Chemistry of Metalloproteins: Problems and Solutions in Bioinorganic Chemistry

By Joseph J. Stephanos and Anthony W. Addison

Addresses the full gamut of questions in metalloprotein science

Formatted as a question-and-answer guide, this book examines all major families of metal binding proteins, presenting our most current understanding of their structural, physicochemical, and functional properties. Moreover, it introduces new and emerging medical applications of metalloproteins. Readers will discover both the underlying chemistry and biology of this important area of research in bioinorganic chemistry.

Chemistry of Metalloproteins features a building block approach that enables readers to master the basics and then advance to more sophisticated topics. The book begins with a general introduction to bioinorganic chemistry and metalloproteins. Next, it covers:

• Alkali and alkaline earth cations
• Metalloenzymes
• Copper proteins
• Iron proteins
• Vitamin B12
• Chlorophyll

Chapters are richly illustrated to help readers fully grasp all the chemical concepts that govern the biological action of metalloproteins. In addition, each chapter ends with a list of suggested original research articles and reviews for further investigation of individual topics.

Presenting our most current understanding of metalloproteins, Chemistry of Metalloproteins is recommended for students and researchers in coordination chemistry, biology, and medicine.

Each volume of the Wiley Series in Protein and Peptide Science addresses a specific facet of the field, reviewing the latest findings and presenting a broad range of perspectives. The volumes in this series constitute essential reading for biochemists, biophysicists, molecular biologists, geneticists, cell biologists, and physiologists as well as researchers in drug design and development, proteomics, and molecular medicine with an interest in proteins and peptides.

• Language: English
• Publisher: Wiley
• Release date: Jul 22, 2014
• ISBN: 9781118801529

Joseph J. Stephanos

Joseph J. Stephanos is associate professor of inorganic, bioinorganic, biophysics chemistry at Menoufia University. He has been postdoctoral research associate at Pennsylvania University, postdoctoral instructor and adjunct associate professor at Drexel University and has held various teaching positions leading to the current one. Dr. Stephanos’ research interests concern inorganic studies of biologically active molecules, studying model compounds, their structure and bonding, and the chemistry of metalloproteins and ligands binding, with special reference to mechanistic aspects and structure/function relation. He is the author and coauthor of several articles and one previous book, Chemistry of Metalloproteins: Problems and Solutions in Bioinorganic Chemistry.

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CONTENTS

Cover

Wiley Series in Protein and Peptide Science

Title Page

Copyright

Preface

Chapter 1: Introduction

Proteins: Formation, Structures, and Metalloproteins

References

Chapter 2: Alkali and Alkaline Earth Cations

References

Chapter 3: Nonredox Metalloenzymes

Carboxypeptidases

Carbonic Anhydrase

Alcohol Dehydrogenase

References

Chapter 4: Copper Proteins

Introduction

Electronic Spectra of Copper Ions

ESR Spectra of Copper Ions

Copper Proteins

Plastocyanin

Azurin and Stellacyanin

Superoxide Dismutase

Hemocyanin

Ascorbic Oxidase

References

Chapter 5: Iron Proteins

Introduction

Electronic Spectra of Iron Ions

Mössbauer Spectroscopy of Iron Ions

ESR Spectra of Iron (III)

Iron Bioavailability

Siderophores

Iron Storage and Transfer Proteins

Ferritin

Transferrin

Dioxygenase Iron Proteins

Iron–Sulfur Proteins

Rubredoxin

Ferredoxins

2Fe–2S Ferredoxins

4Fe–4S Ferredoxins

Aconitase

Hydroxylases

Hydrogenases

Nitrogenases

Binuclear Iron Proteins

Hemerythrin

Ribotide Reductase, Purple Acid Phosphate, and Methane Monooxygenase

Hemoproteins: Classification and Behavior of Heme in Absence of Globins

Myoglobin and Hemoglobin

Myoglobin

Hemoglobin

Cytochrome c

Electron Transfer in Porphyrins and Metalloporphyrins

Catalases

Peroxidases

Cytochrome P-450

Electronic Spectra of Hemoproteins

ESR Spectra of Hemoproteins

References

Chapter 6: Vitamin B12

References

Chapter 7: Chlorophyll

References

Index

End User License Agreement

List of Tables

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 3-1

Table 3-2

Table 4-1

Table 5-1

Table 5-2

Table 5-3

Table 5-4

Table 5-5

Table 5-6

Table 5-7

Table 5-8

Table 5-9

Table 5-10

Table 5-11

Table 5-12

Table 5-13

List of Illustrations

Figure 1-1

Figure 1-2

Figure 1-3

Scheme 1-1

Figure 1-4

Figure 1-5

Figure 1-6

Figure 1-7

Figure 1-8

Scheme 1-2

Scheme 1-3

Figure 1-9

Figure 1-10

Figure 1-11

Figure 1-12

Figure 1-13

Figure 1-14

Figure 1-15

Figure 1-16

Figure 1-17

Figure 1-18

Figure 1-19

Scheme 1-4

Figure 1-20

Scheme 1-5

Scheme 1-6

Scheme 1-7

Figure 2-1

Figure 2-2

Scheme 2-1

Figure 2-3

Figure 2-4

Scheme 2-2

Figure 2-5

Figure 2-6

Figure 2-7

Figure 2-8

Scheme 2-3

Scheme 2-4

Scheme 2-5

Figure 2-9

Scheme 2-6

Figure 2-10

Scheme 2-7

Figure 2-11

Scheme 2-8

Scheme 3-1

Scheme 3-2

Figure 3-1

Scheme 3-3

Scheme 3-4

Scheme 3-5

Scheme 3-6

Figure 3-2

Scheme 3-7

Scheme 3-8

Scheme 3-9

Figure 3-3

Scheme 3-10

Scheme 3-11

Figure 4-1

Figure 4-2

Figure 4-3

Figure 4-4

Figure 4-5

Figure 4-6

Figure 4-7

Figure 4-8

Figure 4-9

Figure 4-10

Figure 4-11

Figure 4-12

Figure 4-13

Figure 4-14

Figure 4-15

Figure 4-16

Figure 4-17

Figure 4-18

Figure 4-19

Figure 4-20

Figure 4-21

Figure 4-22

Figure 4-23

Scheme 4-1

Scheme 4-2

Figure 4-24

Figure 4-25

Scheme 4-3

Figure 4-26

Scheme 4-4

Scheme 4-5

Figure 5-1

Figure 5-2

Figure 5-3

Figure 5-4

Figure 5-5

Figure 5-6

Figure 5-7

Figure 5-8

Figure 5-9

Figure 5-10

Figure 5-11

Figure 5-12

Figure 5-13

Figure 5-14

Scheme 5-1

Figure 5-15

Figure 5-16

Figure 5-17

Figure 5-18

Figure 5-19

Figure 5-20

Figure 5-21

Figure 5-22

Figure 5-23

Figure 5-24

Figure 5-25

Figure 5-26

Figure 5-27

Figure 5-28

Scheme 5-2

Scheme 5-3

Scheme 5-4

Figure 5-29

Figure 5-30

Figure 5-31

Scheme 5-5

Scheme 5-6

Scheme 5-7

Scheme 5-8

Scheme 5-9

Scheme 5-10

Figure 5-32

Figure 5-33

Figure 5-34

Figure 5-35

Figure 5-36

Figure 5-37

Scheme 5-11

Scheme 5-12

Scheme 5-13

Figure 5-38

Scheme 5-14

Scheme 5-15

Scheme 5-16

Figure 5-39

Figure 5-40

Scheme 5-17

Scheme 5-18

Scheme 5-19

Figure 5-41

Figure 5-42

Scheme 5-20

Scheme 5-21

Scheme 5-22

Scheme 5-23

Scheme 5-24

Figure 5-43

Figure 5-44

Scheme 5-25

Figure 5-45

Scheme 5-26

Scheme 5-27

Figure 5-46

Figure 5-47

Figure 5-48

Figure 5-49

Scheme 5-28

Figure 5-50

Figure 5-51

Figure 5-52

Scheme 5-29

Figure 5-53

Figure 5-54

Figure 5-55

Figure 5-56

Figure 5-57

Figure 5-58

Scheme 5-30

Figure 5-59

Figure 5-60

Figure 5-61

Scheme 5-31

Scheme 5-32

Scheme 5-33

Scheme 5-34

Scheme 5-35

Scheme 5-36

Figure 5-62

Figure 5-63

Scheme 5-37

Figure 5-64

Figure 5-65

Figure 5-66

Scheme 5-38

Scheme 5-39

Scheme 5-40

Scheme 5-41

Figure 5-67

Figure 5-68

Scheme 5-42

Scheme 5-43

Scheme 5-44

Scheme 5-45

Figure 5-69

Figure 5-70

Figure 5-71

Figure 5-72

Figure 5-73

Figure 5-74

Figure 5-75

Scheme 5-46

Figure 5-76

Figure 5-77

Figure 5-78

Figure 5-79

Figure 5-80

Scheme 5-47

Figure 5-81

Figure 5-82

Figure 5-83

Figure 6-1

Scheme 6-1

Scheme 6-2

Figure 6-2

Scheme 6-3

Scheme 6-4

Scheme 6-5

Scheme 6-6

Scheme 6-7

Scheme 6-8

Figure 7-1

Figure 7-2

Figure 7-3

Figure 7-4

Figure 7-5

Scheme 7-1

Scheme 7-2

Figure 7-6

Figure 7-7

Scheme 7-3

Figure 7-8

Figure 7-9

Figure 7-10

Figure 7-11

Figure 7-12

Wiley Series in Protein and Peptide Science

Vladimir N. Uversky, Series Editor

Metalloproteomics • Eugene A. Permyakov

Instrumental Analysis of Intrinsically Disordered Proteins: Assessing Structure and Conformation • Vladimir Uversky and Sonia Longhi

Protein Misfolding Diseases: Current and Emerging Principles and Therapies • Marina Ramirez-Alvarado, Jeffery W. Kelly, and Christopher M. Dobson

Calcium Binding Proteins • Eugene A. Permyakov and Robert H. Kretsinger

Protein Chaperones and Protection from Neurodegenerative Diseases • Stephan Witt

Transmembrane Dynamics of Lipids • Philippe Devaux and Andreas Herrmann

Flexible Viruses: Structural Disorder in Viral Proteins • Vladimir Uversky and Sonia Longhi

Protein Families: Relating Protein Sequence, Structure, and Function • Christine A. Orengo and Alex Bateman

Chemistry of Metalloproteins: Problems and Solutions in Bioinorganic Chemistry • Joseph J. Stephanos and Anthony W. Addison

Chemistry of Metalloproteins

Problems and Solutions in Bioinorganic Chemistry

Joseph J. Stephanos

Anthony W. Addison

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Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

Stephanos, Joseph J., author.

Chemistry of metalloproteins: problems and solutions in bioinorganic chemistry/by Joseph J. Stephanos, Anthony W. Addison.

p.; cm. – (Wiley series in protein and peptide science)

Includes bibliographical references and index.

ISBN 978-1-118-47044-2 (paperback)

I. Addison, A. W., author. II. Title. III. Series: Wiley series in protein and peptide science.

DNLM: 1. Metalloproteins–chemistry–Examination Questions. QU 18.2]

QP551

572′.6076–dc23

2013041995

Preface

This book is an attempt to reveal the chemical concepts that rule the biological action of metalloproteins. The emphasis is on building up an understanding of basic ideas and familiarization with basic techniques. Enough background information is provided to introduce the field from both chemical and biological areas. It is hoped that the book may be of interest to workers in biological sciences, and so, primarily for this purpose, a brief survey of relevant properties of transition metals is presented.

The book is intended for undergraduates and postgraduates taking courses in coordination chemistry and students in biology and medicine. It should also be a value to research workers who would like an introduction to this area of inorganic chemistry. It is very suitable for self-study; the range covered is so extensive that the book can serve as a student's companion throughout his or her university career. At the same time, teachers can turn to it for ideas and inspirations.

The book is divided into seven chapters and covers a full range of topics in bioinorganic chemistry. It is well-illustrated and each chapter contains suggestions for further reading, providing access to important review articles and papers of relevance. A reference list is also included, so that the interested reader can readily consult the literature cited in the text.

It is hoped that the present book will provide the basis for a more advanced study in this field.

Joseph J. Stephanos

Anthony W. Addison

1

Introduction

The discipline of bioinorganic chemistry is concerned with the function of metallic and most of nonmetallic elements in biological processes. Also, it is the study of the chemistry, structure, and reactions of the metalloprotein molecules belonging to the living cell.

The precise concentrations of different ions, for instance, in blood plasma indicate the importance of these ions for biological processes, (Table 1-1).

Table 1-1 Ion Concentration in Extracellular Blood Plasma

Such elements fall into four broad classifications: the polluting, contaminating, beneficial, and essential elements.

Polluting elements: Pb, Hg, and Cd

Contaminating elements: vary from person to person

Beneficial elements: Si, V, Cr, Se, Br, Sn, F, and Ni

Essential elements: H, C, N, O, Na, Mg, K, Ca, P, S, Cl, Mo, Mn, Fe, Co, Cu, Zn, and I (Fig. 1-1).

Figure 1-1 Distribution of elements essential for life (Cotton and Wilkinson, 1980).

Twenty-five elements are currently thought to be essential to warm-blooded animals (Table 1-2).

Table 1-2 Percentage Composition of Essential Elements in Human Body

Essentiality has been defined according to certain criteria:

A physiological deficiency appears when the element is removed from the diet.

The deficiency is relieved by the addition of that element to the diet.

A specific biological function is associated with the element.

Every essential element follows a dose–response curve, shown in Fig. 1-2. At lowest dosages the organism does not survive, whereas in deficiency regions the organism exists with less than optimal function.

Figure 1-2 The dose-response curves of selenium and fluoride.

The ten ions classified as trace metal are Fe, Cu, Mn, Zn, Co, Mo, Cr, Sn, V, and Ni, and the four classified as bulk metals are Na, K, Mg, and Ca. The nonmetallic elements are H, B, C, N, O, F, Si, P, S, Cl, Se, and I.

Biological Roles of Metal Ions

What are the general roles of metal ions in biological systems?

The general roles of metal ions in biological systems are summarized in Table 1-3.

Table 1-3 Role of Metal Ions and Examples

Metals in biological systems function in a number of different ways:

Groups 1 and 2 metals operate as structural elements or in the maintenance of charge,osmotic balance, or nerve impulses.

Transition metal ions that exist in single oxidation states, such as zinc (II), function as structural elements in superoxide dismutase and zinc fingers or as triggers for protein activity, e.g., calcium ions in calmodulin or troponin C.

Transition metals that exist in multiple oxidation states serve as electron carriers, e.g., iron ions in cytochromes or in iron–sulfur clusters of the enzyme nitrogenase or copper ions in azurin and plastocyanin.

As facilitators of oxygen transport, e.g., iron ions in hemoglobin or copper ions in hemocyanin.

As sites at which enzyme catalysis occurs, e.g., copper ions in superoxide dismutase or iron and molybdenum ions in nitrogenase.

Metal ions may serve multiple functions, depending on their location within the biological system, so that the classifications in Table 1-3 are somewhat arbitrary and/or overlapping.

Proteins: Formation, Structures, and Metalloproteins

This section is designed to introduce the chemistry of proteins. The text broadly includes where and how the proteins are formed, along with the structure and formation of metalloproteins.

Following the introduction of organelles and their functions within the cell, the discussion will be concerned with the general structure of deoxyribonucleic acid (DNA) and how the nucleus maintains its control of cell growth, division, and formation of [messenger, transfer, and ribosomal ribonucleic acid (mRNA, tRNA, rRNA)]. This is followed by how mRNA and tRNA master the formation of proteins within a cell. Then, primary, secondary, tertiary, and quaternary structures of the formed proteins and the factors that control each of these structures are discussed.

Specific points about the ligation of various metal ions to different amino acids within the proteins are made, and the binding stabilities of various metal ions toward different amino acids are arranged.

The general formulas, side chains, and corresponding names of the common natural α-amino acids, the formation of the peptide chain from the amino acids, and the physiological roles of proteins are described.

The chemistry of the prosthetic and cofactors is explored. Enough basic biochemistry is presented to enable the student to understand the discussions that follow.

Organelles and Their Functions

Identify the organelles and their functions within the cell.

Cells are the building blocks of all living things.

There are similarities in the appearance, chemical constituents, and activities of all cells (Fig. 1-3).

Figure 1-3 (a) Animal cell and (b) plant cell.

Different structures within the cell are called organelles.

Each organelle has an important, specific function in the cell.

The mitochondria are responsible for conversion of food into usable energy (metabolism):

They contain enzymes for cell metabolism.

More than 50% of the energy produced by mitochondrial oxidation of carbohydrates is recaptured as adenosine diphosphate (ADP) and converted into adenosine triphosphate (ATP).

The derived energy is trapped in ATP molecules (Scheme 1-1).

Scheme 1-1 Derived energy is trapped in adenosine triphosphate molecules (ATP).

ATP can diffuse rapidly throughout the cell, delivering energy to sites where it is required for cellular processes.

In green plants, chloroplasts contain chlorophyll molecules and other pigments.

Chlorophyll and other pigments in chloroplasts absorb light energy from the sun and use it to produce ATP, glucose, and oxygen.

Ribosomes are round particles (mRNA) that are sent by the nucleus to activate protein synthesis.

The mRNA causes a specific protein molecule to be synthesized from the pool of amino acids present in the cell cytoplasm.

The nucleus, or command station, contains information for the development and operation of the cell.

This information is stored chemically in long molecular strands called DNA. A combination of DNA and protein forms fine strands of chromatin. When a cell is about to divide, the chromatin strands coil up and become densely packed, forming chromosomes.

The number of chromosomes varies with the species: Humans have 23, the fruit fly has 4, corn has 10, and the mosquito has 3.

Structure of DNA

What is the general structure of deoxyribonucleic acids, DNA?

Polymerization of nucleoside phosphates produces the nucleic acids, DNA and RNA.

DNA is a giant molecule with molecular weight of order 1 billion or more.

The information is chemically stored by nitrogen-base molecules that are bonded to the sugar residues of the sugar–phosphate chain.

There are four nitrogen bases:

Two purines, which are bicyclic molecules:

Two pyrimidines, which are monocyclic:

The order in which they appear on the chain makes up the molecular message (Fig. 1-4).

Figure 1-4 Order of N bases on chain.

The DNA molecule is also capable of duplicating itself and dividing.

Under a microscope we can see the duplicated chromosomes divide equally as the cell divides.

The DNA double strand forms when the bases on the two adjacent single strands form hydrogen bonds:

Adenine and thymine form a hydrogen bonded pair, or complementary base pair.

Cytosine and guanine also form a complementary base pair (Fig. 1-5).

Figure 1-5 DNA double strand.

These complementary base pairs are conformed by the base ratios: G/C = 1 and A/T = 1 (Table 1-4).

Table 1-4 Nitrogen-Base Content of DNA from Different Organisms

Cell Growth and Division

How does the nucleus maintain its control of cell growth and division?

During ordinary cell division called mitosis, two new cells result from a single parent.

Each daughter has the same number of chromosomes as the parent.

If DNA is the molecular stuff of the chromosome, it must be able to reproduce itself.

The DNA double helix rewinds and separates into two single strands (Fig. 1-6).

As the unwinding occurs, the single strands act as templates for synthesis of new complementary strands.

When the parent DNA double helix has completed its unwinding, two new DNA double-stranded molecules are formed.

The process by which new DNA is formed is called replication.

Figure 1-6 DNA double helix rewinds and separates into two single strands.

Protein Synthesis

How can proteins be synthesized in cells?

The order of the N bases on the DNA molecule determines the order of amino acids in the protein molecule.

While DNA is in the nucleus, the proteins are synthesized on ribosomes outside the nucleus as follows:

As the DNA double helix unwinds, the N base segment becomes exposed.

The DNA molecule serves as template for the synthesis of mRNA molecule.

The synthesis of mRNA is analogous to the replication synthesis of DNA (Fig. 1-7).

Figure 1-7 Synthesis of mRNA.

mRNA has structure similar to DNA but contains:

Ribose instead of deoxyribose

N-base uracil instead of thymine:

After mRNA is synthesized, it is transported out of the nucleus and becomes attached to the ribosomes, where the protein syntheses begin (Fig. 1-8).

Figure 1-8 Protein synthesis.

At the ribosomes, the order of the bases on the mRNA determines the amino acid sequence in the protein molecule.

The amino acid sequence is determined by a triplet code on the mRNA molecule.

A group of three N bases represents a code for signifying a single amino acid (Scheme 1-2).

Scheme 1-2 Genetic codes.

The amino acids are brought to the mRNA at the ribosomes by much smaller RNA molecules called tRNA.

Each tRNA has a triplet of bases, which is complementary to an amino acid code on mRNA.

The tRNA molecules bring the amino acids to the ribosomes as they move along the mRNA strand, and the amino acids are knit into the growing protein chain.

After the tRNA has discharged its amino acid passenger, it moves out into the cytoplasm, finds another amino acid, and returns to the ribosome surface.

Common Natural α-Amino Acids

Give the general formula, side chain, and corresponding name of the common natural α -amino acids.

There are 20 common natural amino acids.

The general formula for an α-amino acids is

They are summarized in Table 1-5.

Table 1-5 L-α-amino Acids

Peptide Chain Formation

How can the peptide chain be formed from the amino acids?

Linear polymerization by condensation to yield amide peptide linkage (Scheme 1-3).

All proteins are polypeptides.

Scheme 1-3 Polypeptide formation.

Protein physiological functions

What are the physiological roles of proteins?

The physiological roles of proteins are:

Structural: finger nails, hair, and skin

Transport: oxygen, electrons, and iron

Catalysis: enzymes responsible for all synthesis of proteins, DNA, and organics

Structural Features of Proteins

Define: primary, secondary, tertiary, and quaternary structures. And what are the factors that control each of these structures?

The properties and functions of a particular protein depend on the sequence of the amino acids in the protein, or the primary structure.

The primary structure determines higher levels of structures.

These structural details are crucial to the biological role of a protein.

The secondary structure arises