Haem Structure and Function

Abstract

Haem is an iron‐containing cofactor that is universally utilised from single‐cell microbes to vertebrates. The porphyrin ring is the organic framework that coordinates the iron ion, and nature modifies the structure of this functionally versatile ring to create haems with different chemical properties. In addition, the type and the number of iron‐binding ligands from the haem protein's scaffold, which includes histidine, methionine and cysteine residues, also modulate the chemistry of haem. These interactions afford haem to function in dioxygen (O2) transport, as in myoglobin and haemoglobin; in electron transport, as in mono‐ and multihaem cytochromes and in enzymic reactions as in oxidases. Furthermore, the structural interactions between the haem and the proteinaceous ligands fine‐tune reduction potentials and give rise to distinct electronic absorption spectra that are useful for biochemical studies of haem proteins. As studies of haem and haem proteins continue, new functions are being discovered, including in the regulation of key cellular processes.

Key Concepts

  • Haem is an iron ion coordinated to a substituted porphyrin ring, called protoporphyrin IX (PPIX) and serves as a cofactor for a functionally diverse group of proteins.
  • The porphyrin ring can be structurally modified to produce haem types b, c, a, o or d.
  • The haem iron ion can coordinate five or six ligands where the five‐coordinate complexes can bind small ligands such as O2 and/or participate in catalysis.
  • The highly conjugated π‐electron system of haem's porphyrin provides characteristic electronic absorbance spectrum for different types of haems and haem proteins.
  • Factors such as the type and the number of axial ligands to the haem iron, the nature of substituents to the porphyrin ring and charges near the haem centre contribute to modulating the reduction potential of haems.
  • Both the O2‐carrier haemoglobin and the enzyme peroxidase possess five‐coordinate His ligation systems, yet vastly different functions, illustrating the broad functional range of haem proteins by use of different protein environments.

Keywords: haem; heme; porphyrin; protoporphyrin IX; cofactor; cytochrome; iron; electron transport; oxygen transport

Figure 1. (a) Structure of haem, or iron protoporphyrin IX. The porphyrin ring is drawn in black with substituents in red (methyl), green (vinyl) and blue (propionic acids). This substituted porphyrin is referred to as protoporphyrin IX (PPIX). (b) The basic tetrapyrrole unit. Four pyrroles A–D are connected by methene bridges (red) to create porphyrin. The 1–24 numbering scheme is based on the International Union of Pure and Applied Chemistry – International Union of Biochemistry (IUPAC‐IUB) Joint Commission nomenclature. By convention, the two nitrogen atoms not involved in the conjugated system are drawn at positions 21 and 23. (c) Three‐dimensional representation of haem looking down the porphyrin plane and (d) parallel to the porphyrin plane.
Figure 2. Structures of the four haem types: b, c, a and o with examples of proteins containing those haems. Modifications from haem b are in colour.
Figure 3. The two structures of haem d where pyrrole ring C is saturated. The diol derivative on the left cyclises to form the lactone ring on the right.
Figure 4. UV–vis spectrum (electronic absorption) of mitochondrial horse heart cytochrome c. The black trace is the oxidised Fe(III) spectrum; blue trace is the reduced Fe(II) spectrum. Upon reduction of the iron ion, the Soret peak shifts to 416 nm from 408 nm, and two distinct peaks at 550 and 520 nm, designated α and β peaks, appear in the Q band region.
Figure 5. The general catalytic cycle of cytochrome P450. (a) In the resting enzyme, the ferric iron ion is in six‐coordinate low‐spin state with a H2O ligand in the distal position (trans to the proximal cysteinate ligand). As the substrate RH approaches the ferric ion, H2O is displaced, and the iron ion becomes five coordinate with a change to a high‐spin state as shown in (b). Electron donation from a redox partner results in the deoxy ferrous species which then binds O2 to form the oxyferrous complex (c) which is typically depicted as a ferric superoxo species in (d). Addition of another electron forms a ferric peroxide adduct (e), and subsequent protonation yields a ferric hydroperoxo complex in (f). Heterolytic cleavage of the O–O bond yields water and a high‐valent oxoferryl Fe(IV)O species (Compound I) shown in (g). The oxygen atom from the high‐valent iron‐oxo species is transferred to the substrate yielding the hydroxylated product R(O)H.
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References

Banci L, Bertini I, Luchinat C and Turano P (2007) Electron transfer, respiration, and photosynthesis. In: Bertini I, Gray HB, Stiefel EI and Valentine J (eds) Biological Inorganic Chemistry: Structure and Reactivity, pp. 229–261. Sausalito, CA, USA: University Science Books.

Brown SB, Dean TC and Jones P (1970) Aggregation of ferrihaems. Dimerization and protolytic equilibria of protoferrihaem and deuteroferrihaem in aqueous solution. The Biochemical Journal 117: 733–739.

Dydio P, Key HM, Nazarenko A, et al. (2016) An artificial metalloenzyme with the kinetics of native enzymes. Science 354: 102–106.

Gouterman M (1961) Spectra of porphyrins. Journal of Molecular Spectroscopy 6: 138–163.

Gouterman M (1978) Optical spectra and electronic structure of porphyrins and related rings. In: Dolphin D (ed.) The Porphyrins, Volume III pp. 1–165. New York, NY, USA: Academic Press.

Hough MA and Andrew CR (2015) Cytochromes c': structure, reactivity and relevance to haem‐based gas sensing. Advances in Microbial Physiology 67: 1–84.

Hu R‐G, Wang H, Xia Z and Varshavsky A (2008) The N‐end rule pathway is a sensor of heme. Proceedings of the National Academy of Sciences 105: 76–81.

Jameson GB and Ibers JA (2007) Dioxygen carriers. In: Bertini I, Gray HB, Stiefel EI and Valentine J (eds) Biological Inorganic Chemistry: Structure and Reactivity, Volume III pp. 354–387. Sausalito, CA, USA: University Science Books.

Karlson P (1981) The nomenclature of tetrapyrroles. A report. Journal of Clinical Chemistry and Clinical Biochemistry 19: 43–47.

Kennedy GY and Vevers HG (1976) A survey of avian eggshell pigments. Comparative Biochemistry and Physiology Part B: Comparative Biochemistry 55: 117–123.

Key HM, Dydio P, Clark DS and Hartwig JF (2016) Abiological catalysis by artificial haem proteins containing noble metals in place of iron. Nature 534: 534–537.

Kim HJ, Khalimonchuk O, Smith PM and Winge DR (2012) Structure, function, and assembly of heme centers in mitochondrial respiratory complexes. Biochimica et Biophysica Acta 1823: 1604–1616.

Kumar S and Bandyopadhyay U (2005) Free heme toxicity and its detoxification systems in human. Toxicology Letters 157 (3): 175–188.

Liu J, Chakraborty S, Hosseinzadeh P, et al. (2014) Metalloproteins containing cytochrome, iron‐sulfur, or copper redox centers. Chemical Reviews 114: 4366–4469.

Mak PJ and Denisov IG (2018) Spectroscopic studies of the cytochrome P450 reaction mechanisms. Biochimica et Biophysica Acta 1866: 178–204.

Makinen WM and Churg AK (1983) Structural and Analytical Aspects of the Electronic Spectra of Hemeproteins. London: Addison‐Wesley.

Mense SM and Zhang L (2006) Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases. Cell Research 16: 681–692.

Moore GR and Pettigrew GW (1990) Cytochromes c: Evolutionary, Structural, and Physicochemical Aspects. Berlin: Springer.

Mowat CG and Chapman SK (2005) Multi‐heme cytochromes–new structures, new chemistry. Dalton Transactions (Cambridge, England: 2003) (21): 3381–3389.

Nelson DR, Zeldin DC, Hoffman SMG, et al. (2004) Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative‐splice variants. Pharmacogenetics 14: 1–18.

Olson JS and Phillips GN Jr (1997) Myoglobin discriminates between O2, NO, and CO by electrostatic interactions with the bound ligand. Journal of Biological Inorganic Chemistry 2: 544–552.

Ow Y‐LP, Green DR, Hao Z and Mak TW (2008) Cytochrome c: functions beyond respiration. Nature Reviews. Molecular Cell Biology 9: 532–542.

Poulos TL (2014) Heme enzyme structure and function. Chemistry Review 114: 3919–3962.

Puustinen A and Wikström M (1991) The heme groups of cytochrome o from Escherichia coli. Proceedings of the National Academy of Sciences of the United States of America 88: 6122–6126.

Reedy CJ and Gibney BR (2004) Heme protein assemblies. Chemistry Review 104: 617–649.

Rittle J and Green MT (2010) Cytochrome P450 compound I: capture, characterization, and C–H bond activation kinetics. Science 330: 933–937.

Schejter A, Plotkin B and Vig I (1991) The reactivity of cytochrome c with soft ligands. FEBS Letters 280: 199–201.

Schmitt TH, Frezzatti WA and Schreier S (1993) Hemin‐induced lipid membrane disorder and increased permeability: a molecular model for the mechanism of cell lysis. Archives of Biochemistry and Biophysics 307: 96–103.

Shimizu H, Schuller DJ, Lanzilotta WN, et al. (2001) Crystal structure of Nitrosomonas europaea cytochrome c peroxidase and the structural basis for ligand switching in bacterial di‐heme peroxidases. Biochemistry 40: 13483–13490.

Wessling‐Resnick M (2000) Iron transport. Annual Review of Nutrition 20: 129–151.

Williams PA, Fülöp V, Garman EF, et al. (1997) Haem‐ligand switching during catalysis in crystals of a nitrogen‐cycle enzyme. Nature 389: 406–412.

With TK (1974) Porphyrins in egg shells (short communication). Biochemical Journal 137: 596.2–598.

Zhuang J, Reddi AR, Wang Z, et al. (2006) Evaluating the roles of the heme a side chains in cytochrome c oxidase using designed heme proteins. Biochemistry 45: 12530–12538.

Further Reading

Bertini I, Gray HB, Stiefel EI and Valentine J (eds) (2007) Biological Inorganic Chemistry: Structure and Reactivity. Sausalito, CA, USA: University Science Books.

Kim HJ, Khalimonchuk O, Smith PM and Winge DR (2012) Structure, function, and assembly of heme centers in mitochondrial respiratory complexes. Biochim Biophys Acta 1823: 1604–1616.

Liu J, Chakraborty S, Hosseinzadeh P, et al. (2014) Metalloproteins containing cytochrome, iron‐sulfur, or copper redox centers. Chemical Reviews 114: 4366–4469.

Moore GR and Pettigrew GW (1990) Cytochromes c: Evolutionary, Structural, and Physicochemical Aspects. Berlin: Springer.

Poulos TL (2014) Heme enzyme structure and function. Chemical Reviews 114: 3919–3962.

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Kim, Hyung J(Apr 2018) Haem Structure and Function. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000605.pub2]