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ADVANCES IN CLINICAL CHEMISTRY
VOLUME 47
Advances in
CLINICAL
CHEMISTRY
Edited by

GREGORY S. MAKOWSKI
Clinical Laboratory Partners, LLC
Newington, Connecticut
USA

VOLUME 47

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09 10 11 12 10 9 8 7 6 5 4 3 2 1
 CONTENTS

CONTRIBUTORS ................................................................................ ix

PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

Amyloidosis
KOSTANDINOS SIDERAS AND MORIE A. GERTZ

1. Abstract ... ................................................................................... 2

2. Historical Perspective....................................................................... 2
3. Pathogenesis ................................................................................. 3
4. Diagnosis.. ................................................................................... 14
5. Classification, Clinical Presentation, and Prognosis of Amyloidosis.................. 20
6. Treatment . ................................................................................... 28
References. ................................................................................... 36

Urinary Markers in Colorectal Cancer

BO FENG, FEI YUE, AND MIN-HUA ZHENG

1. Abstract ... ................................................................................... 45

2. Introduction ................................................................................. 46
3. Potential Urinary Markers for Colorectal Cancer ...................................... 47
4. Analytical Techniques and Data Analysis ............................................... 50
5. Conclusions .................................................................................. 53
References. ................................................................................... 53

Effect of Hormone Replacement Therapy on Inflammatory Biomarkers

PANAGIOTA GEORGIADOU AND EFTIHIA SBAROUNI

1. Abstract ... ................................................................................... 60

2. Introduction ................................................................................. 60
3. Inflammation and Vascular Disease ...................................................... 62
4. Mechanisms of Action of HRT in Vascular Biology ................................... 65
5. Effects of HRT on Inflammatory Markers .............................................. 71
6. Conclusion ................................................................................... 82
References. ................................................................................... 83

v
vi CONTENTS

Personalized Clinical Laboratory Diagnostics

KEWAL K. JAIN

1. Abstract....................................................................................... 96
2. Introduction.................................................................................. 96
3. Basic Concepts of Personalized Medicine ................................................ 96
4. Molecular Diagnostic Technologies for Personalized Medicine. ....................... 99
5. Role of PCR in Development of Personalized Medicine.. .............................. 99
6. Combined PCR–Enzyme-Linked Immunosorbent Assay (ELISA).................... 102
7. Non-PCR Methods.......................................................................... 103
8. Direct Molecular Analysis Without Amplification ...................................... 103
9. SNP and Personalized Medicine ........................................................... 103
10. Genetic Variations in the Human Genome Other Than SNPs ......................... 105
11. Role of Biomarkers in Personalized Medicine ........................................... 108
12. Application of Biochip Technology in Developing
Personalized Medicine ...................................................................... 109
13. Role of Nanobiotechnology-Based Diagnostics in
Personalized Medicine ...................................................................... 111
14. Role of Cytogenetics in Personalized Medicine .......................................... 114
15. Integration of Molecular Diagnostics and Therapeutics ................................ 116
16. Concluding Remarks and Future Prospects.. ............................................ 117
References .................................................................................... 118

Verification of Method Performance for Clinical Laboratories

JAMES H. NICHOLS

1. Abstract....................................................................................... 121
2. Introduction.................................................................................. 122
3. ISO Quality Management System: The Fundamentals of Quality..................... 123
4. Laboratory Quality Standards in Regulations and
Accreditation Guidelines ................................................................... 129
5. Comparison of Quality Requirements .................................................... 131
6. Performing Method Verification........................................................... 132
7. Summary ..................................................................................... 136
References .................................................................................... 136

Interpreting the Proteome and Peptidome in Transplantation

TARA K. SIGDEL, R. BRYAN KLASSEN, AND MINNIE M. SARWAL

1. Abstract....................................................................................... 140
2. Introduction.................................................................................. 140
3. Application of Proteomics and Peptidomics in Transplantation....................... 155
4. Important Issues ............................................................................. 160
5. Conclusion ................................................................................... 162
References .................................................................................... 163
 CONTENTS vii

Biomarkers in Long-Term Vegetarian Diets

IRIS F.F. BENZIE AND SISSI WACHTEL-GALOR

1. Introduction ................................................................................. 172

2. Possible Nutritional Deficiencies in Association with Long-Term
Vegetarian Diets. ............................................................................ 173
3. Biomarkers of Oxidant/Antioxidant Balance in Association
with Vegetarian Diets....................................................................... 186
4. Biomarkers that Reflect Lower Risk of Disease in Long-Term Vegetarians ......... 194
5. Biomarkers to Differentiate the Vegetarian from the Nonvegetarian................. 207
6. Summary and Recommendations for Clinical Chemistry .............................. 209
References. ................................................................................... 210

Effect of Caloric Restriction on Oxidative Markers

JAN ŠKRHA

1. Abstract ... ................................................................................... 224

2. Introduction ................................................................................. 224
3. Foods and ROS Generation ............................................................... 225
4. Mitochondria as a Source of Reactive Oxygen and Nitrogen Species ................ 226
5. Caloric Restriction and Oxidative Stress ................................................. 229
6. Oxidative Stress Markers by Caloric Restriction........................................ 232
7. Data Interpretation ......................................................................... 240
8. Conclusions .................................................................................. 241
References. ................................................................................... 242

INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
COLOR PLATE SECTION AT THE END OF THE BOOK
 CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

IRIS F.F. BENZIE (171), Department of Health Technology and Informatics,

The Hong Kong Polytechnic University, Kowloon, Hong Kong

BO FENG (45), Department of General Surgery, Ruijin Hospital, Shanghai Jiao

Tong University School of Medicine, Shanghai 200025, China

PANAGIOTA GEORGIADOU (59), 2nd Department of Cardiology, Onassis

Cardiac Surgery Center, Athens, Greece

MORIE A. GERTZ (1), Division of Hematology, Mayo Clinic College of

Medicine, Rochester, Minnesota 55905, USA

KEWAL K. JAIN (95), Jain PharmaBiotech, Basel, Switzerland

R. BRYAN KLASSEN (139), Department of Pediatrics—Nephrology, Stanford

University Medical School, Stanford University, Stanford, California 94305,
USA

JAMES H. NICHOLS (121), Professor of Pathology, Tufts University School of

Medicine and Medical Director, Clinical Chemistry, Baystate Health, Spring-
field, Massachusetts 01199, USA

MINNIE M. SARWAL (139), Department of Pediatrics—Nephrology, Stanford

University Medical School, Stanford University, Stanford, California 94305,
USA

EFTIHIA SBAROUNI (59), 2nd Department of Cardiology, Onassis Cardiac

Surgery Center, Athens, Greece

ix
x CONTRIBUTORS

KOSTANDINOS SIDERAS (1), Division of Hematology, Mayo Clinic College of

Medicine, Rochester, Minnesota 55905, USA

TARA K. SIGDEL (139), Department of Pediatrics—Nephrology, Stanford

University Medical School, Stanford University, Stanford, California 94305,
USA

JAN ŠKRHA (223), Laboratory for Endocrinology and Metabolism and 3rd
Department of Internal Medicine, 1st Faculty of Medicine, Charles University
in Prague, U Nemocnice 1, 128 08 Prague 2, Czech Republic

SISSI WACHTEL-GALOR (171), Department of Health Technology and

Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong

FEI YUE (45), Department of General Surgery, Ruijin Hospital, Shanghai Jiao
Tong University School of Medicine, Shanghai 200025, China

MIN-HUA ZHENG (45), Department of General Surgery, Ruijin Hospital,

Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
 PREFACE

I am pleased to present volume forty‐seven of Advances in Clinical

Chemistry series.
In this first volume for 2009, an array of relevant clinical laboratory topics
is presented. The biochemistry of amyloidosis is explored with respect to the
microenvironment, mechanisms of organ dysfunction, and the role of toxic
intermediates. The importance of low molecular weight urinary biomarkers
associated with colorectal cancer, one of the most commonly diagnosed
cancers worldwide, is reviewed using a metabolomic approach. The role of
hormone replacement therapy is investigated with respect to inflammatory
biomarkers and vascular disease in women. It is noteworthy that cardiovas-
cular disease risk is typically underestimated in the female population.
A wonderful review on personalized clinical laboratory diagnostics is pre-
sented by a leader in the field of pharmacogenomics. Verification of method
performance is reviewed with respect to a number of international quality
standards, accreditation agencies, and regional laws. Another topic, applica-
tion of the proteome to impact on organ transplantation outcomes, is also
presented. This volume is concluded by two reviews on diet. In the first paper,
biomarkers associated with vegetarian diets are explored. The second review
investigates the role of caloric restriction on lifespan as evidenced by impact
on oxidative markers.
I extend my appreciation to each contributor of volume forty‐seven and
thank colleagues who contributed to the peer review process. I extend my
thanks to my Elsevier editorial liaison, Gayathri Venkatasamy.
I sincerely hope the first volume of 2009 will be enjoyed by our diverse
readership. As always, I warmly invite comments and suggestions for future
review articles for the Advances in Clinical Chemistry series.
In keeping with the tradition of the series, I would like to dedicate volume
forty‐seven to my father‐in‐law Dr Gale R. Ramsby.
GREGORY S. MAKOWSKI

xi
 ADVANCES IN CLINICAL CHEMISTRY, VOL. 47

AMYLOIDOSIS
Kostandinos Sideras and Morie A. Gertz1

Division of Hematology, Mayo Clinic College of Medicine,

Rochester, Minnesota 55905, USA

1. Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Historical Perspective. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.1. Structure of the Amyloid Fibril . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.2. Amyloid Aggregation Mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.3. Interactions of the Amyloid Fibril with the Microenvironment . . . . . . . . . . . . . 9
3.4. Tropism of Amyloid Proteins for DiVerent Organs . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.5. Mechanisms of Organ Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
4. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.1. Suspecting the Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.2. Screening for Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4.3. Establishing the Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
4.4. Typing of Amyloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4.5. Imaging of Amyloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
5. Classification, Clinical Presentation, and Prognosis of Amyloidosis . . . . . . . . . . . . . . 20
5.1. Primary Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.2. Secondary Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.3. Familial Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5.4. Senile Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
5.5. Localized Amyloidosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
6.1. Strategies Aimed at Eradicating the Production of the
Amyloid Precursors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
6.2. Native Protein Structure Stabilizing Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
6.3. Amyloid Fibril Destabilizing Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
6.4. Immunologic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
6.5. Supportive Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
6.6. Treatment of Localized Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

1
Corresponding author: Morie A. Gertz, e‐mail: [email protected]

0065-2423/09 $35.00 Copyright 2009, Elsevier Inc.

DOI: 10.1016/S0065-2423(09)47001-X All rights reserved.
2 SIDERAS AND GERTZ

1. Abstract

Amyloidosis is a heterogeneous group of diseases in which an otherwise

normal protein, with or without proteolytic cleavage, forms insoluble amy-
loid fibrils. These, in turn, deposit in various organs and cause dysfunction.
A wide range of diseases are associated with amyloidosis such as Alzheimer’s
disease, multiple myeloma, other plasma cell disorders, and chronic inflam-
mation, either as a cause, or result, of amyloid production. This heterogene-
ity in cause and presentation leads to an incomplete understanding of the
pathophysiology of amyloid disease. As such, study of this complicated
disease process presents significant challenges. The purpose of this review
article is to introduce the biochemistry of amyloidosis including ultrastruc-
ture analysis, models of monomer aggregation, the importance of the amy-
loid microenvironment, and the mechanisms of organ dysfunction, including
the role of ‘‘toxic intermediates.’’ Pathophysiologic analysis of amyloidosis
will focus on diagnostic tools as well as the classification of the various forms
of amyloidosis. Finally, treatment of amyloidosis will be reviewed including
traditional and established modalities. We will also introduce new and novel
treatment options as they relate to the basic pathophysiology of this complex
and heterogeneous disorder.

2. Historical Perspective

Although the term ‘‘amyloid’’ was first used in botany as early as 1838
by Matthias Schleiden to describe plant starch, and subsequently in 1854 by
Rudolf Virchow to describe abnormal macroscopic deposits, the disease of
amyloidosis, though with diVerent names, was known at least since the mid‐
seventeenth century [1–3]. Anatomists and pathologists frequently described
organs with a ‘‘lardaceous’’ or ‘‘waxy’’ appearance and a major debate in the
mid‐nineteenth century consisted of whether the disease was caused by
deposition of a lard‐like or a starch‐like substance. Professor Karl von
Rokitansky from Vienna was the main proponent of the idea of ‘‘lardaceous
change’’ (wax). On the other hand, the German (Berlin) professor Rudolf
Virchow believed that a starch‐like substance was responsible for the abnor-
mal spleens he examined. He had come to that conclusion after he stained
the abnormal deposits with a combination of iodine and sulfuric acid, and
found that, just like starch, the tissues stained pale blue, and thus must be
carbohydrate, coining the term amyloid.
Both Rokitansky and Virchow were wrong. George Budd found no
lardaceous substance in the liver of a patient with amyloidosis and in 1859
 AMYLOIDOSIS 3

Friedreich, Nicolau, and Kekule found no starch‐like substance in the

spleens described by Virchow, suggesting, to their credit, that the ‘‘amyloid’’
substance was probably albuminoid in nature [4]. In 1920, Schmiedeberg
described the similarity of amyloid to serum globulin, which strongly
suggested its proteinaceous nature.
Early reports of amyloidosis were invariably described in patients with
chronic inflammatory conditions like tuberculosis, syphilis, leprosy, and
rheumatoid arthritis. These were the early reports of secondary (AA) amy-
loidosis. However, occasional reports in patients without inflammatory
conditions were also made. Sir Samuel Wilks is credited to be the first
physician to describe such a patient, a 56‐year‐old with ‘‘lardaceous change.’’
This was probably the first report of a patient with primary (AL) amyloid-
osis. Soyka was the first to describe both cardiac amyloidosis in patients of
advanced age and senile amyloidosis.
The Congo red stain, which since 1884 was used in the textile industry to
stain cotton, was used by Bennhold in 1922 to stain amyloid, for which it was
found to have a strong aYnity [1]. However, it was Divry and Florkin who in
1927 found that Congo red stained amyloid exhibited green birefringence
under polarized light. The first description of the amyloid fibril came from
Cohen and Calkins in 1959 who noticed the fibrillar structure of amyloid
when viewed under the electron microscope, thus being the first to definitely
conclude that amyloid was not ‘‘amorphous’’ as suggested by its appearance
under the light microscope [5]. Finally, in 1968, Eanes and Glenner discov-
ered the b‐pleated sheet nature of the amyloid fibril which explained some of
the resistance of the structure to the action of solvents [6].

3. Pathogenesis

3.1. STRUCTURE OF THE AMYLOID FIBRIL

Since Cohen and Calkins described the ‘‘fibrillar’’ nature of amyloid,
multiple investigators used electron microscopy to further characterize the
structure of the amyloid fibril [2]. Amyloid from diVerent human and animal
sources was found to be composed of similar, rigid, nonbranching fibrils of
indeterminate, long length (anywhere from 100 to 1600 nm), with an average
width of 7.0–12 nm [2]. Each amyloid fibril in turn is composed of a number
of b‐pleated sheets (protofilaments), each 2.5–3.5 nm in diameter, which run
along the longitudinal axis of the amyloid fibril and slowly twist [7] creating a
helical repeat of b‐pleated sheets of about every 11.5 nm. The b‐pleated
sheets run perpendicular to the long axis of the fibril. This structure has
4 SIDERAS AND GERTZ

been called the continuous b‐sheet helix [8] or the cross‐b spine, and is
responsible for the characteristic cross‐b X‐ray diVraction pattern of amyloid
(Fig. 1). Further examination of the ultrastructure of the cross‐b spine has
shown it to be a cross‐double b‐sheet, with side chains protruding from the
two sheets forming a dry, tightly self‐complementing steric zipper, bonding
the sheets [9]. Every segment is bound to its two neighboring segments
through stacks of both backbone and side‐chain hydrogen bonds (Fig. 2).
Despite this similarity at the protofilament level, the amyloid precursor
proteins do not share a common sequence homology, size, function, or
tertiary structure. At least 25 diVerent human proteins have been described
as precursors to amyloid fibrils and cause a variety of diVerent amyloid‐
related diseases [10] (Table 1). Examples include the monoclonal l or k
immunoglobulin light chain which causes AL amyloidosis (related to plasma
cell disorders), the serum amyloid A protein (SAA) related to systemic
inflammatory conditions (secondary or AA amyloidosis), and the Val30Met
and Gly47Val transthyretin (TTR) variants related to hereditary amyloid-
osis. In addition to these 25 proteins that have the ability to form amyloid
fibrils in vivo, there are a number of synthetic amyloid fibrils in existence
which are used for research purposes. Moreover, there are many other
proteins that are capable of forming fibrillar deposits when taken out of
physiologic conditions but do not have the ability to cause amyloidosis in the
human body.
Another organizational diVerence between diVerent types of amyloid is at
the number of protofilaments that form the amyloid fibril. The amyloid fibril,
visible in vivo, is composed of anywhere from three to six protofilaments

115 Å
24 b-strands

FIG. 1. Molecular model of the common core protofilament structure of amyloid fibrils.
A number of b‐sheets (four illustrated here) make up the protofilament structure. These sheets
run parallel to the axis of the protofilament, with their component b‐strands perpendicular to the
fibril axis. With normal twisting of the b‐strands, the b‐sheets twist around a common helical axis
that coincides with the axis of the protofilament, giving a helical repeat of 115.5 Å containing 24
b‐strands (this repeat is indicated by the boxed region). Reprinted from Ref. [7], Copyright 1997,
with permission from Elsevier.
 AMYLOIDOSIS 5

A Asn3
Gly1 B
Gln5
Asn2 Gln4
Tyr7
Asn6
Asn3 Gln5

4.87 Å

b a Gln5 Asn3
b Gln4
Gln5 Tyr7
c Asn2 Asn3
c
C a D a
c c

Wet
interface
Dry
interface

E Asn6 Asn2
Gln4 Gly1
Asn3 Gln5 Tyr7
3.0
2.9 2.8 2.9 2.8 3.1
2.9 3.2
2.9
2.8 2.8 3.0
2.9
3.0 2.9 2.7 3.2 2.9
2.9 2.9 2.8 3.1
2.9 2.8 3.2
2.9
2.8 2.8 3.0 2.9
2.9 2.7 3.2 2.9
b 2.8
a

FIG. 2. Structure of GNNQQNY, a seven‐residue peptide segment from the yeast protein
Sup35. Unless otherwise noted, carbon atoms are colored in purple or grey/white, oxygen in
red, and nitrogen in blue. [9] (A) The pair‐of‐sheets structure of the fibril‐forming peptide
GNNQQNY. The dry interface is between the two sheets, with the wet interfaces on the outside
6 SIDERAS AND GERTZ

which are laterally associated with each other. For example, the amyloid
fibril of Val30Met TTR, the most common type of familial amyloidosis, is
composed of four protofilaments arranged in a square array around an
electron‐lucent center, whereas the amyloid fibril of amyloid Ab (which
causes Alzheimer’s disease) is composed of five or six protofilaments [11].

3.2. AMYLOID AGGREGATION MECHANISMS

Despite this knowledge, advances in understanding the amyloid fibril at
the atomic level have been more diYcult. It is not clear, for example, if the
specific amino acid sequence plays a role in determining the ability of a
protein to form a cross‐b spine, to what extent it aids in the stabilization of
the amyloid fibril, and how this sequence aVects interaction of the amyloid
fibril with the microenvironment (i.e., amyloid P component, heparan sulfate
proteoglycans (HSPG), apolipoprotein E, extracellular matrix, lipid bilayer).
A number of models have been proposed in this regard [12] (Fig. 3).
Partially folded intermediates are thought to play an important role in the
pathogenesis of amyloidosis. It is thought that thermodynamic instability of the
protein native structure leads to partially folded intermediates several of which
have been shown to form amyloid fibrils readily [13, 14]. The same mechanism
is thought to lead to amorphous deposits of immunoglobulin light chains and it
is unclear why some proteins favor deposition as amyloid fibrils versus amor-
phous deposits. The process appears to be dependent on the specific partially
folded structure as diVerent intermediates of the same protein have been shown
to deposit either as amyloid fibrils or amorphous deposits [15].
At a diVerent organizational level, oligomers can act as intermediates in
the process of fibrilogenesis as well. For example, in the case of b‐2‐micro-
globulin, the formation of the final amyloid fibril is proceeded by the

surfaces. (B) The steric zipper viewed edge on (down the a‐axis). (C) The GNNQQNY crystal
viewed down the sheets (i.e., from the top of panel a, along the b‐axis). Six rows of b‐sheets run
horizontally. Peptide molecules are shown in black and water molecules are represented by redþ.
Notice that the sheets are in pairs, with a closely spaced pair (8.5 Å) alternating with a wider
spaced (15 Å) pair. The wide spaces between sheets (wet interfaces) are filled with water
molecules, whereas the closely spaced interfaces (dry interfaces) lack waters, other than those
hydrating the caroboxylate ions at the C‐termini of peptides. The atoms in the lower left unit cell
are shown as spheres representing van der Waals radii. (D) The steric zipper. This is a close up view
showing the remarkable shape complementarity of the Asn and Gln side chains protruding into the
dry interface. (E) Views of the b‐sheets from the side (down the c axis), showing three b‐strands
with the interstrand hydrogen bonds. Side chain carbon atoms are highlighted in yellow. Back-
bone hydrogen bonds are shown by purple or black dots and side chain hydrogen bonds by yellow
dots. The length of each hydrogen bond is noted in Å units. Reprinted from Ref. [9], Copyright
2005, with permission from Macmillan Publishers Ltd.
 AMYLOIDOSIS 7

TABLE 1
SOME OF THE PROTEINS KNOWN TO CAUSE CLINICAL AMYLOID DISEASE IN HUMANS

Major causative Major clinical

Precursor protein Human disease association manifestation

Immunoglobulin Primary (AL) Plasma cell disorders Renal, cardiac, GI,

light chain amyloidosis peripheral nervous
system
Immunoglobulin Primary (AH) Plasma cell disorders Much less frequent than
heavy chain amyloidosis AL amyloidosis
Serum amyloid A Secondary (AA) Inflammation Renal
amyloidosis
Transthyretin (TTR) Familial Mutation of ATTR Peripheral nervous
system, heart
Senile Wild‐type ATTR, Multiple organs,
aging cardiac most
clinically prominent
Apolipoprotein AI Familial Mutation of Apo‐AI Very slowly progressive
disease
Apolipoprotein AII Familial Point mutation of Renal
stop codon
leading to
additional 20
amino acid
residues
Lysozyme Familial Mutation of Kidney, liver, lungs,
lysozyme and spleen
Fibrinogen Aa‐chain Familial Mutation of Renal
fibrinogen
Aa‐chain
Gelsolin Familial Mutation of gelsolin Corneal dystrophy,
(Finish type) cranial neuropathy,
and cutis laxa
Cystatin C Familial Mutation of cystatin Amyloid angiopathy
(Islandic type) and cerebral
hemorrhage
b‐2‐Microglobulin Ab2M Hemodialysis Joints

formation of dimeric, tetrameric, and hexameric intermediates in time scales

much faster than the time scale of fibrilogenesis itself (minutes to hours versus
weeks to months) [16]. In this model, the monomer (b‐2‐microglobulin)
requires activation to an ‘‘activated state’’ (in the presence of copper)
which then rapidly forms oligomers, by the sequential addition of dimmers,
within minutes to hours. These oligomers form by the process known as
domain swapping. Oligomers then form mature amyloid in timescales of
weeks to months.
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