Bioinorganic Chemistry Module No and Title 1: Introduction

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Paper No. 15: Bioinorganic Chemistry

Module No. 1: Introduction: Bioinorganic Chemistry

Subject Chemistry

Paper No and Title 15: Bioinorganic Chemistry

Module No and

Title

1: Introduction: Bioinorganic Chemistry

Module Tag CHE_P15_M1

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TABLE OF CONTENTS

1. Learning Outcomes

2. Introduction

3. Metal function in Metalloproteins

4. Functions of metalloenzymes

5. Communication roles for metals in Biology

6. Interactions of metal ions and nucleic acids

7. Metal-Ion Transport and Storage

7.1 General aspects of storage and transport of metal-ions

7.2 Iron: Function, Storage and Transport

7.2.1. Function

7.2.2. Iron storage

7.2.2.1. Ferritin

7.2.2.2. Hemosiderin

7.2.3. Transport of Iron: Transferrin

7.3 Calcium: Function, Storage and Transport

7.3.1. Function

7.3.2. Calcium Storage

7.3.3. Calcium Pump

7.4 Copper: Function, Storage and Transport

7.4.1. Function

7.4.2. Storage of Copper

7.4.3. Copper transport

8. Summary

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1. Learning Outcomes

After studying this module, you shall be able to

Know the importance of inorganic elements.

Categorize the inorganic elements according to their roles in the biological system.

Learn the function of important elements such as Iron, Calcium and Copper.

Identify the general aspects of storage and transport of metal-ions.

Know the role of metals in medicine.

2. Introduction

Bioinorganic chemistry constitutes the discipline at the interface of the more classical areas of

inorganic chemistry and biology. Although biology is generally related to organic chemistry,

inorganic elements are also important to life processes. Table 1 lists the essential inorganic elements

together with some of their known roles in biology. Bioinorganic chemists study these inorganic

species according to their function in vivo.

Inorganic elements have also been artificially introduced into biological systems as probes of

structure and function. Heavy metals such as mercury and platinum are used by X-ray

crystallographers and electron microscopists to help elucidate the structures of macromolecules.

Paramagnetic metal ions have been valuable in magnetic-resonance applications. Metal-containing

compounds have been used not only as biological probes, but also as diagnostic and therapeutic

pharmaceuticals. The mechanisms of action of platinum anticancer drugs, gold antiarthritic agents,

and technetium radiopharmaceuticals are some currently active topics of investigation in

bioinorganic chemistry.

Bioinorganic chemistry, thus has two major components: the study of naturally occurring inorganic

elements in biology and the introduction of metals into biological systems as probes and drugs.

Peripheral but essential aspects of the discipline include investigations of inorganic elements in

nutrition, of the toxicity of inorganic species (including the ways in which such toxicities are

overcome both by the natural systems and by human intervention), and storage and transport of

metal-ions in biology.

Table 1. Essential inorganic elements and their role in biology.

Metal Function

Sodium Charge carrier; osmotic balance

Potassium Charge carrier; osmotic balance

Magnesium Structure; hydrolase; isomerase

Calcium Structure: trigger; charge carrier

Vanadium Nitrogen fixation; oxidase

Molybdenum Nitrogen fixation; oxidase; oxo transfer

Tungsten Dehydrogenase

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Manganese Photosynthesis; oxidase; structure Iron Oxidase; dioxygen tramped and storage; electron transfer: nitrogen fixation

Cobalt Oxidase; alkyl group transfer

Nickel Hydrogenase; hydrolase

Copper Oxidase; dioxygen transport: electron transfer

Zinc Structure; hydrolase

3. Metal Function in Metalloproteins

Metals are commonly found as natural constituents of proteins. Nature has learned to use the special

properties of metal ions to perform a wide variety of specific functions associated with life

processes. Metalloproteins that perform a catalytic function are called metalloenzymes.

Metalloproteins are a class of biologically important macromolecules and account for nearly half

of all proteins in biology. They are responsible for performing some of the most difficult yet

important functions, including photosynthesis, respiration, water oxidation, oxygen transport,

electron transfer, oxygenation and nitrogen fixation.

4. Functions of Metalloenzyme

Metalloenzymes are a subclass of metalloproteins that perform specific catalytic functions. A net

chemical transformation occurs in the molecule, termed a substrate, being acted upon by the

metalloenzyme. Some remarkable transformations for which no simple analogues exist in small-

molecule chemistry under comparable conditions includes the catalytic reduction of N2, to NH3,

(nitrogen fixation), the oxidation of water to O2, and the reduction of gem-diols to monoalcohols

(reduction of ribonucleotides).Classification of Metalloenzymes is done as per their function.

Within each category there are usually several kinds of metal centers that can catalyze the required

chemical transformation, a situation analogous to that already encountered for respiratory proteins.

The reasons for this diversity are shrouded in evolutionary history, but most likely include

bioavailability of a given element in the geosphere biosphere interface during the initial

development of a metalloenzyme, as well as pressure to evolve multiple biochemical pathways to

secure the viability of critical cellular functions.

5. Communication Roles for Metals in Biology

Metal ions are used in biology as triggers for specific cellular functions, and to regulate gene

expression. Studies of these cellular communication roles are an exciting frontier area in

bioinorganic chemistry. Magnetotactic bacteria use magnetite, Fe3O4, as an internal compass for

navigation of the microorganisms. They orient on the Earth's magnetic pole and, when transported

to the opposite hemisphere, become disoriented and swim upward. Some bees, homing pigeons,

and even humans are also believed to use magnetite in their brains for orientation purposes. Alkali

and alkaline earth ions, especially Na+, K+, and Ca2+, are used in biology to trigger cellular

responses. The firing of neurons by the rapid influx of sodium ions across the cell membrane and

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the regulation of intracellular functions of calcium-binding proteins such as calmodulin are two

examples of the phenomenon. In fact, Ca2+ has been referred to as a "second messenger," since

primary signals, such as the binding of hormones to the cell surface, are converted into changes in

the intracellular concentration of this ion. Among the most recently discovered metal-ion classes

in biology are the zinc fingers that occur in many proteins which regulate transcription.

6. Interactions of Metal Ions and Nucleic Acids

Metal ions also interact directly with DNA and RNA. Some of these interactions are rather

nonspecific, for instance, the stabilization of nucleic-acid structures by Na+ and Mg2+ ions through

electrostatic interactions that shield the charged phosphate groups from one another. Recently,

more specific binding of metal ions to nucleic acids has been discovered. Thus, Mg2+ and other

divalent metal ions serve as cofactors for activating catalytic RNA molecules; and monovalent

cations such as K+ stabilize the structure of telomeres, units that terminate the DNA double helix

at the ends of chromosomes. The relative stability of these structures may be dictated by the

concentrations Na+ and K+ in the cell. Finally, some inorganic-based drugs such as cisplatin act by

coordinating directly to DNA and metal complexes have been used as cleaving agents to probe, the

tertiary structures of nucleic acids.

7. Metal-Ion Transport and Storage

How do metal ions get into cells and how are they stored? This topic is an active area of

investigation in bioinorganic chemistry, although it cannot be classified with the others according

to metal function. The most thoroughly studied metal in this respect is iron. Iron enters bacterial

cells following chelation by low-molecular-weight compounds called siderophores that are

excreted by the bacteria. In mammals, iron is bound and transported by the serum protein

transferrin, and it is stored by terrain in most life forms. The nearly spherical, hollow shell of this

latter protein has the capacity to bind up to 4,500 Fe3+, ions. Details about how iron is passed among

these protein systems are incomplete and under active investigation. Copper is transported by the

serum protein ceruloplasmin, and another such protein, albumin, is also known to bind and transport

metal ions. Metallothionein is a cysteine-rich protein that is expressed in large amounts when

excess quantities of certain metal ions, including toxic ones such as Cd2+ or Pb2+, are present in

cells. Metallothionein thus serves a protective role and may also be involved in the control of metal

transport, storage, and concentration under more normal conditions.

7.1. General aspects of storage and transport of metal-ions

Charged Ions must pass through a Hydrophobic Membrane

Neutral gases (O2, CO2) and low charge density ions (anions) can move directly

through the membrane

High charge density cations require help

Once inside the cell, metal ions must be transported to the location of their use, then

released or stored for later

Release from ligand is often not trivial

Storage requires additional molecules

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7.2. Iron: Storage and transport

Iron is essential in small amounts for both plant and animal life. However, it is toxic in large

quantities.

Biologically iron is the most important transition element and it is involved in several

different processes:

As an oxygen carrier in the blood of mammals, birds and fish (Hb).

For oxygen storage in muscles tissue (Mb).

As an electron carrier in plants, animals and bacteria (cytochromes) and for electron

transfer in plants and bacteria (ferredoxins).

For storage and transport of Fe in animals (ferretin and transferrin).

As nitrogenase (the enzyme in dinitrogen fixing bacteria).

As a number of other enzymes: aldehyde oxidase, catalase and peroxidase and succinic

dehydrogenase.

Iron enters bacterial cell following chelation by low-molecular-weight components called

siderophores that are excreted by bacteria in most life forms.

In mammals, iron is bound and transported by serum protein transferrin, and it is stored by

ferritin.

7.2. 1. Iron storage

Iron which has been released into the cell must either be used immediately for biosynthesis or

stored in a safe form.

In humans, iron is stored mainly in the bone marrow, spleen and liver.

About 10% of all the iron in the body is in storage.

Two proteins are involved in iron storage:-

Ferritin

Haemosiderin.

7.2.1.1. Ferritin

Ferritin is a huge hollow spherical protein, with a wall mostly made up of α-helical peptide

chains. (Figure 2)

Fe2+ is oxidized and transported into the ferritin interior and deposited as an iron mineral

core, traditionally described as ferrihydrite, which is attached to the inner wall of the

sphere. Up to 4500 Fe can be stored although the normal value is about 2000.

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Figure 2. Ferritin

7.2.1.2. Hemosiderin

Hemosiderin is another storage form for iron in organism, in particular during iron

overloading.

Hemosiderin was first isolated from horse spleen in 1929.

Although the structures of the iron cores of ferritin and hemosiderin are similar, the protein

component of hemosiderin is largely unknown.

The iron/protein ratio in hemosiderin is even higher than in ferritin and is assumed that this

insoluble species is formed via lysosomal decomposition of ferritin.

Protease in the lysosome degrade the protein shell of ferritin, the released iron core

dissociates and reforms as the amorphous hemosiderin.

7.2.2. Transport of iron: Transferrin

Transferrins are iron-binding blood plasma glycoproteins that control the level of

free iron in biological fluids. (Figure 3)

Transferrin binds iron very tightly, but reversibly.

Contains two specific high-affinity Fe (III) binding sites.

The affinity of transferrin for Fe (III) is extremely high (1023 M−1 at pH 7.4) but decreases

progressively with decreasing pH below neutrality.

Transferrin without iron known as “ apotransferrin ”.

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Figure 3. Transferrin

Once carbonate binds in this site, the metal binding site is fully organised, so that the Fe

(III) can now coordinate in an octahedral, oxygen rich environment of ligands favourable

for such a relative hard metal ion.

7.3. Calcium

7.3.1. Function:

Signal pathways (Ex: Muscle Contraction)

Skeletal Material

Concentration:

Outside of Cell [Ca2+] = 0.001 M

Inside Cell [Ca2+] = 10-7 M

Ca2+-ATPase in Cell Membrane controls concentration

7.3.2. Calcium storage

CaCO3 in a protein matrix makes up egg shells and coral skeletons

Calcium Hydroxyapatite in a collagen framework is the stored form of Ca2+ in bones and

teeth: Ca10(PO4)6(OH)2

Collagen: triple helix fibrous protein

Hydroxyapatite crystallizes around the collagen

When needed, Ca2+ can be released and reabsorbed

7.3.3. Calcium pump

Calcium pumps are ATPases that transport ions using energy obtained from the hydrolysis

of ATP across membranes.

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Calcium ATPases are members of the P-type family of ion pumps, which are responsible

for the ATP dependent active transport of ions across a wide variety of cellular membranes.

The protein is far less stable when these calcium ions are removed. It was solved by adding

a drug molecule that binds near the calcium-binding site and freezes the protein into a

stable, but non-functioning form.

The calcium pump is an amazing machine with several moving parts. It is found in the

membrane.

It has a big domain poking out on the outside of the sarcoplasmic reticulum, and a region

that is embedded in the membrane, forming a tunnel to the other side.

When an ATP breaks, calcium pump transfers two Ca2+ ions through the membrane and

two or three hydrogen ions back in opposite direction.

In this process of pumping, a phosphate is transferred from the ATP to a special aspartate

amino acid in the pump, number 351.

The switching is controlled by large motions of the ATP-binding domains, which push and

pull on the protein surrounding the tunnel, opening and closing it appropriately.

Permanent activation of the pump, by calmodulin, is physiologically as harmful to cells as

its absence.

The concept is now emerging that the global control of cell Ca2+ may not be the main

function of the pump; in some cell types, it could even be irrelevant.

The main pump role would be the regulation of Ca2+ in cell microdomains in which the

pump co-segregates with partners that modulate the Ca2+ message and transduce it to

important cell functions.

7.4. Copper

7.4.1. Function O2 transport (hemocyanin in crustacean and mollusks)

O2 activation (Cu oxidases)

electron transfer (plastocyanin)

Availability

Third most abundant transition metal ion in organisms

300 mg in a human body

Ksp(Cu(OH)2) = 2.6 x 10-19 [Cu2+] = 2.6 x 10-5

Solubility means less specialized transport and storage

7.4.2. Storage of Copper

After its hepatic uptake, copper may be stored within hepatocytes, secreted into plasma, or

excreted in bile.

The biliary route represents the major excretory pathway of copper and largely accounts

for its hepatic turnover.

Copper retamed by hepatocytes is mostly bound to specific metal-binding proteins,

primarily metallothionein, or incorporated into several cuproenzymes.

Impairments of homeostatic mechanisms in brain copper metabolism have been associated

with neurodegeneration in human disorders such as Menkes disease, Wilson's disease and

Alzheimer's disease.

7.4.3. Copper transport

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Intakes of copper at doses that exceed physiologic demands are normally met with efficient

homeostatic mechanisms.

Ceruloplasmin, albumin, and transcuprein, and to a lesser extent certain amino acids, are

major copper-transporting constituents in circulating plasma.

Studies with radioactive copper have established that after intestinal absorption copper

appears in the portal bloodstream bound to albumin and, to a much smaller extent, amino

acids. This copper is rapidly transported to the liver.

Considering the number of copper atoms massed within its structure, ceruloplasmin can be

considered to be an effective vehicle for shuttling copper out of the liver and delivering

clusters of copper atoms into a variety of nonhepatic cells and tissues.

8. Metals in medicine

Many first encounter the use of metals in medicine as well as metal toxicity through literature. The

use of iron and copper can be traced to the ancient Greeks and Hebrews through their writings.

Lewis Carroll's Mad Hatter suffered from mercury poisoning. Among metal ions commonly used

over the centuries were Hg2+ for the treatment of syphilis. Mg2+ for intestinal disorders, and Fe2+

for anemia. These early examples represent crude approaches, the refinement of which did not,

until recently, begin to match in sophistication or efficacy the contributions of organic chemists,

who introduced sulfa drugs, penicillin, and mechanism-based inhibitors such as metho-trexate.

One of the leading anticancer drugs is cis-[Pt(NH3)2Cl2]. Cisplatin administered by intravenous

injection for the treatment of testicular, ovarian, and head and neck tumors. Cisplatin cures

testicular cancer, when diagnosed early enough, in more than 90 percent of the cases. Auranofin,

[Au(PEt3)(ttag)], where ttag is tetra-O-acetylthioglucose, is the first orally administered drug for

the treatment of rheumatoid arthritis. It is an important member of the class of antiarthritic gold

agents, the others of which are injected. The third example is [Tc(CNR)6]+, M which the technetium

is supplied as its 99mTc radioisotope. This class of complexes is selectively taken up by myocardial

tissue and has proved to be excellent for imaging the heart. Platinum, gold, and technetium, three

nonessential transition elements, have found a place in medicine. Given the range and variety of

inorganic compounds, the potential applications of inorganic chemistry to improving human health

are boundless. This aspect of bioinorganic chemistry, now in its infancy, seems destined to be an

area of rapid and significant growth.

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Figure 4. Metals in Medicine: Therapy and Diagnostic

Anticancer Therapeutics

Cisplatin was the first metal-based medicinal agent to enter into worldwide clinical use

for the treatment of cancer. Figure 5 displays various platinum based anticancer agents.

The Pt2+ of the {Pt(NH3)2}2+ unit binds covalently to deoxyribonucleic acid (DNA), more

specifically, to the N-7 of either guanine (G) or adenine (A) in the dinucleotide sequences

GG and AG to form interstrand cross-links and 1,2- or 1,3-intrastrand cross-links.

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Figure 5. Recently discovered Platinum based anticancer agent

Figure 5 represents some of the antimicrobial and anti-parasitic metallodrugs

Figure 6. Antimicrobial and Antiparasitic Metallodrugs

One arsenic drug that is still used

against trypanosomiasis

(sleeping sickness)today,

despite its severe side effect of

encephalopathy, is melarsoprol.

Antimony-based drugs have been

prescribed against cutaneous and

mucocutaneousleishmaniasis (skin

ulcers)

The history of bismuth drugs is

closely connected to gastrointestinal disorders, but bismuth is also

coadministered in the fight against the

bacterium Helicobacter pylori

(H. pylori).

Silver ions are incorporated into

surgical wound dressing cloths

(e.g.,Acticoat) and catheters (e.g.,

SilverSoaker) for infection prevention

or into textiles for the treatment of

acute neurodermitis.

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9. Summary

Bioinorganic chemistry includes the study of both natural phenomena such as the

behavior of metalloproteins as well as artificially introduced metals, including those that

are non-essential, in medicine and toxicology.

Metal ions are used in biology as triggers for specific cellular functions, and to regulate

gene expression.

In mammals, iron is bound and transported by serum protein transferrin, and it is stored by

ferritin.

Hemosiderin is another storage form for iron in organism, in particular during iron

overloading.

Calcium pumps are ATPases that transport ions across membranes using energy obtained

from the hydrolysis of ATP.

Major cooper-transporting constituents in circulating plasma are Ceruloplasmin, albumin,

and transcuprein, and to a lesser extent certain amino acids.

Metal coordination compounds in therapy has open an array of possibilities, which

traditional organic or biological molecules cannot fulfill any longer due to growing drug

resistance.

Metallodrugs hold still tremendous potential to help mankind overcome drug resistance

and to find new cures in medicine.

Bioinorganic Chemistry Module No and Title 1: Introduction

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