Metallothioneins bind metals (Homo sapiens)

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4, 13, 14, 18, 20...6, 12, 21, 30, 322, 6, 273221, 8, 11, 15, 23...5, 16, 373310, 23, 29, 35, 36, 397, 191, 8, 9, 3124, 26cytosolCd2+ Cd2+MT1BMT1A:7Zn2+MT1H:7Zn2+MT2A Cu1+ Cu1+MT1X MT1M MT4Zn2+MT3 MT3 MT1B MT1B:7Zn2+MT1X As3+ MT1E Zn2+ Zn2+ Zn2+ Cd2+MT1A:7Cd2+Cu1+ Zn2+ Cd2+ MT1E:7Zn2+Cd2+ Zn2+MT1G:7Zn2+Zn2+ MT1A Zn2+ Zn2+ MT1A Cd2+ Zn2+Zn2+Zn2+ MT2A:7Zn2+MT1FMT4:10Cu1+MT1X:7Cd2+MT1F:7Zn2+Cu1+Cu1+ MT1X:7Zn2+MT1F Zn2+MT1AMT3 Zn2+MT3MT1G Cd2+ MT2A:10Cu1+Zn2+MT4:7Zn2+MT4:7Cd2+MT1H:7Cd2+MT1A MT3:12Cu1+MT2A MT1XMT4 MT1M Cd2+ MT1F:7Cd2+MT1E MT2A Zn2+ MT1B Cd2+MT1F Cd2+Cu1+Cd2+MT1H MT1HCd2+Cd2+ MT4 MT4 Zn2+ MT2A:7Cd2+MT3:4Zn2+:4Cu+MT1M:7Zn2+Zn2+MT1B:7Cd2+Zn2+ MT1G:7Cd2+MT2AMT1E:7Cd2+Cd2+ MT1H Cd2+Cd2+ MT1M:7Cd2+MT3 MT1G MT3:7Zn2+Cu2+Cd2+ Cd2+Cd2+Cd2+As3+MT1GMT3:7Cd2+Zn2+MT1A:6As3+MT1MCu1+ Cd2+Zn2+Zn2+ Zn2+Cd2+ MT1E17, 3823, 29, 3517, 386, 12, 21, 30, 328, 3117, 387, 195, 16, 37724, 2617, 3817, 382, 6, 2722


Description

Metallothioneins are highly conserved, cysteine-rich proteins that bind metals via thiolate bonds (recent general reviews in Capdevila et al. 2012, Blindauer et al. 2014, reviews of mammalian metallothioneins in Miles et al. 2000, Maret 2011, Vasak and Meloni 2011, Thirumoorthy et al. 2001, Babula et al. 2012). Mammals contain 4 general metallothionein isoforms (MT1,2,3,4). The MT1 isoform has radiated in primates to 8 or 9 functional proteins (depending on classification of MT1L). Each mammalian metallothionein binds a total of 7 divalent metal ions in two clusters, the alpha and beta clusters. Though the functions of metallothioneins have not been fully elucidated, they appear to participate in detoxifying heavy metals (reviewed in Sharma et al. 2013), storing and transporting zinc, and redox biochemistry. Metallothioneins interact with many other cellular proteins, with most interactions involving proteins of the central nervous system (reviewed in Atrian and Capdevila 2013). View original pathway at Reactome.

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Reactome Author: May, Bruce

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114806view16:30, 25 January 2021ReactomeTeamReactome version 75
113250view11:31, 2 November 2020ReactomeTeamReactome version 74
112468view15:42, 9 October 2020ReactomeTeamReactome version 73
101377view11:26, 1 November 2018ReactomeTeamreactome version 66
100915view21:01, 31 October 2018ReactomeTeamreactome version 65
100456view19:36, 31 October 2018ReactomeTeamreactome version 64
100003view16:19, 31 October 2018ReactomeTeamreactome version 63
99556view14:53, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99185view12:42, 31 October 2018ReactomeTeamreactome version 62
93884view13:42, 16 August 2017ReactomeTeamreactome version 61
93452view11:24, 9 August 2017ReactomeTeamreactome version 61
87923view13:00, 25 July 2016RyanmillerOntology Term : 'classic metabolic pathway' added !
86546view09:20, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
As3+ MetaboliteCHEBI:35828 (ChEBI)
As3+MetaboliteCHEBI:35828 (ChEBI)
Cd2+ MetaboliteCHEBI:48775 (ChEBI)
Cd2+MetaboliteCHEBI:48775 (ChEBI)
Cu1+ MetaboliteCHEBI:49552 (ChEBI)
Cu1+MetaboliteCHEBI:49552 (ChEBI)
Cu2+MetaboliteCHEBI:29036 (ChEBI)
MT1A ProteinP04731 (Uniprot-TrEMBL)
MT1A:6As3+ComplexR-HSA-5661211 (Reactome)
MT1A:7Cd2+ComplexR-HSA-5661235 (Reactome)
MT1A:7Zn2+ComplexR-HSA-5661213 (Reactome)
MT1AProteinP04731 (Uniprot-TrEMBL)
MT1B ProteinP07438 (Uniprot-TrEMBL)
MT1B:7Cd2+ComplexR-HSA-5662575 (Reactome)
MT1B:7Zn2+ComplexR-HSA-5662583 (Reactome)
MT1BProteinP07438 (Uniprot-TrEMBL)
MT1E ProteinP04732 (Uniprot-TrEMBL)
MT1E:7Cd2+ComplexR-HSA-5662590 (Reactome)
MT1E:7Zn2+ComplexR-HSA-5662567 (Reactome)
MT1EProteinP04732 (Uniprot-TrEMBL)
MT1F ProteinP04733 (Uniprot-TrEMBL)
MT1F:7Cd2+ComplexR-HSA-5662561 (Reactome)
MT1F:7Zn2+ComplexR-HSA-5662578 (Reactome)
MT1FProteinP04733 (Uniprot-TrEMBL)
MT1G ProteinP13640 (Uniprot-TrEMBL)
MT1G:7Cd2+ComplexR-HSA-5662582 (Reactome)
MT1G:7Zn2+ComplexR-HSA-5662585 (Reactome)
MT1GProteinP13640 (Uniprot-TrEMBL)
MT1H ProteinP80294 (Uniprot-TrEMBL)
MT1H:7Cd2+ComplexR-HSA-5662589 (Reactome)
MT1H:7Zn2+ComplexR-HSA-5662579 (Reactome)
MT1HProteinP80294 (Uniprot-TrEMBL)
MT1M ProteinQ8N339 (Uniprot-TrEMBL)
MT1M:7Cd2+ComplexR-HSA-5662581 (Reactome)
MT1M:7Zn2+ComplexR-HSA-5662570 (Reactome)
MT1MProteinQ8N339 (Uniprot-TrEMBL)
MT1X ProteinP80297 (Uniprot-TrEMBL)
MT1X:7Cd2+ComplexR-HSA-5662568 (Reactome)
MT1X:7Zn2+ComplexR-HSA-5662591 (Reactome)
MT1XProteinP80297 (Uniprot-TrEMBL)
MT2A ProteinP02795 (Uniprot-TrEMBL)
MT2A:10Cu1+ComplexR-HSA-5662969 (Reactome)
MT2A:7Cd2+ComplexR-HSA-5662574 (Reactome)
MT2A:7Zn2+ComplexR-HSA-5662577 (Reactome)
MT2AProteinP02795 (Uniprot-TrEMBL)
MT3 ProteinP25713 (Uniprot-TrEMBL)
MT3:12Cu1+ComplexR-HSA-5662992 (Reactome)
MT3:4Zn2+:4Cu+ComplexR-HSA-5662563 (Reactome)
MT3:7Cd2+ComplexR-HSA-5662584 (Reactome)
MT3:7Zn2+ComplexR-HSA-5662573 (Reactome)
MT3ProteinP25713 (Uniprot-TrEMBL)
MT4 ProteinP47944 (Uniprot-TrEMBL)
MT4:10Cu1+ComplexR-HSA-5662637 (Reactome)
MT4:7Cd2+ComplexR-HSA-5662648 (Reactome)
MT4:7Zn2+ComplexR-HSA-5662640 (Reactome)
MT4ProteinP47944 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
Zn2+MetaboliteCHEBI:29105 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
As3+R-HSA-5661230 (Reactome)
Cd2+R-HSA-5661219 (Reactome)
Cd2+R-HSA-5662595 (Reactome)
Cd2+R-HSA-5662596 (Reactome)
Cd2+R-HSA-5662597 (Reactome)
Cd2+R-HSA-5662599 (Reactome)
Cd2+R-HSA-5662608 (Reactome)
Cd2+R-HSA-5662610 (Reactome)
Cd2+R-HSA-5662617 (Reactome)
Cd2+R-HSA-5662620 (Reactome)
Cd2+R-HSA-5662622 (Reactome)
Cd2+R-HSA-5662649 (Reactome)
Cu1+R-HSA-5662647 (Reactome)
Cu1+R-HSA-5662986 (Reactome)
Cu1+R-HSA-5663002 (Reactome)
Cu2+R-HSA-5662613 (Reactome)
MT1A:6As3+ArrowR-HSA-5661230 (Reactome)
MT1A:7Cd2+ArrowR-HSA-5661219 (Reactome)
MT1A:7Zn2+ArrowR-HSA-5661217 (Reactome)
MT1AR-HSA-5661217 (Reactome)
MT1AR-HSA-5661219 (Reactome)
MT1AR-HSA-5661230 (Reactome)
MT1B:7Cd2+ArrowR-HSA-5662610 (Reactome)
MT1B:7Zn2+ArrowR-HSA-5662603 (Reactome)
MT1BR-HSA-5662603 (Reactome)
MT1BR-HSA-5662610 (Reactome)
MT1E:7Cd2+ArrowR-HSA-5662595 (Reactome)
MT1E:7Zn2+ArrowR-HSA-5662614 (Reactome)
MT1ER-HSA-5662595 (Reactome)
MT1ER-HSA-5662614 (Reactome)
MT1F:7Cd2+ArrowR-HSA-5662596 (Reactome)
MT1F:7Zn2+ArrowR-HSA-5662623 (Reactome)
MT1FR-HSA-5662596 (Reactome)
MT1FR-HSA-5662623 (Reactome)
MT1G:7Cd2+ArrowR-HSA-5662617 (Reactome)
MT1G:7Zn2+ArrowR-HSA-5662618 (Reactome)
MT1GR-HSA-5662617 (Reactome)
MT1GR-HSA-5662618 (Reactome)
MT1H:7Cd2+ArrowR-HSA-5662597 (Reactome)
MT1H:7Zn2+ArrowR-HSA-5662619 (Reactome)
MT1HR-HSA-5662597 (Reactome)
MT1HR-HSA-5662619 (Reactome)
MT1M:7Cd2+ArrowR-HSA-5662599 (Reactome)
MT1M:7Zn2+ArrowR-HSA-5662621 (Reactome)
MT1MR-HSA-5662599 (Reactome)
MT1MR-HSA-5662621 (Reactome)
MT1X:7Cd2+ArrowR-HSA-5662622 (Reactome)
MT1X:7Zn2+ArrowR-HSA-5662615 (Reactome)
MT1XR-HSA-5662615 (Reactome)
MT1XR-HSA-5662622 (Reactome)
MT2A:10Cu1+ArrowR-HSA-5662986 (Reactome)
MT2A:7Cd2+ArrowR-HSA-5662608 (Reactome)
MT2A:7Zn2+ArrowR-HSA-5662598 (Reactome)
MT2AR-HSA-5662598 (Reactome)
MT2AR-HSA-5662608 (Reactome)
MT2AR-HSA-5662986 (Reactome)
MT3:12Cu1+ArrowR-HSA-5663002 (Reactome)
MT3:4Zn2+:4Cu+ArrowR-HSA-5662613 (Reactome)
MT3:7Cd2+ArrowR-HSA-5662620 (Reactome)
MT3:7Zn2+ArrowR-HSA-5662606 (Reactome)
MT3:7Zn2+R-HSA-5662613 (Reactome)
MT3R-HSA-5662606 (Reactome)
MT3R-HSA-5662620 (Reactome)
MT3R-HSA-5663002 (Reactome)
MT4:10Cu1+ArrowR-HSA-5662647 (Reactome)
MT4:7Cd2+ArrowR-HSA-5662649 (Reactome)
MT4:7Zn2+ArrowR-HSA-5662653 (Reactome)
MT4R-HSA-5662647 (Reactome)
MT4R-HSA-5662649 (Reactome)
MT4R-HSA-5662653 (Reactome)
R-HSA-5661217 (Reactome) The MT1A metallothionein binds 7 zinc(II) atoms, 3 at the N-terminal beta domain and 4 at the C-terminal alpha domain (Sunderland et al. 2012). Binding is non-cooperative (Sunderland et al. 2012) and occurs via thiolate bonds between zinc and cysteine residues of the protein. MT1A binds 5 atoms of zinc before clustering of the zinc occurs (Summers et al. 2013). The 2 remaining zinc atoms bind MT1A with significantly less affinity (Summers et al. 2013).
R-HSA-5661219 (Reactome) MT1A binds 7 atoms of cadmium(II), 3 atoms at the N-terminal beta domain and 4 atoms at the C-terminal alpha domain (Rigby Duncan et al. 2008, Sunderland and Stillman 2008, Sutherland et al. 2012). A fifth cadmium atom bound to the alpha domain may be an intermediate formed during metal exchange (Rigby Duncan et al. 2008). Binding of cadmium is non-cooperative (Rigby Duncan and Stillman 2007, Sunderland and Stillman 2008). As inferred from mouse Mt1, MT1A may show less preference for zinc compared with cadmium and may therefore serve more than other metallothionein isoforms to detoxify cadmium.
R-HSA-5661230 (Reactome) Metallothionein MT1A binds 6 atoms of arsenic(III), 3 atoms at the N-terminal beta domain and 3 atoms at the C-terminal alpha domain (Ngu and Stillman 2006, Irvine et al. 2013). Each arsenic atom binds 3 cysteine thiols (Ngu and Stillman 2006, Irvine et al. 2013).
R-HSA-5662595 (Reactome) As inferred from MT1A, the metallothionein MT1E binds 7 atoms of cadmium(II) non-cooperatively.
R-HSA-5662596 (Reactome) As inferred from MT1A, the metallothionein MT1F binds 7 atoms of cadmium(II) non-cooperatively.
R-HSA-5662597 (Reactome) As inferred from MT1A, the metallothionein MT1H binds 7 atoms of cadmium(II) non-cooperatively.
R-HSA-5662598 (Reactome) The metallothionein MT2A binds 7 atoms of zinc(II) in two clusters, one at the N-terminal beta domain and one at the C-terminal alpha domain (Stillman et al. 2000, Yang et al. 2007). The cluster at the alpha domain is more stable than the cluster at the beta domain, making the beta domain a better zinc donor (Jiang et al. 2000). Each cluster assembles independently (Jiang et al. 2000).
R-HSA-5662599 (Reactome) As inferred from MT1A, the metallothionein MT1M binds 7 atoms of cadmium(II) non-cooperatively.
R-HSA-5662603 (Reactome) As inferred from MT1A, the metallothionein MT1B binds 7 atoms of zinc(II) non-cooperatively.
R-HSA-5662606 (Reactome) The metallothionein MT3 binds 7 zinc(II) atoms in 2 clusters, one cluster of 4 atoms at the C-terminal alpha domain and one cluster of 3 atoms at the N-terminal beta domain (Eriste et al. 2003, Knipp et al. 2005, Meloni et al. 2007, Meloni et al. 2008, Meloni et al. 2009, Wu et al. 2014). Though MT3 has a lower overall affinity for zinc than MT2A does (Palumaa et al. 2005), MT3 is capable of binding an additional zinc atom with a binding constant of 100 micromolar (Eriste et al. 2003, Palumaa et al. 2005, Meloni et al. 2009). Stoichiometries up to MT3:11Zn2+ have been observed but the MT3:7Zn2+ form is more stable and predominates (Palumaa et al. 2002, Eriste et al. 2003, Palumaa et al.).
R-HSA-5662608 (Reactome) The metallothionein MT2A binds 7 atoms of cadmium(II), a cluster of 4 atoms at the alpha domain at the C-terminus and a cluster of 3 atoms at the beta domain at the N-terminus (Pan et al. 1999).
R-HSA-5662610 (Reactome) As inferred from MT1A, the metallothionein MT1B binds 7 atoms of cadmium(II) non-cooperatively.
R-HSA-5662613 (Reactome) MT3:7Zn2+ releases 3 zinc ions and binds 4 copper ions at the N-terminal beta domain (Roschitszi et al. 2003, Meloni et al. 2007, Meloni et al. 2008). By this mechanism MT3 is able to scavenge free copper ions and swap metal with an aggregated amyloid beta:copper(II) complex and a alpha-synuclein:copper(II) complex and thereby abolish production of reactive oxygen species (Meloni et al. 2008, Meloni and Vasak 2011, Pedersen et al. 2012, Luo et al. 2013). The copper ions are divalent (copper(II), Cu2+) before binding but univalent (copper(I), Cu1+) after binding (Meloni et al. 2008).
R-HSA-5662614 (Reactome) As inferred from MT1A, the metallothionein MT1E binds 7 atoms of zinc(II) non-cooperatively.
R-HSA-5662615 (Reactome) As inferred from MT1A, the metallothionein MT1X binds 7 atoms of zinc(II) non-cooperatively.
R-HSA-5662617 (Reactome) As inferred from MT1A, the metallothionein MT1G binds 7 atoms of cadmium(II) non-cooperatively.
R-HSA-5662618 (Reactome) As inferred from MT1A, the metallothionein MT1G binds 7 atoms of zinc(II) non-cooperatively.
R-HSA-5662619 (Reactome) As inferred from MT1A, the metallothionein MT1H binds 7 atoms of zinc(II) non-cooperatively.
R-HSA-5662620 (Reactome) The metallothionein binds 7 atoms of cadmium(II) in 2 clusters, 4 atoms at the C-terminal alpha domain and 3 atoms at the N-terminal beta domain (Palumaa et al. 2002, Palumaa et al. 2005, Wu et al. 2014). MT3 binds cadmium with a lower affinity than MT2A does (Palumaa et al. 2005). MT3 can bind more than 7 cadmium atoms, however the MT3:7Cd2+ complex is most prevalent (Palumaa et al. 2002, Palumaa et al. 2005). Exposure of MT3:7Cd2+ to nitric oxide causes release of cadmium (Wang et al. 2008).
R-HSA-5662621 (Reactome) As inferred from MT1A, the metallothionein MT1M binds 7 atoms of zinc(II) non-cooperatively.
R-HSA-5662622 (Reactome) As inferred from MT1A, metallothionein MT1X binds 7 atoms of cadmium(II) non-cooperatively.
R-HSA-5662623 (Reactome) As inferred from MT1A, the metallothionein MT1F binds 7 atoms of zinc(II) non-cooperatively.
R-HSA-5662647 (Reactome) As inferred from the mouse homolog, MT4 binds 10 atoms of copper(I).
R-HSA-5662649 (Reactome) As inferred from the mouse homolog, MT4 binds 7 atoms of cadmium(II).
R-HSA-5662653 (Reactome) As inferred from the mouse homolog, MT4 binds 7 atoms of zinc(II).
R-HSA-5662986 (Reactome) The metallothionein MT2A binds 10 atoms of copper(I). Complexes with up to 12 atoms of Cu+ are observed, however the predominant form appears to be MT2A:10Cu+ (Banci et al. 2010, Chung et al. 2010). Metallothioneins and CuZn-SOD have the highest affinities of cellular proteins for copper(I), but metallothioneins are incapable of removing copper from other cellular enzymes (Banci et al. 2010).
R-HSA-5663002 (Reactome) The metallothionein MT3 is able to bind 12 copper(I) atoms when fully saturated (Roschitzki et al. 2002). Initially, 4 copper(I) atoms bind to each of the alpha and beta domains followed by the binding of 4 more copper(I) atoms. As inferred from the mouse homolog, MT3 exhibits a Cu-thionein character stronger than that of the MT1 and MT2 isoforms and it displays a high capacity to bind Cu+ provided that this occurs in a non-oxidative milieux.
Zn2+ArrowR-HSA-5662613 (Reactome)
Zn2+R-HSA-5661217 (Reactome)
Zn2+R-HSA-5662598 (Reactome)
Zn2+R-HSA-5662603 (Reactome)
Zn2+R-HSA-5662606 (Reactome)
Zn2+R-HSA-5662614 (Reactome)
Zn2+R-HSA-5662615 (Reactome)
Zn2+R-HSA-5662618 (Reactome)
Zn2+R-HSA-5662619 (Reactome)
Zn2+R-HSA-5662621 (Reactome)
Zn2+R-HSA-5662623 (Reactome)
Zn2+R-HSA-5662653 (Reactome)
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