. (September 2009). "Exploration of uncharted regions of the protein universe". PLoS Biol. 7 (9): e1000205. doi:10.1371/journal.pbio.1000205. PMC 2744874. PMID 19787035. 
  4. ^ a b c Goodacre, N. F.; Gerloff, D. L.; Uetz, P. (2013). "Protein Domains of Unknown Function Are Essential in Bacteria". MBio 5 (1): e00744–e00713. doi:10.1128/mBio.00744-13. PMID 24381303. 
  5. ^ a b c Häuser, R.; Pech, M.; Kijek, J.; Yamamoto, H.; Titz, B. R.; Naeve, F.; Tovchigrechko, A.; Yamamoto, K.; Szaflarski, W.; Takeuchi, N.; Stellberger, T.; Diefenbacher, M. E.; Nierhaus, K. H.; Uetz, P. (2012). Hughes, Diarmaid, ed. "RsfA (YbeB) Proteins Are Conserved Ribosomal Silencing Factors". PLoS Genetics 8 (7): e1002815. doi:10.1371/journal.pgen.1002815. PMC 3400551. PMID 22829778. 

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "Inositol oxygenase". More...

Inositol oxygenase Edit Wikipedia article

myo-inositol oxygenase
Mouse miox.png
Structure of the mouse myo-inositol oxygenase monomer, generated from 2HUO, colored by secondary structure element.
Symbol MIOX
Alt. symbols ALDRL6
Entrez 55586
HUGO 14522
OMIM 606774
RefSeq NM_017584
UniProt Q9UGB7
Other data
EC number
Locus Chr. 22 q

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] The enzyme employs a unique four-electron transfer at its Fe(II)/Fe(III) coordination sites and the reaction proceeds through the direct binding of myo-inositol followed by attack of the iron center by diatomic oxygen. This enzyme is part of the only known pathway for the catabolism of inositol in humans[2] and is expressed primarily in the kidneys.[3][4] Recent medical research regarding MIOX has focused on understanding its role in metabolic and kidney diseases such as diabetes, obesity and acute kidney injury. Industrially-focused engineering efforts are centered on improving MIOX activity in order to produce glucaric acid in heterologous hosts.


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.[5] This 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 [5] in 2006 followed by the human MIOX[6] in 2008.

The overall structure of the mouse MIOX is primarily helical with five alpha helices forming the core of the protein.[5] 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.[7] 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 structure superimposes closely onto the mouse MIOX structure, sharing 86% sequence identity over the structural alignment but with some differences in the residues surrounding the active site.[6] The human enzyme is characterized by eight alpha helices and a small anti-parallel two-stranded beta sheet.[6]

the MIOX protein fold diverges from that of other non-heme di-iron oxygenases including ribonucleotide reductase and soluble methane monooxygenase.[8] Instead, MIOX closely resembles proteins in the HD-domain superfamily based on its highly conserved metal binding strategy and the presence of the four His ligands on the iron center.[5]


MIOX can accept D-myo-inositol as well as the less abundant chiro isomer of inositol as substrates.[9] A series of crystallization, spectroscopy and density functional theory experiments have revealed a putative mechanism (shown right) for the oxidation of myo-inositol.[10][11][12] ENDOR spectroscopy was used to determine that the substrate directly binds to the Fe(II)/Fe(III) di-iron center of MIOX most likely through the O1 atom of myo-inositol.[7] 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.[5] 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

Myo-inositol can be ingested from fruits and vegetables and actively transported into cells or instead directly synthesized from glucose.[13] In the kidney, MIOX converts myo-inositol to glucuronic acid which is then able to enter the glucuronate-xylulose pathway for conversion to xylulose-5-phosphate.[13] This product can then easily enter the pentose phosphate pathway. Hence, MIOX enables the conversion and catabolism of inositol to generate NADPH and other pentose sugars.

Disease Relevance.

Myo-inositol is a component of the inositol phosphates and phosphoinositides that serve as secondary messengers in many cellular processes including insulin action. Due to its exclusive expression in the kidney, research has focused on understanding the potential role of both myo-inositol levels and MIOX activity on metabolic diseases like diabetes mellitus and obesity. Depletion of MIOX and accumulation of polyols, such as inositol and xylitol, have been cited as contributing factors in complications associated with diabetes.[14] Additionally, a recent study has shown that MIOX is upregulated in the diabetic state with its transcription heavily regulated by osmolarity, glucose levels and oxidative stress.[15] This upregulation is associated with the formation of reactive oxidative species that lead to interstitial injury in the kidney.[15]

There is also interest in evaluating MIOX expression as a potential biomarker of acute kidney injury. MIOX expression was shown to increase in the serum of animals and plasma of critically ill patients within 24 hours of acute kidney injury specifically.[16] An immunoassay of MIOX expression may potentially predict these life-threatening injuries earlier than the current diagnostic—detection of plasma creatine.

Industrial Relevance

The MIOX enzyme has been the object of intense metabolic engineering efforts to produce glucaric acid through biosynthetic pathways. In 2004, the U.S. Department of Energy released a list of the top value-added chemicals from biomass which included glucaric acid—the direct product of the oxidation of glucuronic acid. The first biosynthetic production of glucaric acid was achieved in 2009 with use of the uronate dehydrogenase (UDH) enzyme.[17] Since then, the MIOX enzyme has been engineered for improved glucaric acid production through numerous strategies including appendage of an N-terminal SUMO-tag, directed evolution[18] and also the use of modular, synthetic scaffolds to increase its effective local concentration.

The conversion of myo-inositol to glucaric acid--a top value-added chemical from biomass--can be achieved with a combination of MIOX and UDH enabling heterologous production of glucaric acid.

See also


  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. ^ 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. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ a b Croze, Marine L.; Soulage, Christophe O. (2013-10-01). "Potential role and therapeutic interests of myo-inositol in metabolic diseases". Biochimie 95 (10): 1811–1827. doi:10.1016/j.biochi.2013.05.011. ISSN 1638-6183. PMID 23764390. 
  14. ^ 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. 
  15. ^ a b Tominaga, Tatsuya; Dutta, Rajesh K.; Joladarashi, Darukeshwara; Doi, Toshio; Reddy, Janardan K.; Kanwar, Yashpal S. (2016-01-15). "Transcriptional and Translational Modulation of myo-Inositol Oxygenase (Miox) by Fatty Acids: IMPLICATIONS IN RENAL TUBULAR INJURY INDUCED IN OBESITY AND DIABETES". The Journal of Biological Chemistry 291 (3): 1348–1367. doi:10.1074/jbc.M115.698191. ISSN 1083-351X. PMC 4714220. PMID 26578517. 
  16. ^ Gaut, Joseph P.; Crimmins, Dan L.; Ohlendorf, Matt F.; Lockwood, Christina M.; Griest, Terry A.; Brada, Nancy A.; Hoshi, Masato; Sato, Bryan; Hotchkiss, Richard S. (2014-05-01). "Development of an immunoassay for the kidney-specific protein myo-inositol oxygenase, a potential biomarker of acute kidney injury". Clinical Chemistry 60 (5): 747–757. doi:10.1373/clinchem.2013.212993. ISSN 1530-8561. PMC 4128578. PMID 24486646. 
  17. ^ Moon, Tae Seok; Yoon, Sang-Hwal; Lanza, Amanda M.; Roy-Mayhew, Joseph D.; Prather, Kristala L. Jones (2009-02-01). "Production of glucaric acid from a synthetic pathway in recombinant Escherichia coli". Applied and Environmental Microbiology 75 (3): 589–595. doi:10.1128/AEM.00973-08. ISSN 1098-5336. PMC 2632142. PMID 19060162. 
  18. ^ Shiue, Eric; Prather, Kristala L. J. (2014-03-01). "Improving D-glucaric acid production from myo-inositol in E. coli by increasing MIOX stability and myo-inositol transport". Metabolic Engineering 22: 22–31. doi:10.1016/j.ymben.2013.12.002. ISSN 1096-7184. PMID 24333274. 

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Myo-inositol oxygenase Provide feedback

MIOX is the enzyme myo-inositol oxygenase. It catalyses the first committed step in the glucuronate-xylulose pathway, It is a di-iron oxygenase with a key role in inositol metabolism. The structure reveals a monomeric, single-domain protein with a mostly helical fold that is distantly related to the diverse HD domain superfamily. The structural core is of five alpha-helices that contribute six ligands, four His and two Asp, to the di-iron centre where the two iron atoms are bridged by a putative hydroxide ion and one of the Asp ligands. The substrate is myo-inositol is bound in a terminal substrate-binding mode to a di-iron cluster [1]. Within the structure are two additional proteinous lids that cover and shield the enzyme's active site [2].

Literature references

  1. Brown PM, Caradoc-Davies TT, Dickson JM, Cooper GJ, Loomes KM, Baker EN;, Proc Natl Acad Sci U S A. 2006;103:15032-15037.: Crystal structure of a substrate complex of myo-inositol oxygenase, a di-iron oxygenase with a key role in inositol metabolism. PUBMED:17012379 EPMC:17012379

  2. Thorsell AG, Persson C, Voevodskaya N, Busam RD, Hammarstrom M, Graslund S, Graslund A, Hallberg BM;, J Biol Chem. 2008;283:15209-15216.: Structural and biophysical characterization of human myo-inositol oxygenase. PUBMED:18364358 EPMC:18364358

This tab holds annotation information from the InterPro database.

InterPro entry IPR007828

Inositol oxygenase (EC) is involved in the biosynthesis of UDP-glucuronic acid (UDP-GlcA), providing nucleotide sugars for cell-wall polymers. It may be also involved in plant ascorbate biosynthesis [PUBMED:15660207, PUBMED:14976233].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan HD_PDEase (CL0237), which has the following description:

This clan includes a range of phosphohydrolase enzymes with a common helical fold.

The clan contains the following 10 members:

HD HD_2 HD_3 HD_4 HD_5 HDOD MIOX PDEase_I TraI_2 tRNA_NucTran2_2


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Curation and family details

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Seed source: Pfam-B_2804 (release 7.7)
Previous IDs: DUF706;
Type: Family
Author: Finn RD
Number in seed: 20
Number in full: 465
Average length of the domain: 225.60 aa
Average identity of full alignment: 50 %
Average coverage of the sequence by the domain: 75.99 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.6 20.6
Trusted cut-off 20.6 20.7
Noise cut-off 20.3 20.5
Model length: 249
Family (HMM) version: 12
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Species distribution

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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the MIOX domain has been found. There are 4 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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