metal coordination chemistry in the study … nternational j ournal of p harmaceutical b iological...

International Journal of Pharmaceutical

Biological and Chemical Sciences

e-ISSN: 2278-5191

International Journal of Pharmaceutical, Biological and Chemical Sciences (IJPBCS)

| JUL-SEPT 2014 | VOLUME 3 | ISSUE 3 | 36-45 www.ijpbcs.net or www.ijpbcs.com

Review Article

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METAL COORDINATION CHEMISTRY IN THE STUDY OF

BIOLOGICAL PATHWAY AND PROCESSES: A REVIEW

Jiayue Chen1, Keita Fukuzumi

2, Benny Ip

2, Florence

1, Abigail P. Cid

3

1Department of Biotechnology, Division of Applied Science, Osaka University,

1-1 Yamadaoka, Suita, Osaka Prefecture 565-0871, Japan 2Department of Applied Chemistry, Osaka University-1 Yamadaoka, Suita, Osaka Prefecture 565-0871, Japan

3International College, Osaka University, 1-30 Machikaneyama-cho,

Toyonaka, Osaka Prefecture, 560-0043, Japan

*Corresponding Author Email: [email protected]

1. INTRODUCTION

Coordination chemistry is a study of compounds formed

between metal ions and neutral or negatively charged

molecule called ligand, and this resulting compound is

called metal complex or coordination compound. The

coordination chemistry was pioneered by Nobel Prize

winner Alfred Werner (1866-1919), who created a

coordination theory of transition metal complexes [1].

Werner recognized the there are several forms of cobalt-

ammonia chloride. These compounds have different

physicalcharacteristics. The chemical formula is same,

but the arrangement of chloride ions that precipitate was

not always same, such as [Co (NH3)5Cl] Cl2 and [Co

(NH3)6] Cl3. Also these compounds are geometrically

different, having cis- and trans- conformations. Factors

such as metal ions involved, type of ligand, combination

of ligands, shape and bond angle all affect the character

of the coordination compound of coordination

compound. Bioinorganic chemistry, on the other hand,

is the interface of biology and inorganic chemistry which

emerged around 1962 in one of the Gordon Research

Conference "metals in biology" and was originally called

as "metals and metal binding in biology". Biological

system is a very diverse, sensitive and dynamic system

where varieties of metal ions are also found. Therefore it

is almost as expected to see coordination compound

involved in such a system. In this review, the topics

discussed are the basic ability of metal ions to coordinate

and then release ligands in some processes, and to

oxidize and reduce in other processes makes them ideal

for use in biological systems. Based on these features,

some important roles of metal complex in biological

pathways and life processes, and application for

Biomedical field are explored.

2. METAL COMPLEX AND BIOLOGICAL

LIGANDS

Biologically relevant ligands are categorized as

bioligands. Coordination complexes composed of metal

ion and bioligands have significant roles in biological

pathway. Metal ions act as Lewis acid, which able to

ABSTRACT:

Bioinorganic chemistry is the interface between biology and inorganic chemistry which is also referred to as metals and metal

binding in biology. The ability of metal ions to coordinate and then release ligands in some processes, and to oxidize and

reduce in other processes makes them ideal for use in biological systems. This review article highlights some important roles of

metal complex in biological pathways and life processes, application for biomedical field, and also potential biological

functions of metals that still left to be discovered and explored for development of new application in bioinorganic field.

KEYWORDS: Coordination Metals Complex; Metal; Biological Ligands; Enzyme; Photosynthesis; MRI agents

Abigail Cid* et al; METAL COORDINATION CHEMISTRY IN THE STUDY OF ……

International Journal of Pharmaceutical, Biological and Chemical Sciences (IJPBCS) | JULY-SEPT 2014 | VOLUME 3 | ISSUE 3 | 36-45| www.ijpbcs.net

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accept lone pairs of electron donated by ligands that act

as Lewis base. Often in biological system, rather than

small molecule ligands, we found biological ligands,

which form coordination complex that greatly affects the

biological pathway. The biological ligand for metal ions

is categorized into three classes: (A) Peptides with its

amino acid side chains, (B) macrocylic chelate ligands,

and (C) nucleobases (nucleic acids).

A. Amino Acids as biological ligands

Approximately one-third of all functional proteins and

enzyme in our body requires metal ion as cofactor to

perform its specific role [1]. These proteins have metal

binding site in the 3D-structure which then the metals

are usually covalently bound to the polypeptide

backbone by endogenous ligand provided by amino acid

side residues, such as histidine, methionine, cysteine,

tyrosine, aspartate, and glutamate [2]. The typical

coordination numbers are 4 or 6; however it is often

found in certain enzyme that the coordination with

amino acid residues is not complete [3]. This incomplete

coordination is a fundamental structure for catalytic

activity of enzyme, as the open site remains available for

coordination with substrate. On the other hand, this open

site structure is not observed in protein that function in

electron transfer.

The metal complex formed at metal sites of the protein

has tremendous biological function [1].

Structural—configuration of protein in tertiary or

quaternary structure, such as

Storage—uptake, binding, and release of metal ion, for

example ferritins (store Fe (III) intracellularly) [4] and

metallothioneins.

Electron transfer—uptake, release, storage of electrons,

such as iron-sulfur protein, blue copper protein, and

cytochrome [5].

Dioxygen binding-metal-O2 coordination and

decoordination, such as myoglobin, hemoglobin [6],

hemerythrins[7], and hemocyanins.

Catalytic—substrate binding and activation, turnover,

such as hydrolytic enzyme (peptidase, phosphatase),

which generally employ Mg (II) or Zn (II) in their active

sites [8].

The specificity of metal ion in forming complex with

certain protein leads to the application of metal complex

protein in chromatography method, namely IMAC

(Immobilized Metal Ion Affinity Chromatography). By

utilizing the affinity of transition metal ions like Zn (II),

Cu(II), Ni(II), and Co(II) ions toward cysteine, histidine,

and tryptophan in aqueous solution, the metal ions are

immobilized to a support, such as agarose in order to

fractionate and purify proteins in solutions [9].

B. Macrocyclic Chelate Ligands

Macrocylic ligands are polydentate ligands containing

their donor atoms, either incorporated or attached to the

cyclic backbone [10]. Generally, macrocylic ligands

contain at least three donor atoms and the macrocylic

rings should contains at minimum of nine atoms.

Macrocylic ligand complexes are involved in number of

fundamental biological systems has long been

recognized. Macrocylic derivatives enhance the kinetic

and thermodynamic stabilities of important complexes as

the metal ions is held tightly in the cavity of macrocyles

such that the biological function is not impaired with

competitive binding with other metal ion or

demetallation reactions [11]. The selectivity of metal ion

according to the chelate ring size also introduce a

selectivity for metal ion in binding to certain macrocylic

chelate, which then crucial in ligand recognition. These

macrocylic chelate ligands is crucial in biological

pathway such as porphyrin ring (Figure 1A) of the iron-

containing heme proteins in oxygen transport of red

blood cell and chlorin complex (Figure 1B) of

magnesium in chlorophyll for photosynthesis of plant.



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(A) (B)

Figure 1: The structure of (A) porphyrin ring part of hemeconnected to Fe and (B) chlorin ringpart of

chlorophyll a attached to Mg as macrocycles chelate ligands [11]

.

C. Nucleobases as biological ligands

Coordination chemistry has long been focused on the

role of metal ions in nucleic acid such as DNA

replication, transcription, translation, denaturation,

renaturation, RNA polymerization [12]. The cellular

regulation of DNA requires metallonuclease to catalyze

and repair DNA strand breaks. Nucleobases can exist in

different tautomeric forms and can be mono or

multidenate ligands. As the overall charge of nucleic

acid is negative, positive charged metal ions can bind

and affect hydrogen-bond interactions of base pairing in

DNA. The most important function of metal-nucleobase

complex can be seen in the chemotherapeutical of cancer

cell. The most recent founding is the inorganic construct

such as cisplatin and bimetallic rhodium acetate exert

antitumor activity by inner-sphere coordination to DNA

[13]. cis-diamminedichloroplatinum(II) or cisplatin is

widely used DNA-damaging agent in cancer therapy.

Cisplatin cross-links to DNA forming intra and inter-

strands abduct, thus further bend the DNA and damage

DNA and resulting cell-cycle arrest and apoptosis [14][15].

However, one of the major downside of cisplatin and its

derivatives is having damaging side effects to healthy

cells. Better understanding of biological pathway

involved in cisplatin toxicity will bring a development of

new cisplatin therapeutic strategy since up to this day,

only few papers have been published on the cisplatin-

induced apoptosis pathway [14]. Recent advances in the

field of chemotherapy include the development of

targeted anticancer agents, compounds that are directed

towards a specific biomarker of cancer, with hope to

reduce the side effect. This greater selectivity is obtained

by tailored several transition metal complex towards

biomolecules associated with cancer [16]. The rhodium

metalloisertors is one of the notably success compounds,

which can specifically bind to nucleic acid base

mismatched in DNA [16]. There are also some research

showing the replacement of cisplatin such as trans,trans-

[{PtCl2(NH3)}2(piperazine)][17] and [PtCl2(hpip)][18],

which are potential antitumor agents. The further

research on this field will bring enormous potential

towards a better cancer therapy.

3. METAL COMPLEX AFFECTS ENZYME

ACTIVITES

Coordination compounds can also affect some enzyme

activities. We know that small molecules are able to

selectively inhibiting a particular enzyme, which are

usually organic compounds. Controlling enzyme activity

by coordination compounds plays an important role in

discovering new inorganic drug candidates [19].

Furthermore, the advantage that metal-binding

compounds and metal complexes can provide such kind

of unique properties contributing to enzyme inhibition

that are not found in conventional in conventional

organic molecules [20]. The mechanisms that how they

control the enzyme activity varies from different

complexes. Some compounds directly bind to the active

side of the enzyme and blocking access of the substrate

to the enzyme. In contrast to those binding directly to



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active site, some complexes bind to the non active site of

substrate or enzyme, changing their conformation in

order to prevent the correct binding of substrate to

enzyme. Other enzyme itself contains coordination

structure and functions the catalysis. There are many

other kinds of mechanisms as well but in this article we

mainly talk about the following examples.

A. Enzyme inhibition by binding to an active site of

the enzyme.

Porphyrins are typical enzyme inhibitor, which inhibit

the activity of acetylcholinesterase (AChE)[21][22].

Tetraphenylporphyrin (Figure 2) can form different kind

of metal complex with different functions by changing

the coordination center (e.g. Fe, Zn, Cu, Co, etc.). A

common example, which can be found in the structure of

myoglobin and hemoglobin in our body, is the

tetraphenylporphyrin complex with Fe as coordination

center. Monosulfonatetetraphenylporphyrin (TPPS1) is

able to forms a 1:1 complex with electric eel AChE,

changing its conformation and thus inhibit the enzyme

activity [23]. White and Harmon (2002) have observed

changes by measuring the absorbance of both TPPS1 and

AChE [23]. They reported that TPPS1 is an effective

reversible competitive inhibitor of AChE, which means

that TPPS1 competes directly with the normal substrate

for an enzymatic binding site of AChE. Therefore the

coordination compound acts as a competitive inhibitor

that binding the active site of AChE in order to reduce

the concentration of free enzyme available for substrate

binding.

B. Metal complexes can promote nucleophilic

catalysis by water ionization.[24]

The metal complexes are able to cause water ionization

through the metal ion in coordination center. The metal

ion provides charge that enables it to bind with water

molecules, making the water molecule more acidic than

free one. Thus, OH- ion can exist in environment with

pH below neutral. Then it promotes the nucleophilic

catalysis.One typical example is the catalytic mechanism

of carbonic anhydrase. Carbonic anhydrase is an enzyme

catalyzes the reaction as shown below.

Typical example of this reaction is metal complex

structure with Zn2+ ion as coordination center (Figure 3).

The water molecule first binds to the fourth liganding

position of Zn2+ ion, resulting in water ionization. The

Zn2+bound OH- becomes a potent nucleophile, which can

attack the CO2, converting it into HCO3- (Figure 4). At

last the catalytic site is regenerated back to the initial

state and ready to catalyze another CO2.

Figure 3.The ribbon model of carbonic anhydrase.

Taken from

http://guweb2.gonzaga.edu/faculty/cronk/biochem/C

-index.cfm?definition=carbonic_anhydrase.

Figure 2.Tetraphenyl porphyrin metal complex



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4. ROLE OF METAL COMPLEX IN LIFE

PROCESSES

Many enzymes and proteins have metal ions embedded

in them that play key roles in catalysis. In bio-inorganic

chemistry, the development of ―small inorganic

coordination complexes‖ is vital in macroscopic view of

―wide life processes‖ as it provides the process with

structural and functional support. Several of well-known

life processes, in which metal complex holds a crucial

role, include but is not limited to, artificial

photosynthesis, metalloproteins and metalloenzymes.

Photosynthesis consists of the processes of light

harvesting, charge-separation, water reduction and

oxidation, and CO2 fixation. In the core of each

photosynthetic system is the reaction center. Artificial

reaction centers have been modeled on the Marcus

theory of electron transfer [25]. For instance, the

application of emizco, ethyl 4-methyl-5-

imidazolecarboxylate, the metal salts

CoC12.6H2O, CoBr2, Co(NO3)2.6H2O and their metal

coordination compounds [Co(emizco)2C12],

[Co(emizco)2Br2].H2O,

[Co(emizco)2(H2O)2](NO3)2.2H2O in the characterization

of CO2+ coordination on photosynthesis was performed

[26]. The results showed that the emizco coordination

compounds inhibit photosynthetic electron flow and

ATP-Synthesis [26]. These were typical of Hill reaction

inhibitors. Another model of an artificial reaction core

utilized a mononuclear ruthenium complex to show

multiple proton-coupled electron transfer toward multi-

electron transfer reactions [27]. In the context, a new

Ruthenium (II) complex, [Ru(trpy) (H2bim)(OH2)]

(PF6)2 was developed to demonstrate the four-step

proton-coupled electron transfer (PCET) shown in

Figure 5.

Figure 4.The mechanism of carbonic anhydrase catalyzed reaction. Imi = imidazole, quoted from Voet & Voet

(2013) [24]



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Figure 5.A schematic view of the four-step PCET reaction ofRu(trpy)(H2bim)(OH2)](PF6)2 to give the four-

electron oxidized species, [RuIV

(trpy)(bim)(O))]2+

.(H2bim = 2,2’-biimidazole and trpy = 2,2’:6’,2”-terpyridine)

modified from Kobayashi et al. (2012) [27]

Bio-inorganic chemistry is a growing interdisciplinary

study in the fields of nanomaterial science and

biotechnology. Intricate enzymatic reactions such as

protein assembly employ the use of coordination metals.

Protein assemblies are often used as molecular scaffolds

[28]. In metal homeostasis, the formation of specific

protein-metal complexes are used to effect uptake and

efflux to name a few. Metal transporters move metal ions

across the impermeable cell membrane in directional

fashion. These protein complexes, metallochaperones,

traffic metals within a cellular compartment by readying

such complexes for transfer via appropriate acceptor

proteins. Metallochaperones have been identified for

copper [29]

, nickel [30]

, and iron-sulfur protein [31]

biogenesis. In light of recent research, it has also been

suggested that the periplasmicZn(II) binding protein,

YodA, has characteristics consistent with zinc

chaperones in E. coli. [32]

The acquisition of essential metal ions is of the

importance to bacterial systems. This requires the intake

of metal ions into the cytosol, genes are expressed to

encode for plasma membrane-bound transporters.

However, this system is of a negative feedback

inhibition. When the cytosolic concentration of metal

complexes becomes too high, the aforementioned genes

are repressed. Simultaneously, the effects of metal

complexes have to be mitigated. This occurs under the

forms of sequestration by intracellular chelators, such as

Cys-rich metallothioneins [33], ferritin-like

bacterioferritins, DPS complexes [34], or efflux of metal

complexes/ions from the cytosol [35].

5. METAL-RESPONSIVE MRI AGENTS

As one of the application of metal complex in medical

field, MRI has been widely used for investigation of the

anatomy and function of body in different condition.

Magnetic Resonance Imaging (MRI) provides a three

dimensional images of biological structure with

relatively high resolution, in harmless method. Its

popularity among medical field results from nuclear

magnetic resonance of water proton in the body using

energy from an oscillating magnetic field. Therefore the

contrast in the image depends on the concentration of

water of the region and on the longitudinal (T1) and

transverse (T2) relaxation times of its protons[36].

Under magnetic field, water protons are all aligned

parallel to its external field. However when a

radiofrequency pulse (RF pulse) is sent, it inverts the

magnetization vector of water proton that was previously

aligned with the external magnetic field. The time it

takes for the spins to realign with the external field is

characterized by T1. This time can be significantly

reduced if the spins are in contact with a local



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paramagnetic center because it has much stronger

magnetic field of its own compared with that of water

proton, so interacting with stronger magnetic field results

in stronger signal intensity. Coordination complexes that

leave open coordination sites for water molecules to

access the inner-sphere of paramagnetic metal ions

(particularly Gd3+ with 7 unpaired f electrons, but also

high-spin Fe3+ and Mn2+ with 5 d electrons) are therefore

excellent candidates as agents that enhance MR images

via a T1mechanism[20].

MRI agent for calcium

Gadolinium (Gd) is a paramagnetic metal. When used in

MRI, it may show certain tissue, abnormalities and

diseases more clearly visible on the image. However

gadolinium itself is toxic, so it is usually bonded to non-

metal ions. GOPTA-Gd is a MRI contrast agent

consisting of BAPTA (1, 2- bis (o-aminophenoxyl)-

ethane-N, N, N', N'- tetraacetic acid) Ca2+

chelating motif

onto which Gd (DOTA)(1,4,7,10-tetraazacyclododecane-

1,4,7,10-tetraacetic acid) macrocycles fused. After Ca2+

is bound to DOPTA-Gd, the molecule undergoes a

conformational change that opens up the hydrophilic

face of the tetraazacyclododecanemacrocycle[37]. In

short, Ca2+ opens up a space for water to directly

interfere with Gd3+ center, (Figure 6A to A’) therefore

increasing accessibility of water to Gd3+. The discovery

of this conformational change provided a template for

other Gd based molecule, such as EDTA (B), APTRA

(o-aminophenol-N, N, O-triacetate) (C) and EGTA (D).

Figure 6.A schematic view of the chelating reaction of GOPTA-Gd (A to A’). Structures of other Gd based MR

agents (B, C and D). Taken from Li et. al, 2002 [37]

Making of probe functioning in biological media

The probe that is functional in biological environment

was created according to the idea of GOPTA-Gd as

discussed in previous section. Previously, the DOTA-

based probes all suffer from a loss of relaxivity in

biological media, most likely due to anions in the

buffered aqueous solution displacing water from Gd3+ in

the Ca2+ added form [38]. However, the Ca2+ response of

the EGTA-based probe in a complex cell culture medium

designed to mimic the brain extracellular medium gave

about 10% change in relaxivity over the 0.8 – 1.2 mM

[Ca2+] range which is a similar condition to that of brain

[39]. One of the challenges in making such probes is to

limit its chemical selectivity to the target metal ion only.

Since biological median is polar, protic and high in ionic

strength, selectivity over various metal ions present is

very hard[6]. Also it is also desired to have high relaxivity

and modulations in relaxivity so that it minimizes the



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amount of contrast agent needed, minimizing the

potential side effect [40]. But in above case, EGTA-based

probe was selective in Ca2+ and were not affected by

other ions such as Mg2+

. Also the relaxivity in biological

media was significantly better than that of DOTA based

one.

MRI agents for zinc and copper

While Ca2+ enhanced Gd-based probes are widely

investigated, probes that are sensitive to metal ions like

Zn2+ and Cu2+ has been also made by decreasing the

number of carboxylic acid arms to lower the affinity for

Ca2+ while retaining affinity for these d-block metals.In

2007, Major et al. discovered that binding of Zn2+

to Gd-

diaminoacetate3 (diaminoacetate3, diaminoacetate with

three methylenes) increases relaxivity[41] (Figure 7). In

2006, Queand Chang found CG1 (Copper-Gad1), that

shows increase in relaxivity in the presence of Cu2+[42].

They are both interfered by non-target ion of Zn2+ and

Cu2+ but are not affected by the presence of Ca2+.

Figure 7.A schematic view of binding of Zn to Gd-DAA3. Adopted from Major et. al, 2007 [41]

Magnesium and Potassium detection

For the function of muscle and nerve cells, the body

must control its intracellular and extracellular K+

concentration. The activities such as muscle contraction

are relying on membrane potential which is caused by

uneven concentration of K+. In 2007, Hifumi et al.

introduced gadolinium complex KMR-K1 which has two

15-crown-5 ethers into a Gd–DTPA core[43]. It showed a

slight decrease in relaxivity when K+ is added and the

agent does not respond to Na+, Mg2+, or Ca2+. Even

though the relaxivity decreased, the difference in

relaxivity leads to visualization in MRI. This was an

important discovery since it was a first potassium ion

selective gadolinium complex. At the same time, KMR-

Mg, a Gd–DTPA-derivative modified with one charged

β -diketonewas also introduced. The compound also

showed reduced relaxivity when Mg2+ is present in

median, which made it a first magnesium ion selective

gadolinium complex. Due to the difference in relaxivity

when certain ion is present, MRI can detect the presence

of the target ion just by looking at the image.

6. CONCLUSIONS AND OUTLOOK

There are obvious and crucial role of coordination metal

complex in biological pathway and processes. The works

cited in this review brought us to ainsights on how metal

trafficking in organism affects the biological pathway

and the whole biological process. As we seek to

understand the role of coordination metal complex in

biology, there will be more research opportunities to

develop better strategies for intercepting and manipulate

biological pathway and processes. Moreover, innovative

research on the design, functionality, and reactivity of a

certain metal complex can enlighten new biological

applications for metal complex such as a new MRI agent

or a DNA-probing agent.



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