Table Of ContentNUTRITION K
. D
a Vitamin-Binding
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s
h
in
a
m
Vitamin-Binding Proteins ur Proteins
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i | S
Functional Consequences . D
a
k
s
h Functional Consequences
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Diverse in chemical nature, water soluble and lipid soluble vitamins are essential micronutrients am
u
that react with specific protein entities and are transported to sites for participation in r
t
i
intracellular events, both at the genomic and non-genomic levels. Thus, metabolic pathways
and intracellular signaling are influenced by vitamins or their derivatives through vitamin
binding to specific proteins. Vitamin-Binding Proteins: Functional Consequences examines
the function of various vitamins based on this binding, as well as their role as antioxidants,
V
leading to effects on intracellular mechanisms. This book explores the resulting functional
consequences at the level of cells, tissues, and organs as well as the neurological, endocrine, i
t
and immune systems.
a
m
The text addresses the effects that lead to both normal physiological function and pharmacological
activity with significant therapeutic potential in a wide spectrum of disease processes. i
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Leading experts discuss various vitamins including the function of retinoids in development,
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immunity, and obesity; the role of vitamin D in the immune system, infectious processes, and
B
cardiovascular disease; and the effects of vitamins E, C, and K on the vascular system.
i
n
Chapters cover the therapeutic potential of the vitamin B vitamer pyridoxamine and the
6 d
lipid-soluble Banalogue benfotiamine. They also describe various functions of biotin
1 i
as well as gene transcriptional regulation through biotin and biotin-binding proteins. n
The text addresses folate receptor-mediated therapeutics, vitamin B derivatives in tumor g
12
targeting, and implication of ascorbic acid in different disorders. Expounding newer
P
areas of vitamin function, this book explores the interface of physiological vitamin function
r
and pharmacological vitamin action, offering a broad perspective of possible vitamin binding o
therapeutics. t
e
i
n
s
Edited by
Krishnamurti Dakshinamurti
K13765 Shyamala Dakshinamurti
6000 Broken Sound Parkway, NW
Suite 300, Boca Raton, FL 33487
711 Third Avenue
New York, NY 10017
an informa business
2 Park Square, Milton Park
www.crcpress.com Abingdon, Oxon OX14 4RN, UK
Vitamin-Binding
Proteins
Functional Consequences
Vitamin-Binding
Proteins
Functional Consequences
Edited by
Krishnamurti Dakshinamurti
Shyamala Dakshinamurti
Boca Raton London New York
CRC Press is an imprint of the
Taylor & Francis Group, an informa business
CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742
© 2014 by Taylor & Francis Group, LLC
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Version Date: 20130620
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Contents
Preface......................................................................................................................vii
Editors .......................................................................................................................ix
Contributors ..............................................................................................................xi
Chapter 1 Retinoic Acid: Metabolism, Developmental Functions,
and Evolution .....................................................................................1
João E. Carvalho and Michael Schubert
Chapter 2 Serum Retinol-Binding Protein, Obesity, and Insulin Resistance .....31
Pangala V. Bhat and Daniel-Constantin Manolescu
Chapter 3 Retinoic Acid and Immunity ..............................................................49
Yoshishige Miyabe, Chie Miyabe, and Toshihiro Nanki
Chapter 4 Vitamin D Up-Regulated Protein 1 (VDUP1) and the
3
Immune System ..................................................................................57
Hyun Woo Suh, Haiyoung Jung, Young Jun Park, and Inpyo Choi
Chapter 5 Rapid Pre-Genomic Responses of Vitamin D ...................................71
Tremaine M. Sterling, Ramesh C. Khanal, Yu Meng, Yang
Zhang, and Ilka Nemere
Chapter 6 The Role of Vitamin D in Infectious Processes .................................89
Russell W. Chesney
Chapter 7 Vitamin D, Vitamin D Binding Protein, and Cardiovascular
Disease .............................................................................................107
Diane Berry and Elina Hyppönen
Chapter 8 Vitamins E and C: Effects on Matrix Components in the
Vascular System ...............................................................................127
Jean-Marc Zingg, Mohsen Meydani, and Angelo Azzi
v
© 2010 Taylor & Francis Group, LLC
vi Contents
Chapter 9 Vitamin K and Vascular Calcification .............................................157
Chandrasekar Palaniswamy, Wilbert S. Aronow,
Jagadish Khanagavi, and Arunabh Sekhri
Chapter 10 Therapeutic Effects of Pyridoxamine and Benfotiamine ................169
Shyamala Dakshinamurti and Krishnamurti Dakshinamurti
Chapter 11 Multifaceted Therapeutic Potential of Vitamin B ..........................183
6
Shyamala Dakshinamurti and Krishnamurti Dakshinamurti
Chapter 12 Non-Prosthetic Group Functions of Biotin ......................................207
Krishnamurti Dakshinamurti
Chapter 13 Mechanisms of Gene Transcriptional Regulation through Biotin
and Biotin-Binding Proteins in Mammals .......................................219
Janos Zempleni, Dandan Liu, Daniel Camara Teixeira, and
Mahendra P. Singh
Chapter 14 Folate Receptor-Mediated Therapeutics: Folate Receptor-
Mediated Particle Systems for Drug and Gene Delivery in
Cancer Therapy ................................................................................229
Yoshie Maitani
Chapter 15 Vitamin B Derivatives and Preferential Targeting of Tumors .......241
12
Evelyne Furger and Eliane Fischer
Chapter 16 Ascorbic Acid: Binding Proteins and Pathophysiology ...................257
Fryad Rahman and Michel Fontés
© 2010 Taylor & Francis Group, LLC
Preface
Vitamins are essential micronutrients required by all protozoans and metazoans
studied. They are of diverse chemical nature. We have the concept of a ligand (vita-
min) reacting with a specific protein entity, the receptor, facilitating the absorption
and transport of the ligand to the site of action, and further its participation in intra-
cellular events that form part of the cellular signaling mechanisms, including, in
many instances, the regulation of gene expression. Another significant aspect of the
function of many vitamins is their role in cellular oxidation-reduction reactions and
functioning as antioxidants.
The retinoids constitute a group of lipid-soluble morphogens related to retinol that
play a vital role in various biological processes including embryonic pattern forma-
tion, organogenesis, cell proliferation and differentiation, apoptosis, and immunity.
These functions, known to be conserved throughout the chordate phylum, are medi-
ated by the binding of retinoic acid (RA) to two nuclear receptors, retinoic acid
receptors (RAR) and retinoid X receptors (RXR). The interaction of the RA signal-
ing network with other intracellular signaling cascades has been identified. Retinoid
binding protein 4 has been implicated as an adipokine involved in insulin resistance.
The protective role of RA in autoimmune diseases has been recognized.
Vitamin D, which functions as a steroid hormone, binds to a vitamin D recep-
tor (VDR) expressed in most cells. Heterodimerization with RXR and binding to
vitamin D response elements located in the promoter regions induces expressions
of target genes involved in many cellular responses including immune responses.
Through its effect on dendritic cell proliferation and maturation and T cell stimula-
tion, vitamin D regulates adaptive and innate immunity and has a modulating effect
on many inflammatory and autoimmune diseases.
Connective tissue in the vascular system plays an important role in maintenance of
the intact vascular wall. Vitamins E and C influence the extracellular matrix (ECM)
by their antioxidant functions. They bind to specific enzymes and act as cofactors
and regulators with consequent modulation of vascular smooth muscle cell (VSMC)
signal transduction and gene expression. The ability of vitamins E and C to influence
VSMC proliferation, differentiation, and ECM production is important in the mainte-
nance of intact vascular wall and in the repair of atherosclerotic lesions. Actively pro-
liferating cells, but not quiescent cells, are susceptible to ascorbic acid, which inhibits
cell division and promotes necrosis through its action on S-phase progression.
Apart from clotting factor proteins, vitamin K–dependent proteins include a
variety of regulatory proteins. One of them, the matrix Gla-protein (MGP), through
gamma carboxylation of glutamic acid residues, enables it to inhibit extraosseous
calcification. Vascular calcification with its accompanying increased morbidity and
mortality is associated with vitamin K deficiency, suggesting a favorable effect of
vitamin K on vascular calcification.
Implication of advanced glycation end products (AGEs) and advanced lipoxi-
dation end products (ALEs) in the pathogenesis of diabetes-mediated uremic
vii
© 2010 Taylor & Francis Group, LLC
viii Preface
complications as well as in aging and atherosclerosis are well recognized. Any chemi-
cal that would have an inhibitory effect on any of the steps in the process leading to
vascular pathology has therapeutic potential. Benfotiamine, a lipid-soluble form of thi-
amine and pyridoxamine, a vitamin B vitamer, have a significant place in the therapy
6
of micro- and macrovascular defects associated with chronic diseases. Pyridoxamine
is a potent scavenger of reactive carbonyls and inhibits formation of AGEs.
The crucial role played by vitamin B in the nervous system and in neuroendocri-
6
nology is based on the fact that various putative neurotransmitters as well as taurine,
sphingolipids, and polyamines are synthesized by pyridoxal phosphate (PLP)-
dependent enzymes. There are numerous biological effects of vitamin B unrelated
6
to the role of PLP as a coenzyme. PLP is an antagonist of both the voltage-mediated
and the ATP-mediated calcium transport systems. PLP modulates the activities of
steroid hormone receptors and transcription factors. The preventive effect of vitamin
B on tumorigenesis might also derive from the antioxidant functions of this vitamin.
6
Biotin is central to the metabolism of carbohydrates, amino acids, and lipids as
biotin is the prosthetic group of the carboxylases. In addition to this metabolic func-
tion, biotin influences transcription in organisms ranging from bacteria to humans.
Biotin exerts complex effects on cell cycle and gene transcription through epigenetic
mechanisms. Nuclear biotin holocarboxylase synthetase seems to interact with other
chromatin proteins to form a multiprotein gene repressor complex.
Folate has a high affinity for folate receptors (FR) and retains its FR binding affinity
and endocytosis properties even if it is covalently linked to a variety of molecules and
particles. A strategy known as “active targeting” has been developed in which par-
ticles with ligands are designed to interact with tumor cells. This involves biomolecular-
specific recognition. Intravenous injection of folate-linked particles is reported to exhibit
antitumor effect. Rapidly dividing cells, including tumor cells, have a high demand for
vitamin B cofactor than normal cells. Strategies have been developed to use vitamin
12
B as a vehicle for the delivery of cytotoxic drugs or radioactive tracers to tumors.
12
This volume is devoted to a discussion of the function of vitamins based on their
binding to specific proteins as well as their role as antioxidants, leading to effects
on intracellular mechanisms that have a wide-ranging effect on a variety of cellu-
lar processes. Many of these effects have significant therapeutic potential in a wide
spectrum of disease processes. The strategy of using particles bound to folate ligand
in tumor targeting and the use of vitamin B as a vehicle to deliver cytotoxic drugs
12
or radiotracers to tumors have immense therapeutic potential.
As editors, we have assembled the leading experts on the various vitamins to
evaluate the current status of the role of vitamins and their binding proteins in the
regulation of cellular processes with a view to their potential use in therapeutics. The
material presented here has been designed to expand the horizon of researchers in
these associated areas.
We express our gratitude to our colleagues who have spent their time and effort,
in the midst of their busy schedules, to write their respective chapters. We thank our
families for bearing with us during the preparation of this text.
Krishnamurti Dakshinamurti
Shyamala Dakshinamurti
© 2010 Taylor & Francis Group, LLC
