title: Multi-heme proteins: nature's electronic multi-purpose tool.
abstract: While iron is often a limiting nutrient to Biology, when the element is found in the form of heme cofactors (iron protoporphyrin IX), living systems have excelled at modifying and tailoring the chemistry of the metal. In the context of proteins and enzymes, heme cofactors are increasingly found in stoichiometries greater than one, where a single protein macromolecule contains more than one heme unit. When paired or coupled together, these protein associated heme groups perform a wide variety of tasks, such as redox communication, long range electron transfer and storage of reducing/oxidizing equivalents. Here, we review recent advances in the field of multi-heme proteins, focusing on emergent properties of these complex redox proteins, and strategies found in Nature where such proteins appear to be modular and essential components of larger biochemical pathways. This article is part of a Special Issue entitled: Metals in Bioenergetics and Biomimetics Systems.
authors.affiliation: Department of Chemistry, Boston University, Boston, MA 02215, USA.
authors.forename: Kathryn D
authors.initials: KD
authors.lastname: Bewley
authors.forename: Katie E
authors.initials: KE
authors.lastname: Ellis
authors.forename: Mackenzie A
authors.initials: MA
authors.lastname: Firer-Sherwood
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Elliott
mesh_terms: D006420:Hemeproteins / Q000737:chemistry*; D008958:Models, Molecular; D010084:Oxidation-Reduction
chemical_list: D006420:Hemeproteins
keywords: Cytochrome c; Cytochrome c peroxidase; Dissimilatory metal reduction; Electron transfer
references.citation: Mol Microbiol. 2006 Nov;62(3):794-810
references.pmid: 16995898
references.citation: Environ Microbiol. 2008 Nov;10(11):3150-63
references.pmid: 18761666
references.citation: Annu Rev Microbiol. 1993;47:263-90
references.pmid: 8257100
references.citation: J Biol Chem. 2006 Feb 17;281(7):4371-9
references.pmid: 16314410
references.citation: Cell Mol Life Sci. 2001 Oct;58(11):1562-71
references.pmid: 11706984
references.citation: Biochemistry. 2010 Oct 5;49(39):8546-53
references.pmid: 20812758
references.citation: J Bacteriol. 1990 Nov;172(11):6232-8
references.pmid: 2172208
references.citation: Structure. 2012 Jul 3;20(7):1275-84
references.pmid: 22682743
references.citation: Biochem Soc Trans. 2006 Feb;34(Pt 1):146-9
references.pmid: 16417506
references.citation: Nat Struct Biol. 1998 Nov;5(11):1005-12
references.pmid: 9808046
references.citation: Biochemistry. 2011 May 31;50(21):4513-20
references.pmid: 21524102
references.citation: Annu Rev Microbiol. 1994;48:311-43
references.pmid: 7826009
references.citation: Biochemistry. 2012 Dec 21;51(51):10175-85
references.pmid: 23210513
references.citation: Mol Microbiol. 2007 May;64(4):1049-60
references.pmid: 17501927
references.citation: Nat Biotechnol. 2002 Nov;20(11):1093-4
references.pmid: 12410251
references.citation: J Biol Inorg Chem. 2008 Aug;13(6):849-54
references.pmid: 18575901
references.citation: Biochemistry. 2005 Feb 15;44(6):1856-63
references.pmid: 15697211
references.citation: J Biol Chem. 1994 Apr 22;269(16):11878-86
references.pmid: 8163487
references.citation: J Biol Chem. 1984 Nov 10;259(21):13027-36
references.pmid: 6092361
references.citation: Biochim Biophys Acta. 2000 Aug 31;1481(1):18-24
references.pmid: 11004576
references.citation: Microbiol Rev. 1991 Jun;55(2):259-87
references.pmid: 1886521
references.citation: Nat Struct Biol. 1999 Dec;6(12):1108-12
references.pmid: 10581550
references.citation: J Am Chem Soc. 2003 Feb 19;125(7):1738-47
references.pmid: 12580599
references.citation: Biochemistry. 1991 Dec 3;30(48):11466-72
references.pmid: 1660304
references.citation: Nat Struct Biol. 1997 Dec;4(12):1032-8
references.pmid: 9406554
references.citation: J Bacteriol. 2006 Jul;188(13):4705-14
references.pmid: 16788180
references.citation: Structure. 2006 Jan;14(1):107-17
references.pmid: 16407070
references.citation: Mol Microbiol. 2011 Dec;82(6):1515-30
references.pmid: 22040142
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7622-5
references.pmid: 12802018
references.citation: J Bacteriol. 1997 Feb;179(4):1143-52
references.pmid: 9023196
references.citation: Appl Environ Microbiol. 2009 Dec;75(24):7789-96
references.pmid: 19837833
references.citation: J Biol Chem. 1993 Jul 15;268(20):14645-54
references.pmid: 8325841
references.citation: Nat Struct Mol Biol. 2004 Oct;11(10):1023-4
references.pmid: 15361860
references.citation: PLoS One. 2011 Feb 02;6(2):e16649
references.pmid: 21311751
references.citation: Eur J Biochem. 1983 Jul 15;134(1):83-7
references.pmid: 6861765
references.citation: Biochemistry. 2000 Apr 18;39(15):4243-9
references.pmid: 10757972
references.citation: J Bacteriol. 1992 Jun;174(11):3429-38
references.pmid: 1592800
references.citation: Biochim Biophys Acta. 2012 Nov;1824(11):1299-305
references.pmid: 22314272
references.citation: Biochim Biophys Acta. 1999 Oct 12;1434(2):248-59
references.pmid: 10525144
references.citation: J Biol Chem. 1984 Jun 10;259(11):6833-40
references.pmid: 6327697
references.citation: Inorg Chem. 2005 Nov 28;44(24):8999-9006
references.pmid: 16296855
references.citation: Nat Biotechnol. 2002 Nov;20(11):1118-23
references.pmid: 12368813
references.citation: Biochemistry. 2007 Oct 23;46(42):11753-60
references.pmid: 17900177
references.citation: Biochem J. 2013 Jan 1;449(1):101-8
references.pmid: 23067389
references.citation: Appl Microbiol Biotechnol. 2012 Jan;93(1):41-8
references.pmid: 22072194
references.citation: Nature. 1997 Sep 25;389(6649):406-12
references.pmid: 9311786
references.citation: Microbiol Mol Biol Rev. 1997 Dec;61(4):533-616
references.pmid: 9409151
references.citation: Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9384-9
references.pmid: 21606337
references.citation: Biochemistry. 2012 Apr 3;51(13):2747-56
references.pmid: 22417533
references.citation: Microbiol Mol Biol Rev. 1997 Sep;61(3):337-76
references.pmid: 9293186
references.citation: Science. 1988 Jun 3;240(4857):1319-21
references.pmid: 17815852
references.citation: Biochemistry. 2008 Feb 19;47(7):1947-56
references.pmid: 18217775
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19213-8
references.pmid: 20956333
references.citation: Biochemistry. 2012 Dec 18;51(50):10008-16
references.pmid: 23189923
references.citation: J Biol Inorg Chem. 2008 Sep;13(7):1073-83
references.pmid: 18553112
references.citation: J Phys Chem B. 2011 Sep 29;115(38):11208-14
references.pmid: 21838277
references.citation: Structure. 1995 Nov 15;3(11):1225-33
references.pmid: 8591033
references.citation: Science. 2003 Dec 12;302(5652):1967-9
references.pmid: 14671304
references.citation: J Biol Inorg Chem. 2012 Apr;17(4):647-62
references.pmid: 22382353
references.citation: Appl Environ Microbiol. 1990 Sep;56(9):2811-7
references.pmid: 16348289
references.citation: J Am Chem Soc. 2007 Feb 21;129(7):1838-9
references.pmid: 17263529
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22169-74
references.pmid: 20018742
references.citation: Biochemistry. 2001 Nov 13;40(45):13483-90
references.pmid: 11695895
references.citation: J Biol Inorg Chem. 2001 Apr;6(4):390-7
references.pmid: 11372197
references.citation: Nat Struct Biol. 1997 Apr;4(4):276-84
references.pmid: 9095195
references.citation: Mol Microbiol. 2012 Jul;85(2):201-12
references.pmid: 22646977
references.citation: Cell. 1995 May 5;81(3):369-77
references.pmid: 7736589
references.citation: J Biol Inorg Chem. 2010 May;15(4):559-71
references.pmid: 20084531
references.citation: Biochemistry. 1998 Oct 6;37(40):13987-96
references.pmid: 9760233
references.citation: Nature. 1999 Jul 29;400(6743):476-80
references.pmid: 10440380
references.citation: Arch Microbiol. 2002 Oct;178(4):250-5
references.pmid: 12209257
references.citation: J Mol Biol. 2009 Nov 6;393(4):951-65
references.pmid: 19735665
references.citation: Biochemistry. 2004 Nov 23;43(46):14566-76
references.pmid: 15544327
references.citation: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2006 Mar 1;62(Pt 3):215-7
references.pmid: 16511304
references.citation: Appl Environ Microbiol. 2006 Nov;72(11):7345-8
references.pmid: 16936064
references.citation: Eur J Biochem. 2001 Dec;268(24):6559-68
references.pmid: 11737210
references.citation: Biochemistry. 1991 Dec 3;30(48):11459-65
references.pmid: 1660303
references.citation: Chembiochem. 2007 Aug 13;8(12):1440-6
references.pmid: 17634996
references.citation: J Am Chem Soc. 2006 Nov 1;128(43):13978-9
references.pmid: 17061851
references.citation: J Biol Chem. 1993 Jul 15;268(20):14655-62
references.pmid: 8325842
references.citation: Biochem Soc Trans. 2012 Jun 1;40(3):493-500
references.pmid: 22616858
references.citation: Science. 2001 May 18;292(5520):1360-3
references.pmid: 11359008
references.citation: J Bacteriol. 1994 Jan;176(2):504-10
references.pmid: 8288544
references.citation: Nat Rev Microbiol. 2006 Oct;4(10):752-64
references.pmid: 16980937
references.citation: Structure. 2004 Jun;12(6):961-73
references.pmid: 15274917
references.citation: Biochim Biophys Acta. 1983 Feb 28;743(1):23-30
references.pmid: 6297595
references.citation: Metallomics. 2011 Apr;3(4):344-8
references.pmid: 21327265
references.citation: Biochim Biophys Acta. 2006 Apr;1764(4):715-23
references.pmid: 16500161
references.citation: EMBO J. 2006 Dec 13;25(24):5951-60
references.pmid: 17139260
references.citation: Biochemistry. 2006 Jan 24;45(3):821-8
references.pmid: 16411758
references.citation: Appl Environ Microbiol. 2001 Jan;67(1):260-9
references.pmid: 11133454
references.citation: J Biochem. 1974 Jun;75(6):1265-73
references.pmid: 4372235
references.citation: J Biol Chem. 1995 Oct 13;270(41):24264-9
references.pmid: 7592634
references.citation: Biochem Soc Trans. 2008 Oct;36(Pt 5):1005-10
references.pmid: 18793179
references.citation: FEBS Lett. 1983 Oct 31;163(1):25-7
references.pmid: 6628687
references.citation: J Am Chem Soc. 2006 Apr 5;128(13):4330-7
references.pmid: 16569009
references.citation: Chem Rev. 2004 Feb;104(2):617-49
references.pmid: 14871137
references.citation: J Appl Microbiol. 2000 Jan;88(1):98-106
references.pmid: 10735248
references.citation: Biochimie. 1994;76(7):641-54
references.pmid: 7893816
references.citation: J Mol Biol. 1997 Jun 13;269(3):440-55
references.pmid: 9199411
references.citation: J Biol Chem. 2012 Apr 20;287(17):14215-25
references.pmid: 22393052
references.citation: Mol Microbiol. 2001 Feb;39(3):722-30
references.pmid: 11169112
references.citation: Structure. 1997 Sep 15;5(9):1157-71
references.pmid: 9331415
references.citation: Phys Chem Chem Phys. 2011 May 7;13(17):7720-31
references.pmid: 21423952
references.citation: Trends Microbiol. 2010 Jun;18(6):266-74
references.pmid: 20382024
references.citation: Anaerobe. 1995 Aug;1(4):219-26
references.pmid: 16887530
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3968-73
references.pmid: 18316736
references.citation: Biochem Soc Trans. 2011 Dec;39(6):1864-70
references.pmid: 22103541
references.citation: Biochem J. 1994 Jun 15;300 ( Pt 3):907-14
references.pmid: 8010977
references.citation: Environ Microbiol. 2006 Oct;8(10):1805-15
references.pmid: 16958761
references.citation: Chem Rev. 1996 Nov 7;96(7):2951-2964
references.pmid: 11848847
references.citation: J Am Chem Soc. 2002 Oct 2;124(39):11737-45
references.pmid: 12296741
references.citation: Biochemistry. 1978 Jul 25;17(15):2984-9
references.pmid: 698180
references.citation: Biochem Soc Trans. 2012 Dec 1;40(6):1268-73
references.pmid: 23176466
references.citation: Biochemistry. 2003 Aug 12;42(31):9491-7
references.pmid: 12899636
references.citation: Arch Microbiol. 1997 Nov;168(5):362-72
references.pmid: 9325424
references.citation: J Inorg Biochem. 2006 Apr;100(4):551-67
references.pmid: 16434100
references.citation: Arch Biochem Biophys. 1981 Mar;207(1):197-204
references.pmid: 6263189
references.citation: Environ Microbiol. 2008 Feb;10(2):497-505
references.pmid: 18093163
references.citation: Biochem J. 2012 Jun 15;444(3):465-74
references.pmid: 22458729
references.citation: Appl Environ Microbiol. 2005 Dec;71(12):8634-41
references.pmid: 16332857