Comprehensive coordination chemistry II vol 8

Introduction to Volume 8
Since the publication of CCC (1987), bioinorganic chemistry has blossomed and matured as an
interdisciplinary field, which is surveyed in this volume from the perspective of coordination
chemistry. Fully comprehensive coverage of biological inorganic chemistry is not possible, so a
subset of topics is presented that captures the excitement of the field and reflects the scope and
diversity of the systems and research approaches used. As an introduction, a summary of
structural motifs that pervade bioinorganic systems is presented (Chapter 1). Subsequent chapters
focus on the nature of the metal sites in proteins that participate in electron transfer (Chapters 2–4)
and on the transport and storage of metal ions within the biological milieu (Chapters 5–9). The
diverse and biologically important array of metalloproteins that bind and activate dioxygen and
perform oxidation reactions are then discussed (Chapters 10–18). To complete the presentation of
metal–dioxygen chemistry, superoxide processing systems and photosynthetic oxygen evolution
are portrayed (Chapters 19–20). The following sections focus on the activation of other small
molecules (H2, Chapter 21; N2, Chapter 22), mono- and dinuclear metal sites that perform
hydrolysis reactions (Chapters 23–24), and the burgeoning bio-organometallic area (Chapter 25).
Proteins with synergistic metal–radical sites are discussed in Chapter 26. Iron–sulfur clusters are
revisited in Chapter 27, which presents those that are involved in enzyme catalysis rather than
simple electron transfer. The role of metal ions in the environmentally significant process of
denitrification is the focus of Chapter 28. Finally, the binding of metal ions to DNA and RNA
are emphasized in Chapter 29. Together, the array of topics presented in this volume illustrates the
importance of coordination chemistry in the biological realm and the breadth of current bioinorganic chemistry research.
L Que, Jr.
Minnesota, USA
March 2003
W B Tolman
Minnesota, USA
March 2003

xv

COMPREHENSIVE COORDINATION CHEMISTRY II
From Biology to Nanotechnology
Second Edition
Edited by
J.A. McCleverty, University of Bristol, UK
T.J. Meyer, Los Alamos National Laboratory, Los Alamos, USA

Description
This is the sequel of what has become a classic in the field, Comprehensive Coordination Chemistry. The first
edition, CCC-I, appeared in 1987 under the editorship of Sir Geoffrey Wilkinson (Editor-in-Chief), Robert D.
Gillard and Jon A. McCleverty (Executive Editors). It was intended to give a contemporary overview of the
field, providing both a convenient first source of information and a vehicle to stimulate further advances in the
field. The second edition, CCC-II, builds on the first and will survey developments since 1980 authoritatively
and critically with a greater emphasis on current trends in biology, materials science and other areas of
contemporary scientific interest. Since the 1980s, an astonishing growth and specialisation of knowledge
within coordination chemistry, including the rapid development of interdisciplinary fields has made it
impossible to provide a totally comprehensive review. CCC-II provides its readers with reliable and informative
background information in particular areas based on key primary and secondary references. It gives a clear
overview of the state-of-the-art research findings in those areas that the International Advisory Board, the
Volume Editors, and the Editors-in-Chief believed to be especially important to the field. CCC-II will provide
researchers at all levels of sophistication, from academia, industry and national labs, with an unparalleled
depth of coverage.

Bibliographic Information
10-Volume Set - Comprehensive Coordination Chemistry II
Hardbound, ISBN: 0-08-043748-6, 9500 pages
Imprint: ELSEVIER
Price:
USD 5,975

EUR 6,274 Books and electronic products are priced in US dollars (USD) and euro (EUR). USD prices apply
world-wide except in Europe and Japan.EUR prices apply in Europe and Japan. See also information about
conditions of sale & ordering procedures - />cws_home/622954/conditionsofsale, and links to our regional sales offices />contact.cws_home/regional
GBP 4,182.50
030/301
Last update: 10 Sep 2005


Volumes
Volume 1: Fundamentals: Ligands, Complexes, Synthesis, Purification, and Structure
Volume 2: Fundamentals: Physical Methods, Theoretical Analysis, and Case Studies
Volume 3: Coordination Chemistry of the s, p, and f Metals
Volume 4: Transition Metal Groups 3 - 6
Volume 5: Transition Metal Groups 7 and 8
Volume 6: Transition Metal Groups 9 - 12
Volume 7: From the Molecular to the Nanoscale: Synthesis, Structure, and Properties
Volume 8: Bio-coordination Chemistry
Volume 9: Applications of Coordination Chemistry
Volume 10: Cumulative Subject Index
10-Volume Set: Comprehensive Coordination Chemistry II


COMPREHENSIVE COORDINATION CHEMISTRY II

Volume 8:
Bio-coordination Chemistry
Edited by
L. Que, Jr., W.B. Tolman
Contents
Recurring structural motifs in bioinorganic chemistry (L. Que, W. Tolman)

Electron transfer: Cytochromes (K. Rodgers, G.S. Lukat-Rodgers)
Electron transfer: Iron-Sulphur Clusters (R. Holm)
Electron transfer: Cupredoxins (Yi Lu)
Alkali and alkaline earth ion recognition and transport (J.A. Cowan)
Siderphores and transferrins (K.N. Raymond, E.A. Dertz))
Ferritins (A.K. Powell)
Metal ion homeostasis (A.C. Rosenzweig, R.L.Lieberman)
Metallothioneins (P. Gonzalez-Duarte)
Dioxygen-binding proteins (D. Kurtz)
Heme peroxidases (B. Meunier)
Cytochrome P450 (Wonwoo Nam)
Non-heme Di-iron enzymes (S.J. Lippard, Dongwhan Lee)
Non-heme mono-iron enzymes (J.P. Caradonna, T.L. Foster)
Dicopper enzymes (Shinobu Itoh)
Mono-copper oxygenases (M.A. Halcrow)
Multi-metal oxidases (K.D. Karlin et al.)
Molybdenum and Tungsten enzymes (C.D. Garner et al.) Superoxide processing (A.F. Miller)
NO chemistry (J.T. Groves)
Oxygen evolution (G.W. Brudvig, J. Vrettos)
Hydrogen activation (M.Y. Darensbourg, I.P. Georgakaki)
Nitrogen fixation (P.L. Holland)
Zinc hydrolases (E. Kimura, Shin Aoki)
Dinuclear hydrolases (B.A. Averill)
Bio-organometallic chemistry of cobalt and nickel (C.G. Riordan)
Metal-radical arrays (W. Tolman)
Iron sulfur clusters in enzyme catalysis (J.B. Broderick)
Denitrification (R.R. Eady, S.S. Hasnain)
DNA and RNA as ligands (V.J. DeRose et al.)
Reviews (University of Newcastle-Upon-Tyne, UK)
This impressive volume consisting of 29 articles from 45 different authors is an absolute must for all

those looking for an introduction, or already working in the area of Bio-coordination Chemistry.
It is the most up-to-date and comprehensive account yet to appear conveying much of the excitement in a still rapidly expanding area.


8.1
Recurring Structural Motifs
in Bioinorganic Chemistry
L. QUE, JR. and W. B. TOLMAN
University of Minnesota, Minneapolis, Minnesota, USA
8.1.1
8.1.2
8.1.3
8.1.4
8.1.5

8.1.1

INTRODUCTION
COMMON MOTIFS WITH NON-AMINO-ACID LIGANDS
COMMON MOTIFS WITH AMINO-ACID LIGANDS
CONCLUDING REMARKS
REFERENCES

1
1
6
14
14

INTRODUCTION

In the sixteen years since the publication of Comprehensive Coordination Chemistry (CCC,
1987) bioinorganic chemistry has undergone significant development and matured into a
multidisciplinary field with coordination chemistry at its locus.1–6 The field has greatly benefited
from advances in macromolecular crystallography, which have led to the structural characterization of many metalloenzyme active sites. From this ever-expanding database can be discerned a
number of recurring structural motifs, whose physical and reactivity properties can be further
modulated by secondary protein interactions.7 We present the following overview and accompanying gallery of active-site structures to serve as a framework for the more detailed discussions in the
component chapters of this volume. The coverage of topics is not comprehensive; rather, the
choice of examples is meant solely to be illustrative of motifs common to multiple metalloprotein
systems with often diverse functions.

8.1.2

COMMON MOTIFS WITH NON-AMINO-ACID LIGANDS

Perhaps the most recognizable active-site motif in metalloproteins is the tetradentate porphyrin
macrocycle, the organic cofactor associated with heme proteins. The most commonly encountered
is protoporphyrin IX or heme b (Figure 1), found in the active sites of dioxygen-binding globins,
dioxygen-activating cytochrome P450, H2O2-activating peroxidases, and b-type cytochromes
involved in electron transfer (see Chapters 8.2, 8.10–8.12, and 8.17). Addition of cysteinyl
residues to the two vinyl groups on the porphyrin periphery converts heme b to heme c (Figure 1),
which are found in c-type cytochromes that are also involved in electron transfer. With four
equatorial sites of a potentially octahedral metal center occupied by this tetrapyrrole macrocycle,
the chemistry of the iron can be modulated principally by changing the nature of the fifth and
sixth ligands. In electron-transfer proteins, both sites are occupied, usually by His/His or His/Met
residues, as in cytochromes b58 and c553,9 respectively (Figure 2). For oxygen-binding globins and
heme enzymes, only the fifth (or proximal) site is occupied by a protein residue, leaving the sixth
site available for binding small molecules such as O2, CO, NO, or H2O2. The proximal ligand is
1

2

Recurring Structural Motifs in Bioinorganic Chemistry
COOH

HOOC

Z

N

N

N

N

N

N

Fe

Fe
N

N

N

X

HOOC

COOH

N

H

Fe

OH
OH

HOOC

COOH

HOOC

Y
N

H

N
COOH

HOOC

COOH

COOH

HOOC

heme d
siroheme
heme b: X = –CH3;
Y = Z = –CH=CH2
heme c: X = –CH 3;
Y = Z = –CH(SCys)CH3
heme a: X = –CH(O); Y = –CH=CH2;
Z = –CH(OH)CH2CH2CH=C(CH3)CH2CH2CH=C(CH3)CH2CH2CH=C(CH3)2

Figure 1 Drawings of various heme derivatives.

His
Met

N

Fe

Fe
N N

N

His

(a)
Figure 2

N

N N

N

His

(b)

Structures of the active sites of (a) cytochrome b5 (PDB 1CYO); (b) cytochrome c553 (PDB 1B7 V).

typically His (myoglobin,10 hemoglobin, horseradish peroxidase), Tyr (catalase11), or Cys (cytochrome P45012 and chloroperoxidase) (Figure 3). The chemistry of the active site can be further
affected by second-sphere residues such as Glu or Gln that can hydrogen-bond to the proximal
His to modulate its basicity, or those on the distal side that can serve as acids and/or bases to aid
in the binding of dioxygen or the cleavage of the OÀO bond. The presence or absence of the latter
can in fact determine whether a dioxygen moiety in the active site becomes an electrophilic
oxidant, as in the case of hydrocarbon-oxidizing cytochrome P450,13 or acts as a nucleophile, as
in the case of the estradiol-producing enzyme aromatase.14 The rich chemistry of heme proteins
and enzymes is discussed in Chapters 8.11, 8.12, and 8.17.
There are other tetrapyrrole macrocycles found in nature besides protoporphyrin IX (Figure 1).
Differences with the latter can be as simple as changes in the substituents on the porphyrin
periphery, such as in heme a and heme a3, which are key components of the mammalian
respiratory enzyme cytochrome oxidase (see Chapter 8.17). Other disparities can entail changes

in the oxidation level of the macrocycle, such as the two-electron reduced heme d of cytochrome


3

Recurring Structural Motifs in Bioinorganic Chemistry

His

O
O
N
N
N

N

N

N

Fe

Fe
N

N

Ty r
His

(a)

(b)

camphor

O
O
N
N

Fe
N

N

Cys

(c)
Figure 3 Structures of the metal-containing portion of (a) oxymyoglobin (PDB 1A6M); (b) catalase (PDB
1DGF); (c) the oxygen adduct of reduced cytochrome P450 with camphor substrate bound (PDB 1DZ4).

bd of E. coli, and the four-electron reduced sirohemes of sulfite oxidase and nitrite reductase (see
Chapter 8.28). Factor F430 is a highly reduced tetrapyrrole ligand that binds nickel and is
involved in methanogenesis, while cobalt-containing coenzyme B12 has a corrin ring with one
fewer carbon than in the macrocyle (see Chapter 8.25).
Another easily recognizable bioinorganic motif is the iron–sulfur cluster exemplified by the
Fe2S2 rhomb and the Fe4S4 cubane (Figure 4), most often found in ferredoxins involved in lowpotential electron transfer (see Chapter 8.3).15 The iron ions in these clusters typically have a
distorted tetrahedral geometry, with cysteine residues serving as terminal ligands. The Fe2S2

cluster (Figure 4a) cycles between the þ2 and þ1 oxidation states, with redox potentials in the
À200 mV range.16 A variation is the Rieske cluster found in the respiratory electron-transfer chain
and some dioxygenases that operates in the þ200 mV range (Figure 4b).17 In this cluster, the two
terminal cysteinates on one iron are replaced by neutral histidine ligands, resulting in the upshift


4

Recurring Structural Motifs in Bioinorganic Chemistry

Cys

Cys

Cys

S
Fe

S
Fe

Fe

S

S

Cys

Cys

Fe

His
His

Cys
(a)

Cys

Fe
S

S

Fe

Cys

S
Fe
Cys

Cys

Fe
S

(c)
Figure 4 Structures of the (a) Fe2S2(Cys)4 ferrodexin site (PDB 1AWD); (b) Fe2S2(Cys)2(His)2 ‘‘Rieske’’ site
(PDB 1JM1); (c) Fe4S4(Cys)4 ferrodoxin site (PDB 2FDN).

in potential. The Fe4S4 cluster (Figure 4c)18 also typically cycles between the þ2 and þ1 oxidation
states, but can access the þ3 oxidation state in some cases and the 0 oxidation state in the Fe
protein of nitrogenase.19 Iron–sulfur clusters thus provide Nature with considerable flexibility in
the potentials of electrons they can transfer.
There are also cuboidal FeS clusters in which one of the iron sites is significantly different from
the other three. The extreme example is the Fe3S4 cluster, where one of the Fe corners is missing.
Although originally considered to be an artifact of oxidative damage to iron–sulfur proteins, as in
the ferredoxin from Azotobacter vinelandii (Figure 5a),20 such clusters have been found in active
enzymes, e.g., the NiFe hydrogenase,21 and are presumably involved in the electron-transfer chain
needed to deliver electrons to the heterodinuclear NiFe enzyme active site. Aconitase is another
enzyme with a site-differentiated Fe4S4 cluster. This key enzyme of the Krebs cycle catalyzes the
isomerization of citrate to isocitrate (see Chapter 8.27). The isomerization occurs on one specific
Fe of the Fe4S4 cluster. Instead of having a terminal Cys ligand, the unique Fe has a terminal
aqua ligand in the resting state and binds the substrate, thereby increasing its coordination
number during the catalytic cycle (Figure 5b).22 Thus, the aconitase Fe4S4 cluster does not
work as an electron-transfer site in this enzyme, but instead provides a metal center that functions
as a Lewis acid. There is also recent evidence that an Fe4S4 cluster can act both as an electrontransfer site and a Lewis acid center. In S-adenosylmethionine-dependent iron–sulfur enzymes,
one Fe of the cluster acts to bind the carboxylate of the S-adenosylmethionine cofactor prior to
the redox reaction (see Chapter 8.27).
One Fe is replaced by another metal ion in other site-differentiated Fe4S4 clusters. Many of
these examples derive from the chemical reconstitution of an Fe3S4 cluster with another metal ion,
e.g., ZnFe3S4, CoFe3S4, CdFe3S4, etc.15 In addition, CO dehydrogenase has been found to
have an NiFe4S5 cluster that is presumably involved in CO binding and activation (Figure 5c)


5

Recurring Structural Motifs in Bioinorganic Chemistry

S
Fe
Fe
Cys

trans-aconitate

Cys

H2O

Fe

S

S

S
S

S

Cys
Fe

Fe

S

Fe

Cys
Cys

S

(a)

Cys

(b)
“X”

S
Fe

Ni

Cys

Cys

S
His

Fe
Fe

S
Cys

S
Fe

Cys
Cys

(c)
Figure 5 Structures of the (a) Fe3S4(Cys)4 ferredoxin site (PDB 7FD1); (b) aconitase active site with bound
trans-aconitate (PDB 1ACO); (c) NiFe4S5 cluster in carbon monoxide dehydrogenase (PDB 1JQK).

(see Chapter 8.25).23 The novel cluster has a structure that significantly deviates from the
postulated model in which the Ni ion is appended to an intact Fe4S4 cluster; instead, the Ni ion
is integrated into the cluster structure, which could be construed as arising from the coordination
of a (Cys)Ni--S(R)-Fe(Cys)(His) unit to three of four -S atoms of an Fe3S4 cluster.
The iron–sulfur clusters of the MoFe protein of nitrogenase illustrate another variation on the
cuboidal M4S4 theme. The P and M clusters of this protein can be formulated as vertex-shared
bicubane units, perhaps required because the fixation of dinitrogen is thought to occur in twoelectron reduction steps (see Chapter 8.22). For the P cluster, which serves as an electron-storage
and -transfer site, two Fe4S4 clusters combine to share a common 6-S vertex (Figure 6a).24 On
the other hand, the M cluster, which is believed to be the locus of nitrogen-fixing activity, is a
combination of an Fe4S3 and an MoFe3S3 cuboidal unit sharing a common, newly discovered 6vertex, which cannot be a sulfur atom (Figure 6b).24 The electron density associated with this
atom identifies it as a low Z atom, and a 6-N is mechanistically the most attractive possibility.
The third recurring structural motif with non-amino-acid components found in metalloproteins is
the metal–dithiolene unit found in molybdenum- and tungsten-containing oxidases or dehydrogenases
(see Chapter 8.18). The dithiolene is typically a pterin derivative (often with phosphate and/or
nucleotide appendages) and coordinated to Mo or W in a 1:1 or 2:1 stoichiometry (Figure 7).25,26
These units usually function in two-electron redox reactions (cf. ‘‘oxo transfer’’), shuttling between
MIV and MVI oxidation states.

The most recent addition to this group of motifs is the Fe(CO)x(CN)y fragment found in the
active sites of both NiFe and Fe-only hydrogenases (Figure 8).21,27 This organometallic fragment
is connected to a Ni(Cys)4 unit in the NiFe enzyme via two thiolate bridges (Figure 8a) and to


6

Recurring Structural Motifs in Bioinorganic Chemistry

Cys
Cys

Cys Fe

S
Fe

Fe

S

Fe
Fe

Cys

S

S

S

Cys
Fe

S

S

Fe

Fe
Cys

(a)

S
S

S

His

Fe

Fe

S

Mo

S
Fe

S

N

Fe

Fe

Fe

Fe

Cys

S

homocitrate
S
(b)

Figure 6 Structures of the nitrogenase (a) P cluster; (b) molybdenum-iron cofactor (PDB 1M1 N).

another organometallic Fe fragment via a dithiolate bridge in the Fe-only enzyme (Figure 8b).
The unusual organometallic nature of this fragment suggests an important role for H2 activation,
but more work is required to establish the mechanisms of action for these fascinating enzymes
(see Chapter 8.21).

8.1.3

COMMON MOTIFS WITH AMINO-ACID LIGANDS

The tetrahedral M(Cys)4 unit is a commonly found structure in metalloproteins. Besides the Ni
center in NiFe hydrogenases (Figure 8a),21 this motif is also found for M = Fe, Zn, and Cd. An
Fe(Cys)4 site is present in rubredoxin (Figure 9a),28 one of the earliest characterized iron–sulfur
proteins. It also is found in dinuclear superoxide reductases,29 where it is proposed to serve as an
electron-storage site for the superoxide-reducing active site (see Chapter 8.19). The M(Cys)4 unit is
a structural component in Zn-containing alcohol dehydrogenase30 and a fragment of the Zn/Cd
clusters of metallothioneins (Figure 9b; see Chapter 8.9).31 Variations of this tetrahedral motif occur
in Zn-finger proteins where a Zn(His)2(Cys)2 unit is commonly found (Figure 9c).32
The trigonal Cu(Cys)(His)2 unit is a recurring motif in cupredoxins, more commonly known as
‘‘blue’’ copper proteins, which are principally involved in electron transfer in the high potential


Recurring Structural Motifs in Bioinorganic Chemistry

7

Pterin dithiolene

S
O
Mo
O

S
Cytosine diphosphate

H2O(OH–)

(a)

Pterin dithiolene
S
O

Ser
S

S
Mo

Guanosine
diphosphate
(truncated)

DMSO
S
Pterin dithiolene
Guanosine
diphosphate
(truncated)

(b)

Figure 7 Structures of the (a) MoVI site of aldehyde oxidoreductase (PDB 1HLR); (b) DMSO adduct to the
MoIV site of dimethylsulfoxide reductase (PDB 4DMR). The guanine portions of the pterin cofactors in (b)
are omitted for clarity.

range (see Chapter 8.4). The presence of axial ligation and the strength of such interactions with
the copper center modulate the redox potential to provide the range observed for these proteins.33
As illustrated in Figure 10, the cupredoxin site can be trigonal (Figure 10a),34 trigonal pyramidal
(Figure 10b),35 or trigonal bipyramidal (Figure 10c).36 A closely related motif is found in the
delocalized, mixed-valence dicopper(I,II) centers of cytochrome oxidase (Figure 10d)37 and
nitrous oxide reductase,38 which may be construed as a dimeric derivative in which one His on
each Cu is replaced by another ligand (see Chapter 8.17).
The facial M(Xaa)3 unit is another versatile building block, which is suitable for a variety of
metal ions and accommodates tetrahedral, trigonal-bipyramidal, square-pyramidal, and octahedral


8

Recurring Structural Motifs in Bioinorganic Chemistry

Cys

S
S

Fe
Cys

Cys

Fe

CN

“X”

Cys

S

Fe

–

Ni

Fe

S

S

Fe

CO

Fe

Cys

CN–

S
Fe

Cys

Cys

Cys

CO
CN–

CO
CN–
(a)
Figure 8

“X”

(b)

Structures of the active sites of (a) Ni–Fe hydrogenase (PDB 2FRV); (b) Fe-only hydrogenase
(PDB 1HFE).

Cys
Cys
Zn

Cys

Cys

Fe

Cys

Cys

Cys

Cys

Zn

Cd

Cys

Cys

Cys

Cys
Cys
(a)

(b)
Cys
Cys
Zn

His

His
(c)
Figure 9 Structures of the (a) rubredoxin Fe(Cys)4 site (PDB 1BRF); (b) Zn2Cd(Cys)9 metallothionein site
(PDB 4MT2); (c) Zn(His)2(Cys)2 ‘‘zinc finger’’ site (PDB 1A1H).


9

Recurring Structural Motifs in Bioinorganic Chemistry

Met
His

Cys

Cys

Cu

Cu

His
His

His

(a)

(b)

carbonyl

Met

Cys

Cys

His
Cu

His

His

His

Cu
Cu
Cys

Met

carbonyl
(c)

(d)

Figure 10 Structures of the copper–thiolate electron-transfer sites in (a) laccase (PDB 1HFU); (b) plastocyanin (PDB 1KDJ); (c) azurin (PDB 1NWP). Also shown: (d) the delocalized, mixed-valent dicopper(I,II)
‘‘CuA’’ electron-transfer site from cytochrome ba3 (PDB 2CUA).

geometries. The M(His)3 motif is found in the tetrahedral metal sites of several metalloenzymes, such
as carbonic anhydrase (ZnII, Figure 11a),39 nitrite reductase (CuII, Figure 11b),40 and cytochrome c
oxidase (Cu, Figure 11c).41 The fourth position is used to activate the water nucleophile in carbonic
anhydrase, to bind nitrite in nitrite reductase, and to serve as the initial binding site for O2 (or CO) in
cytochrome c oxidase. This motif also provides the remaining ligands of the square-pyramidal ions of
the Cu2(-2:2-O2) core in oxyhemocyanin (Figure 12a)42 and one six-coordinate iron ion of the
diiron site in oxyhemerythrin (Figure 12b).43
An additional recurring facial motif is the 2-His-1-carboxylate triad found in a number of
mononuclear nonheme iron enzymes that activate O2.44,45 This triad serves to hold the iron(II)
center in the active site and provides three solvent-accessible sites to bind exogenous ligands. This
superfamily of enzymes can catalyze a range of oxidative transformations, including the cisdihydroxylation of arene double bonds and the oxidative cleavage of catechols in the biodegradation of aromatics, the formation of the
-lactam and thiazolidine rings of penicillin, the
hydroxylation of Phe, Tyr, and Trp with the help of a tetrahydrobiopterin cofactor, and the
oxidative decarboxylation of an -ketoglutarate co-substrate to generate an oxidant capable of
functionalizing CÀH bonds (see Chapter 8.14). The coordinative versatility of this active-site
motif is illustrated in Figure 13. Figures 13a and 13b show the active-site structures of binary
enzyme–bidentate substrate complexes, an extradiol cleaving catechol dioxygenase with its


10

Recurring Structural Motifs in Bioinorganic Chemistry

H2O

H2O

Cu

Zn
His

His

His
His
His
His
(a)

(b)

His
His

Cu
His

Tyr

Fe
N

N
N

N

(c)

Figure 11 Structures of the active sites of (a) carbonic anhydrase (PDB 1CA2); (b) nitrite reductase (PDB
2NRD); (c) cytochrome c oxidase (heme a3-CuB pair; PDB 1OCR).

His

His

Cu

Cu
Fe

His
His

O

His

O

O
His

OH

O

His

His

Fe

His
His

(a)

Glu

Glu

His

(b)

Figure 12 Structures of the active sites of (a) oxyhemocyanin (PDB 1OXY); (b) oxyhemerythrin (PDB
1HMO).

catecholate substrate (Figure 13a)46 and deacetoxycephalosporin synthase (DAOCS) with its
-ketoglutarate cofactor (Figure 13b),47 both with a sixth site available for O2 binding. Figures
13c and 13d show the active sites of ternary complexes: isopenicillin N synthase (IPNS) with the
coordinated thiolate of its tripeptide substrate and NO bound as a surrogate for O248 and


11

Recurring Structural Motifs in Bioinorganic Chemistry

His
His

Glu

H2O
Fe
H2O

Fe

α-ketoglutarate

Glu
His

His
catechol
(a)

(b)

His

Glu
O
O

ACV
(substrate)

S

Fe
NO

His
H2O

Fe
His
Glu
His

(c)

(d)

Figure 13 Structures of the active sites of (a) 2,3-dihydroxybiphenyl 1,2-dioxygenase complexed with
catechol (PDB 1KND); (b) deacetoxycephalosporin synthase with bound -ketoglutarate (PDB 1RXG);
(c) isopenicillin N synthase with coordinated substrate and NO (PDB 1BLZ); (d) naphthalene dioxygenase
with bound dioxygen in the presence of substrate (not shown) (PDB 1O7M).

naphthalene dioxygenase with a side-on bound dioxygen,49 presumably poised to effect the cisdihydroxylation of a double bond on the nearby arene substrate (not shown). These examples
illustrate how a diversity of reactions can be obtained from the flexibility of the 2-His-1-carboxylate motif, which enables the iron(II) center to bind and activate substrates, cofactors and/or O2.
Other combinations of histidine and carboxylate ligands also can be found in a number of
metalloenzymes. Quercetinase is a copper enzyme that uses a 3-His-1-carboxylate combination
arranged in a square-pyramidal geometry, with one basal site available for the coordination of
substrate (Figure 14a).50 Fe and Mn superoxide dismutases utilize a 3-His-1-carboxylate combination in a sawhorse arrangement to provide coordination sites for two exogenous ligands (Figure
14b).51 These coordination environments can in fact be construed as combinations of M(His)3

and M(His)2(carboxylate) triads. Alternatively, some dimetal hydrolases like the
-lactamase
from S. maltophilia (see Chapter 8.24) combine the two triad types via a hydroxo bridge to
generate a (His)3Zn--OH-Zn(His)2(Asp) active site (Figure 14c).52 Note how, in most examples,
the monodentate carboxylate ligand hydrogen bonds to a bound water or hydroxide.
A number of other metalloenzymes have MII2(His)2(O2CR)4 active sites (see Chapter 8.13).
Most prominent of these are the di-iron enzymes, including the hydroxylase component of
methane monooxygenase (MMOH, Figure 15a)53 and class 1 ribonucleotide reductase R2
proteins (Figure 15b).54 These enzymes have two conserved Asp/Glu(Xaa)nGluXaaXaaHis
sequence motifs in a four-helix bundle that provide the six amino-acid ligands for the di-iron


12

Recurring Structural Motifs in Bioinorganic Chemistry

Glu

H2O

His
His

Mn

His

His

Glu

Cu

His

His

H2O
(a)

(b)

Glu

His
OH

Zn
His

Zn
His

H2O
His
His
(c)

Figure 14 Structures of the active sites of (a) quercetinase (PDB 1JUH); (b) Mn superoxide dismutase (PDB
3MDS); (c) a dizinc

-lactamase (PDB 1SML).

active site. The di-iron center activates O2 and carries out the hydroxylation of alkanes and the
formation of a catalytically essential tyrosyl radical for the conversion of ribonucleotides to
deoxyribonucleotides, respectively. The carboxylates more distant in sequence from the other
two residues act as terminal ligands, while the two near in sequence to the His ligands act to
bridge the iron atoms, with both monodentate and bidentate modes observed. Upon oxidation of
these di-iron(II) enzymes to the di-iron(III) state, there is a change in core structure, resulting in
the shift of one carboxylate bridge to a terminal position (the so-called carboxylate shift55) and the
introduction of an oxo bridge or two hydroxo bridges to neutralize the Lewis acidity of the iron(III)
ions (Figures 15c and 15d).53,56 (An oxo bridge is also observed in the oxidized form of an unrelated
diiron protein hemerythrin (Figure 12b).) Related dinuclear active sites are found for fatty acid
desaturases,57 rubrerythrin,58 the ferroxidase site in ferritins,59 and the dimanganese catalase.60
The crystal structures of nitrile hydratase and acetyl CoA synthase both show a metal center
coordinated to a planar N2S2 unit derived from a CysXaaCys tripeptide, with the nitrogen ligands
arising from the peptide amidates of the Xaa residue and the latter Cys residue. These results
emphasize a point originally made in the explorations of the coordination chemistry of peptide
ligands: that the peptide nitrogen can bind to metal centers, particularly in its anionic form. In the
recently reported structures of acetyl CoA synthase, there is a planar Ni(N2S2) unit derived from
a Cys595Gly596Cys597 tripeptide segment (Figure 16a).61,62 This unit is in turn connected to an
Fe4S4 cluster via an intervening metal ion, which can be Ni, Cu, or Zn in the three structures
reported. In nitrile hydratase, the low-spin iron(III) ion is coordinated to the planar N2S2 unit
from Cys112Ser113Cys114 and additionally ligated by an axial thiolate from nearby Cys109 (Figure
16b).63 The sixth site can be occupied by a solvent molecule, which presumably is involved in


13

Recurring Structural Motifs in Bioinorganic Chemistry

H2O

Asp

Glu

Glu

Glu

H2O

Glu

Fe

Fe

Fe

Glu

Fe

His
His

Glu

His

His

Glu

(a)
H2O

(b)

HO(H) Glu

Glu

Glu

Fe

OH

His

Asp

H2O

Glu
O

Fe

Fe

Glu

H2O

Fe

His
Glu

Glu

His

His

(c)

(d)

Figure 15 Structures of the di-iron active sites of (a) reduced MMOH (PDB 1FYZ); (b) reduced ribonucleotide reductase (PDB 1XIK); (c) oxidized MMOH (PDB 1FZ1); (d) oxidized ribonucleotide reductase (PDB
1AV8).

Cys

acyl

O

S

Cys
S
Fe

Fe

Fe

N
Ni

N

O
O

S
S

S

Cu

Fe

S

N peptide
ligand

Cys

O

N

O

O

NO
S
Fe

N
O

O
S

Cys

N peptide
ligand

O
O

Cys
(a)

(b)

Figure 16 Structures of (a) the multimetallic site of acetyl CoA synthase (PDB 1MJG); (b) the active site of
the NO adduct of nitrile hydratase (PDB 2AHJ).

nitrile hydrolysis, or NO, which is an inhibitor. Further making this active-site structure unique is
the observed post-translational oxidation of the thiolates of Cys112 and Cys114 to a sulfinate
(RSO2À) and a sulfenate (RSOÀ), respectively, required for enzyme activity.


14

Recurring Structural Motifs in Bioinorganic Chemistry

His

Cys
His
Fe

His
His
Glu
Figure 17 Structure of the catalytic active site of superoxide reductase (PDB 1DQI).

As a final example, we note the similarity of the square-pyramidal FeN4(Cysaxial) site found in

superoxide reductase29 (Figure 17) to those of cytochrome P450 (Figure 3c) and chloroperoxidase.
While the N4 units in cytochrome P450 and chloroperoxidase derive from a porphyrin, the four
nitrogens of superoxide reductase are from four His residues. Interestingly, this motif is used in
the two heme enzymes to bind and activate dioxygen moieties to generate a high-valent oxoiron
species capable of substrate oxidations, while the corresponding site in superoxide reductase is
used to protect anaerobes from the toxic effects of superoxide by reducing it to H2O2.

8.1.4

CONCLUDING REMARKS

In this introductory overview, we have attempted to point out structural similarities among
metalloprotein active sites to emphasize how Nature has utilized coordination chemistry to her
advantage, particularly in generating related active sites with different functions. In highlighting
common features, we have necessarily de-emphasized unique sites such as the unusual Cu4(4-S)
cluster of nitrous oxide reductase (see Chapter 8.28) and the critical Mn4 cluster in the oxygenevolving complex of photosynthesis (see Chapter 8.20), whose precise structure is still developing
as higher resolution crystallographic data become available. Also excluded are possible motifs
that may emerge in the areas of metal-ion transport and homeostasis (see Chapters 8.5, 8.6, and
8.8) and metal ion/nucleic acid interactions (see Chapter 8.28). It is our hope that this overview
provides a sufficient basis for underscoring the importance of coordination chemistry in
bioinorganic chemistry.

ACKNOWLEDGMENT
We thank John York for his assistance with generating the figures in this article.

8.1.5

REFERENCES

1. Lippard, S. J.; Berg, J. M. Principles of Bioinorganic Chemistry; University Science: Mill Valley, CA, 1994.

2. Kaim, W.; Schwederski, B. Bioinorganic Chemistry: Inorganic Elements in the Chemistry of Life; Wiley: New York, 1991.
3. Bertini, I.; Gray, H. B.; Lippard, S. J.; Valentine, J. S., Eds. Bioinorganic Chemistry; University Science Books: Mill
Valley, CA, 1994.
4. Frau´sto da Silva, J. J. R.; Williams, R. J. P. The Biological Chemistry of the Elements: The Inorganic Chemistry of Life;
Clarendon Press: Oxford, UK, 1991.
5. Cowan, J. A. Inorganic Biochemistry: An Introduction; 2nd ed.; Wiley-VCH: New York, 1997.
6. Holm, R. H.; Solomon, E. I. Chem. Rev. 1996, 96, 2239–3042, entire issue, edited by Holm Solomon.
7. Holm, R. H.; Kennepohl, P.; Solomon, E. I. Chem. Rev. 1996, 96, 2239–2314.
8. Durley, R. C. E.; Mathews, F. S. Acta Crystallogr. D Biol. Crystallogr. 1996, 52, 65–66.
9. Benini, S.; Gonzalez, A.; Rypniewski, W. R.; Wilson, K. S.; Van-Beeumen, J. J.; Ciurli, S. Biochemistry 2000, 39, 13115–13126.
10. Vojtechovsky, J.; Chu, K.; Berendzen, J.; Sweet, R. M.; Schlichting, I. Biophys. J. 1999, 77, 2153–2174.
11. Putnam, C. D.; Arvai, A. S.; Bourne, Y.; Tainer, J. A. J. Mol. Biol. 2000, 296, 295–309.
12. Schlichting, I.; Berendzen, J.; Chu, K.; Stock, A. M.; Maves, S. A.; Benson, D. E.; Sweet, R. M.; Ringe, D.; Petsko, G. A.;
Sligar, S. G. Science 2000, 287, 1615–1622.


Recurring Structural Motifs in Bioinorganic Chemistry
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.

26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.

56.
57.
58.
59.
60.
61.
62.
63.

15

Ortiz de Montellano, P. R., Ed. Cytochrome P450: Structure, Mechanism, and Biochemistry; 2nd ed.; Plenum: New York, 1995.
Wertz, D. L.; Valentine, J. S. Struct. Bonding 2000, 97, 38–60.
Beinert, H.; Holm, R. H.; Mu¨nck, E. Science 1997, 277, 653–659.
Bes, M. T.; Parisini, E.; Inda, L. A.; Saraiva, L.; Peleato, M. L.; Sheldrick, G. M. to be published (PDB 2FDN).
Boenisch, H.; Schmidt, C. L.; Schaefer, G.; Ladenstein, R. J. Mol. Biol. 2002, 319, 791–805.
Dauter, Z.; Wilson, K. S.; Sieker, L. C.; Meyer, J.; Moulis, J. M. Biochemistry 1997, 36, 16065–16073.
Yoo, S. J.; Angove, H. C.; Burgess, B. K.; Hendrich, M. P.; Mu¨nck, E. J. Am. Chem. Soc. 1999, 121, 2534–2545.
Schipke, C. G.; Goodin, D. B.; McRee, D. E.; Stout, C. D. Biochemistry 1999, 38, 8228–8239.
Volbeda, A.; Garcia, E.; Piras, C.; deLacey, A. L.; Fernandez, V. M.; Hatchikian, E. C.; Frey, M.; Fontecilla Camps,
J. C. J. Am. Chem. Soc. 1996, 118, 12989–12996.
Lauble, H.; Kennedy, M. C.; Beinert, H.; Stout, C. D. J. Mol. Biol. 1994, 237, 437–451.
Drennan, C. L.; Heo, J.; Sintchak, M. D.; Schreiter, E.; Ludden, P. W. Prod. Nat. Acad. Sci. USA 2001, 98,
11973–11978.
Einsle, O.; Tezcan, F. A.; Andrade, S. L. A.; Schmid, B.; Yoshida, M.; Howard, J. B.; Rees, D. C. Science 2002, 297, 1696–1700.
Rebelo, J. M.; Dias, J. M.; Huber, R.; Moura, J. J.; Ramao, M. J. J. Biol. Inorg. Chem. 2001, 6, 791–800.
McAlpine, A. S.; McEwan, A. G.; Bailey, S. J. Mol. Biol. 1998, 275, 613–623.
Nicolet, Y.; Piras, C.; Legrand, P.; Hatchikian, C. E.; Fontecilla-Camps, J. C. Structure Fold. Des. 1999, 7, 13–23.
Bau, R.; Rees, D. C.; Kurtz, D. M.; Scott, R. A.; Huang, H. S.; Adams, M. W. W.; Eidsness, M. K. J. Biol. Inorg.
Chem. 1998, 3, 484–493.

Yeh, A. P.; Hu, Y.; Jenney, F. E., Jr.; Adams, M. W. W.; Rees, D. C. Biochemistry 2000, 39, 2499–2508.
Eklund, H.; Samma, J. P.; Wallen, L.; Branden, C. I.; Akeson, A.; Jones, T. A. J. Mol. Biol. 1981, 146, 561–587.
Braun, W.; Vasak, M.; Robbins, A. H.; Stout, C. D.; Wagner, G.; Kagi, J. H.; Wuthrich, K. Proc. Natl. Acad. Sci.
USA 1992, 89, 10124–10128.
Elrod-Erickson, M.; Benson, T. E.; Pabo, C. O. Structure 1998, 6, 451–464.
Gray, H. B.; Malmstrom, B. G.; Williams, R. J. P. J. Biol. Inorg. Chem. 2000, 5, 551–559.
Ducros, V.; Brzozowski, A. M.; Wilson, K. S.; Ostergaard, P.; Schneider, P.; Svendson, A.; Davies, G. J. Acta
Crystallogr. D 2001, 57, 333–336.
Kohzuma, T.; Inoue, T.; Yoshizaki, F.; Sasakawa, Y.; Onodera, K.; Nagatomo, S.; Kitagawa, T.; Uzawa, S.; Isobe, Y.;
Sugimura, Y.; Gotowda, M.; Kai, Y. J. Biol. Chem. 1999, 274, 11817–11823.
Chen, Z. W.; Barber, M. J.; McIntire, W. S.; Mathews, F. S. Acta Crystallogr. D 1998, D54, 253–268.
Williams, P. A.; Blackburn, N. J.; Sanders, D.; Bellamy, H.; Stura, E. A.; Fee, J. A.; McRee, D. E. Nat. Struct. Biol.
1999, 6, 509–516.
Brown, K.; Tegon, M.; Prudencio, M.; Pereira, A. S.; Besson, S.; Moura, J. J.; Moura, I.; Cambillau, C. Nat. Struct.
Biol. 2000, 7, 191–195.
Eriksson, A. E.; Jones, T. A.; Liljas, A. Proteins 1988, 4, 274–282.
Adman, E. T.; Godden, J. W.; Turley, S. J. Biol. Chem. 1995, 270, 27458–27474.
Yoshikawa, S.; Shinzawa-Itoh, K.; Nakashima, R.; Yaono, R.; Yamashita, E.; Inoue, N.; Yao, M.; Fei, M. J.; Libeu,
C. P.; Mizushima, T.; Yamaguchi, H.; Tomizake, T.; Tsukihara, T. Science 1998, 280, 1723–1729.
Magnus, K. A.; Hazes, B.; Ton-That, H.; Bonaventura, C.; Bonaventura, J.; Hol, W. G. J. Proteins 1994, 19, 302–309.
Holmes, M. A.; Le Trong, I.; Turley, S.; Sieker, L. C.; Stenkamp, R. E. J. Mol. Biol. 1991, 218, 583–593.
Hegg, E. L.; Que, L., Jr. Eur. J. Biochem. 1997, 250, 625–629.
Que, L., Jr. Nat. Struct. Biol. 2000, 7, 182–184.
Vaillancourt, F. H.; Han, S.; Fortin, P. D.; Bolin, J. T.; Eltis, L. D. J. Biol. Chem. 1998, 273, 34887–34895.
Valegard, K.; van Scheltinga, A. C.; Lloyd, M. D.; Hara, T.; Ramaswamy, S.; Perrakis, A.; Thompson, A.; Lee, H. J.;
Baldwin, J. E.; Schofield, C. J.; Hajdu, J.; Andersson, I. Nature 1998, 394, 805–809.
Roach, P. L.; Clifton, I. J.; Hensgens, C. M.; Shibata, N.; Schofield, C. J.; Hajdu, J.; Baldwin, J. E. Nature 1997, 387, 827–830.
Karlsson, A.; Parales, J. V.; Parales, R. E.; Gibson, D. T.; Eklund, H.; Ramaswamy, S. Science 2003, 299, 1039–1042.
Fusetti, F.; Schroeter, K. H.; Steiner, R. A.; Van Noort, P. I.; Pijning, T.; Rozeboom, H. J.; Kalk, K. H.; Egmond, M. R.;
Dijkstra, B. W. Structure 2002, 10, 259–268.

Ludwig, M. L.; Metzger, A. L.; Pattridge, K. A.; Stallings, W. C. J Mol. Biol. 1991, 219, 335–358.
Ullah, J. H.; Walsh, T. R.; Taylor, I. A.; Emery, D. C.; Verma, C. S.; Gamblin, S. J.; Spencer, J. J. Mol. Biol. 1998,
284, 125–136.
Whittington, D. A.; Lippard, S. J. J. Am. Chem. Soc. 2001, 123, 827–836.
Logan, D. T.; Su, X. D.; Aberg, A.; Regnstrom, K.; Hajdu, J.; Eklund, H.; Nordlund, P. Structure 1996, 4, 1053–1064.
Rardin, R. L.; Tolman, W. B.; Lippard, S. J. New J. Chem. 1991, 15, 417–430.
Tong, W.; Burdi, D.; Riggs-Gelasco, P.; Chen, S.; Edmondson, D.; Huynh, B. H.; Stubbe, J.; Han, S.; Arvai, A.;
Tainer, J. Biochemistry 1998, 37, 5840–5848.
Lindqvist, Y.; Huang, W.; Schneider, G.; Shanklin, J. EMBO J. 1996, 15, 4081–4092.
Jin, S.; Kurtz, D. M., Jr.; Liu, Z.-J.; Rose, J.; Wang, B.-C. J. Am. Chem. Soc. 2002, 124, 9845–9855.
Stillman, T. J.; Hempstead, P. D.; Artymiuk, P. J.; Andrews, S. C.; Hudson, A. J.; Treffry, A.; Guest, J. R.; Harrison,
P. M. J. Mol. Biol. 2001, 307, 587–603.
Whittaker, M. M.; Barynin, V. V.; Antonyuk, S. V.; Whittaker, J. W. Biochemistry 1999, 38, 9126–9136.
Doukov, T. I.; Iverson, T. M.; Seravalli, J.; Ragsdale, S. W.; Drennan, C. L. Science 2002, 298, 567–572.
Darnault, C.; Volbeda, A.; Kim, E. J.; Legrand, P.; Verne`de, X.; Lindahl, P. A.; Fontecilla-Camps, J. C. Nat. Struct.
Biol. 2003, 271–279.
Nagashima, S.; Nakasako, M.; Dohmae, N.; Tsujimura, M.; Takio, K.; Odaka, M.; Yohda, M.; Kamiya, N.; Endo, I.
Nat. Struct. Biol. 1998, 5, 347–351.

# 2003, Elsevier Ltd. All Rights Reserved
No part of this publication may be reproduced, stored in any retrieval system or
transmitted in any form or by any means electronic, electrostatic, magnetic tape,
mechanical, photocopying, recording or otherwise, without permission in writing
from the publishers

Comprehensive Coordination Chemistry II
ISBN (set): 0-08-0437486
Volume 8, (ISBN 0-08-0443303); pp 1–15

8.2
Electron Transfer: Cytochromes
K. R. RODGERS and G. S. LUKAT-RODGERS
North Dakota State University, Fargo, USA
8.2.1 INTRODUCTION
8.2.2 HEME ELECTRONIC STRUCTURE AND AXIAL-LIGAND GEOMETRIES
8.2.2.1 Structural Aspects of 6cLS Iron Porphyrinates
8.2.2.2 Out-of-plane Porphyrin Deformation
8.2.2.3 The Frontier Orbitals and Fe–Ligand Bonding
8.2.2.4 Cause and Effect Roles of Axial Ligation
8.2.3 CYTOCHROMES c
8.2.3.1 Function
8.2.3.2 General Classifications
8.2.3.3 Structural Studies of Mitochondrial Cytochromes c
8.2.3.4 Redox-linked Conformational Changes in Class I Cytochromes c
8.2.3.5 Conformational Changes as a Function of pH in Class I Cytochromes c
8.2.3.6 Intramolecular Heme Ligand Rearrangements
8.2.3.6.1 Mitochrondrial cytochrome c folding intermediates
8.2.3.6.2 Redox-driven heme ligand switching in iso-1-cytochrome c (Phe82His)
8.2.3.7 Exogenous Ligand Complexes of Class I Cytochromes c
8.2.3.7.1 Exogenous ligand complexes of ferricytochromes c
8.2.3.7.2 Exogenous ligand complexes of ferrocytochrome c
8.2.3.8 Class II Cytochromes c0
8.2.3.8.1 Structure of cytochromes c0
8.2.3.8.2 Ligand adducts of reduced cytochromes c0
8.2.3.8.3 Folding intermediates of cytochromes c0
8.2.3.8.4 Cytochrome b562
8.2.3.9 Multiheme Cytochromes c
8.2.4 CYTOCHROME b5
8.2.4.1 Heme Orientation Isomers

8.2.4.2 Comparison of Mc and OM Cytochromes b5
8.2.4.3 Axial Heme Ligand Mutants of Cytochrome b5
8.2.5 CYTOCHROME bc1 COMPLEX
8.2.6 CYTOCHROME b6 f COMPLEX
8.2.7 FACTORS REGULATING REDOX POTENTIAL IN CYTOCHROMES
8.2.8 CONCLUDING REMARKS
8.2.9 REFERENCES

8.2.1

17
20
20
20
21
23
24
24
25
28
29
31
34
34
40
41
41
42
43
43

43
45
46
46
47
47
48
48
49
49
50
52
52

INTRODUCTION

The cytochromes are ubiquitous heme proteins (>75,000 known)1 that play essential roles in
biological electron transfer. They were originally classified on the basis of optical absorbance
maxima characteristic of their prosthetic heme groups.2,3 The chemical structures of the most
common biological hemes are shown in Figure 1. Several classes of biological metal-chelating
ligands, macrocyclic tetrapyrroles, include the porphyrins (22eÀ ligands in hemes a, b, and c),
chlorins (20eÀ ligands in heme d), isobacteriochlorins (18eÀ ligands as in heme d1), and corrins
(20eÀ ligands). Heme b in b-type cytochromes is an iron protoporphyrin IX complex in which
the iron atom is ligated to the four pyrrole nitrogen atoms. Hemes a and c are derivatives of heme b.
17


18

Electron Transfer: Cytochromes

HO

2

N

1 I/A

N

3
II/B

N

Fe
N

O
H

N

4

Fe
N

N

7

heme a

O

O
OH

N

8 IV/D

III/C 5

6

heme b

O

HO

O
OH

HO

S

S
N

N
Fe

N

N

heme c

O

O
OH

HO
HO
O

O
O

HO
N

N

N

N

N

heme d

OH
OH
O

O
OH

N
Fe

Fe
N

O

HO

N

heme d 1

O

O
OH

HO

Figure 1 Common biological heme structures. The labeling conventions indicated on the heme b structure
are those commonly found in the literature on solution studies. The Roman numeral designations are used
here. The crystallographic literature uses an Arabic letter labeling scheme that is rotated by À90 (90
counterclockwise) from that shown here.

Cross-linking of the heme b vinyl groups at