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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical
Design
Volume 15, Number 31, 2009
Contents
Latest Development on Zinc Enzymes
Executive Editor: Georgios A. Spyroulias
Editorial: Pp. 3590-3591
[PMID:
19925413 PubMed - indexed for MEDLINE]
Intra- and Interdomain Flexibility in Matrix Metalloproteinases:
Functional Aspects and Drug Design Pp. 3592-3605
Ivano Bertini, Marco Fragai and Claudio Luchinat
[Abstract] [Purchase
Article]
[PMID:
19925414 PubMed - indexed for MEDLINE]
Inhibition of Zinc Metallopeptidases in Cardiovascular
Disease - From Unity to Trinity, or Duality? Pp.
3606-3621
Vincent Dive, Cheng-Fu Chang, Athanasios Yiotakis and
Edward D. Sturrock
[Abstract] [Purchase
Article]
[PMID:
19925415 PubMed - indexed for MEDLINE]
Angiotensin Converting Enzyme (ACE) Inhibitory Peptides:
Production and Implementation of Functional Food
Pp. 3622-3643
F. De Leo, S. Panarese, R. Gallerani and L. R.
Ceci
[Abstract] [Purchase
Article] [PMID:
19925416 PubMed - indexed for MEDLINE]
Insulin-Degrading Enzyme: Structure-Function Relationship
and its Possible Roles in Health and Disease Pp.
3644-3655
A. Fernández-Gamba, M.C. Leal, L. Morelli and
E.M. Castaño
[Abstract] [Purchase
Article]
[PMID:
19925417 PubMed - indexed for MEDLINE]
A New Role for Zn(II) Aminopeptidases: Antigenic Peptide
Generation and Destruction Pp. 3656-3670
Irini Evnouchidou, Athanasios Papakyriakou and
Efstratios Stratikos
[Abstract] [Purchase
Article]
[PMID:
19925418 PubMed - indexed for MEDLINE]
Current Clinical Applications of Botulinum Toxin
Pp. 3671-3680
Daniel D. Truong, Andrea Stenner and Gerhard
Reichel
[Abstract] [Purchase
Article]
[PMID:
19925419 PubMed - indexed for MEDLINE]
It Takes Two to Tango: The Structure and Function
of LIM, RING, PHD and MYND Domains Pp. 3681-3690
J.M. Matthews, M. Bhati, E. Lehtomaki, R.E. Mansfield,
L. Cubeddu and J.P. Mackay
[Abstract] [Purchase
Article]
[PMID:
19925420 PubMed - indexed for MEDLINE]
Ring Finger Ubiquitin Protein Ligases and Their
Implication to the Pathogenesis of Human Diseases
Pp. 3697-3715
Helen C. Ardley
[Abstract] [Purchase
Article]
[PMID:
19925421 PubMed - indexed for MEDLINE]
RING Finger E3
Ubiquitin Ligases: Structure and Drug Discovery Pp.
3716-3731
Christos T. Chasapis and Georgios A. Spyroulias
[Abstract] [Purchase
Article]
[PMID:
19925422 PubMed - indexed for MEDLINE]
Abstracts
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[PMID:
19925413 PubMed - indexed for MEDLINE]
Editorial: Latest Development on
Zinc Enzymes
Zinc (Zn) metal ion along with other transition metals
like copper and iron are of vital significance in living organisms
with zinc being the second most abundant transition metal
ion in living organism following iron. Zn(II) exhibits remarkable
stability in redox processes due to its d10
electronic configuration and is known to be indispensable
to growth and development, to metabolic pathways as well as
to transmission of the genetic message.
The coordination properties of the zinc that allows the metal
to bind within a broad range of tetrahedral sites in proteins
can discriminate the role of zinc in four classes, such as
catalytic, cocatalytic, structural
and protein interface. Zinc metal sites are encountered
in a wide variety of enzymes implicated in synthesis of nucleic
acid and proteins, catalysis, protein/peptide degradation,
signaling etc. Recent studies propose that zinc proteins may
comprise the 10% of the human proteome.
In this issue of Current Pharmaceutical Design journal a variety
of zinc enzymes are discussed and the latest achievements
in the study of their structural and functional properties
are highlighted along with the recent developments in the
design and biological properties of new zinc chelators, which
might act as modulators of enzymes’
function, with potential interest in pharmacology and medicine.
I. Bertini and co-workers [1] at the Center of Magnetic Resonance
and the University of Florence (Italy) provide a report on
the recent advances in Matrix Metalloproteases genetics and
function, highlighting the variability of the structural features
among the family of these enzymes along with their intra-
or inter-domain dynamics that are also taken into account
in latest attempts for design and biological evaluation of
new inhibitors.
E. Sturrock, from the University of Cape Town (South Africa),
V. Dive, from the CEA, Saclay (France), A. Yiotakis from the
University of Athens (Greece) and co-workers [2] present an
overview on the current status of Angiotensin-Converting Enzyme
inhibition reviewing also the progress in of the synchronous
modulation of the function of other Zn-metalloproteases, like
Neutral Endopeptidase and Endothelin-Converting Enzyme, implicated
in blood pressure regulation.
F. De Leo and co-workers [3] from the CNR and University of
Bari (Italy), review the recent development in an alternative
way for Angiotensin-Converting Enzyme inhibition that makes
use of components, especially peptides, from natural sources,
such as milk highlighting the role that functional foods as
natural products of remarkable pharmaceutical value.
E.M. Castaño
and co-workers [4] from Fundación
Instituto Leloir, Buenos Aires (Argentina), review the structural
and functional characteristics of Insulin-degrading enzyme,
which is now recognized as a multifunction protein in a variety
of cellular processes exhibiting a wide spectrum of peptide
substrates having its 3D structure elucidated only recently.
E. Stratikos and co-workers [5] from the NCSR “Demokritos”,
Athens (Greece) reports on the recent progress in the functional
studies of Zn-aminopeptidases, such as ER aminopeptidases,
for which a new role in the immune response have been disclosed
while being a key component in the proteolytic steps that
generate small peptides for presentation onto MHC class I
molecules.
D. Truong from the Parkinson’s
and Movement Disorder Institute, California (USA) and co-workers
from the Department of Movement Disorders, Paracelsus Clinic,
Zwickau (Germany) [6] provides an overview of the beneficiary
effects of Botulinum toxins when used in low concentrations
and reviews the new and emerging clinical application of these
metalloprotease in a extremely broad spectrum of diseases
and neural or muscle disorders.
J.M. Mathews and co-workers [7] form the University of Sydney
(Australia) highlights the structural and functional variations
over a large family of zinc binding domains, such as LIM,
RING, PHD and MYND, capable to bind two zinc metal ions that
although bear similar coordination environment to the classical
zinc-finger binding motifs, they exhibit diverse functionality.
H. Ardley [8] from the Leeds Institute for Molecular Medicine
(UK) provides a complete overview of the role of the RING
finger ubiquitin protein ligases in the ubiquitin proteasome
system and how RING-dependent imbalances of the ubiquitination
pathway are related to the pathogenesis of human diseases.
C.T. Chasapis and G.A. Spyroulias [9] from University of Patras
(Greece) highlight the structural features of the diverse
sub-classes of the RING finger E3 ligases according to the
number of coordinated cysteines and histidines reviewing also
the latest progress in the application of small molecules,
as a novel class of anticancer drugs, to regulate the function
of specific RING E3 ligases with potential interest.
Finally, I wish to thank all the authors and co-authors for
their fruitful collaboration and for making possible the assembly
of these nine wonderful overviews on recent progress in the
field of Zinc Enzymes.
References
[1] Bertini I, Fragai
M, Luchinat C. Intra– and interdomain flexibility in
matrix metalloproteinases: functional aspects and drug design.
Curr Pharm Des 2009; 15(31): 3592-3605.
[2] Dive V, Chang
C-F, Yiotakis A, Sturrock ED. Zinc metallopeptidases in cardiovascular
disease – from unity to trinity, or duality? Curr Pharm
Des 2009; 15(31): 3606-3621.
[3] De Leo F, Panarese
S, Gallerani R, Ceci LR. Angiotensin Converting Enzyme (ACE)
inhibitory peptides: production and implementation of functional
food. Curr Pharm Des 2009; 15(31): 3622-3643.
[4] Fernández-Gamba
A; Leal MC; Morelli L; Castaño EM. Insulin-degrading
enzyme: structure-function relationship and its possible roles
in health and disease. Curr Pharm Des 2009; 15(31): 3644-3655.
[5] Evnouchidou
I, Papakyriakou A, Stratikos E. A new role for Zn(II) aminopeptidases:
antigenic peptide generation and destruction. Curr Pharm Des
2009; 15(31): 3656-3670.
[6] Truong DD, Stenner
A, Reichel G. Current clinical applications of botulinum toxin.
Curr Pharm Des 2009; 15(31): 3671-3680.
[7] Matthews JM,
Bhati M, Lehtomaki E, Mansfield RE, Cubeddu L, Mackay JP.
It takes two to tango: the structure and function of LIM,
RING, PHD and MYND domains. Curr Pharm Des 2009; 15(31): 3681-3696.
[8] Ardley HC. RING
finger ubiquitin protein ligases and their implication to
the pathogenesis of human diseases. Curr Pharm Des 2009; 15(31):
3697-3715.
[9] Chasapis CT,
Spyroulias GA. RING Finger E3 ubiquitin ligases: structure
and drug discovery. Curr Pharm Des 2009; 15(31): 3716-3731.
Prof. Georgios A. Spyroulias, PhD,
Department of Pharmacy,
School of Health Sciences,
University of Patras
Greece
E-mail: G.A.Spyroulias@upatras.gr
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[Purchase
Article]
[PMID:
19925414 PubMed - indexed for MEDLINE]
Intra- and Interdomain Flexibility in Matrix Metalloproteinases:
Functional Aspects and Drug Design
Ivano Bertini, Marco Fragai and Claudio Luchinat
Matrix metalloproteinases are involved in many biological
processes and in a large set of diseases. In the last twenty
years the genetics, functions, and the structural features
of this family of proteolytic enzymes have been investigated
and a large number of synthetic inhibitors designed and tested.
A better knowledge of the dynamical features of these proteins
can be relevant not only to reveal new biological activities
but also to design more specific and selective inhibitors.
Here, we report the common and the distinct structural features
of these proteins, the most recent published information on
protein dynamics in matrix metalloproteinases and the recent
results on the catalytic mechanism. The implications of the
observed intra- and interdomain flexibility in matrix metalloproteinases
for drug design have been analyzed and discussed.
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[Purchase
Article]
[PMID:
19925415 PubMed - indexed for MEDLINE]
Inhibition of Zinc Metallopeptidases in Cardiovascular
Disease - From Unity to Trinity, or Duality?
Vincent Dive, Cheng-Fu Chang, Athanasios Yiotakis and
Edward D. Sturrock
The fusion of therapeutics and diagnostic medicine in an effort
to provide individualized pharmacotherapy frequently requires
the manipulation of drugs that target different enzymes and
receptors. To this end, and as a strategy to increase the
efficiency of drug development pipelines, new chemical entities
are often developed that interact with more than one target.
Angiotensin-converting enzyme (ACE), its homologue ACE2, neutral
endopeptidase (NEP) and endothelin-converting enzyme (ECE-1)
are metallopeptidases that are involved in the metabolism
of biologically active peptides that impact on the regulation
of the cardiovascular system. The benefit of the ACE/NEP;
NEP/ECE and ACE/NEP/ECE dual and triple inhibitors is not
only their possible increased efficacy with respect to blood
pressure control, but also their other activities, such as
antiproliferative, anti-fibrotic and anti-inflammatory, mediated
by angiotensin II and atrial natriuretic peptide. Over the
last few years a number of three-dimensional structures of
these metallopeptidases have advanced our understanding of
the mode of interaction between various ligands and their
target binding sites. This information is invaluable in the
rational design of new and improved drugs. Here we review
the structural basis for the design of single and multiple
metallopeptidase inhibitors for the treatment of cardiovascular
disease. Moreover, we present recent advances in the development
of ACE/ECE-1 inhibitors that are likely to have high potency
and improved side effect profiles.
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Article]
[PMID:
19925416 PubMed - indexed for MEDLINE]
Angiotensin Converting Enzyme (ACE) Inhibitory Peptides:
Production and Implementation of Functional Food
F. De Leo, S. Panarese, R. Gallerani and L. R.
Ceci
In recent decades, the most successful strategy for
controlling blood pressure has been inhibition of the angiotensin-converting
enzyme (ACE). ACE inhibitors of chemical synthesis (captopril,
enalapril, ramipril and trandolapril) have been widely used
clinically to reduce mortality in patients with heart failure,
and in patients with recent myocardial infarction and heart
failure or marked left ventricular dysfunction.
In addition to preventive and therapeutic drugs, increased
attention has been paid to identifying dietary compounds that
may contribute to cardiovascular treatment and prevention.
ACE inhibitory peptides, derived from a multitude of plant
and animal proteins such as milk, soy or fish, represent sources
of health-enhancing components. These ACE inhibitory peptides
can be enzymatically released from precursor proteins in
vitro and in vivo, respectively during food
processing and gastrointestinal digestion. They have shown
the ability to lower blood pressure by limiting the vasoconstrictory
effects of Angiotensin II and potentiating the vasodilatory
effects of Bradykinin. By using specific procedures they may
be generated in or incorporated into functional foods for
the development of 'natural' beneficial health products. Several
products containing peptides with ACE inhibitory properties
are currently on the market or in development. This review
focuses on the use, application and future perspective of
bioactive peptides with properties relevant to cardiovascular
health.
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Article]
[PMID:
19925417 PubMed - indexed for MEDLINE]
Insulin-Degrading Enzyme: Structure-Function Relationship
and its Possible Roles in Health and Disease
A. Fernández-Gamba,
M.C. Leal, L. Morelli and E.M. Castaño
Insulin-degrading enzyme (IDE) or insulysin is a highly conserved
Zn2+-dependent endopeptidase
with an “inverted”
HxxEH motif. In vivo, IDE contributes to regulate
the steady state levels of peripheral insulin and cerebral
amyloid β
peptide (Aβ)
of Alzheimer’s
disease. In vitro, substrates of IDE include a broad
spectrum of peptides with relevant physiological functions
such as atrial natriuretic factor, insulin-like growth factor-II,
transforming growth factor-α,
β-endorphin,
amylin or glucagon. The recently solved crystal structures
of an inactive IDE mutant bound to four different substrates
indicate, in accordance with previous compelling biochemical
data, that peptide backbone conformation and size are major
determinants of IDE recognition and substrate selectivity.
IDE-N and IDE-C halves contribute to substrate binding and
may rotate away from each other leading to open and closed
conformers that permit or preclude the entry of substrates.
Noteworthy, stabilization of substrate β
strands in their IDE-bound form may explain the preference
of IDE for peptides with a high tendency to self-assembly
as amyloid fibrils. These structural requirements may underlie
the capability of some amyloid peptides of forming extremely
stable complexes with IDE and raise the possibility of a dead-end
chaperone-like function of IDE independent of catalysis. Furthermore,
the recent recognition of IDE as a varicella zoster virus
receptor and its putative involvement in muscle cell differentiation,
steroid receptor signaling or proteasome modulation suggest
that IDE is a multi-functional protein with broad and relevant
roles in several basic cellular processes. Accordingly, IDE
functions, regulation or trafficking may partake in the molecular
pathogenesis of major human diseases and become potential
targets for therapeutic intervention.
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Article]
[PMID:
19925418 PubMed - indexed for MEDLINE]
A New Role for Zn(II) Aminopeptidases: Antigenic Peptide
Generation and Destruction
Irini Evnouchidou, Athanasios Papakyriakou and
Efstratios Stratikos
During the last few years a novel role for previously known
Zn(II) aminopeptidases has emerged, attracting a great deal
of scientific interest to these molecules. Aminopeptidases
appear now to play a key role in the last, yet crucial, proteolytic
steps that generate small peptides for presentation onto MHC
class I molecules so that the mature MHC-peptide complexes
can be recognized by cytotoxic T-lymphocytes. In that context,
ER aminopeptidases have been shown to strongly affect the
adaptive immune response. ER aminopeptidase 1 (ERAP1) has
been demonstrated to be a critical determinant of the immune
response by generating mature antigenic epitopes from peptide
precursors that arrive into the ER originating primarily from
intracellular proteins degraded by the proteasome. At least
one more related aminopeptidase, renamed ERAP2, appears to
have important yet distinct roles in antigenic peptide generation.
This review discusses recent findings that help to unravel
the role of ER aminopeptidases in the immune response as well
as the molecular properties that underlie this role. Determining
the exact role and mechanism of action of these aminopeptidases
will potentially provide tools for the pharmaceutical manipulation
of the immune response on a subtle and qualitative level leading
to novel therapeutic opportunities for the treatments of diseases
ranging from autoimmunity to cancer.
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[PMID:
19925419 PubMed - indexed for MEDLINE]
Current Clinical Applications of Botulinum Toxin
Daniel D. Truong, Andrea Stenner and Gerhard
Reichel
Botulinum toxin has long been known for its paralytic
effects on the human voluntary musculature via inhibition
of acetylcholine release at neuromuscular junctions. Its original
clinical use for the treatment of strabismus has expanded
significantly to include neurological conditions related to
muscle hyperactivity and/or spasticity (e.g., dystonia, spasticity,
tics, tremor, dysphonia). Recently, botulinum toxin has been
shown to impact autonomic disorders by acting at acceptors
on glands and smooth muscle, and consequently it has been
used in the management of a number of other conditions including
hypersecretory disorders, pain syndromes, detrusor sphinchter
dyssenergia or overactivity and gastointestinal smooth muscle/sphincter
spasm; it may also reduce pain in patients for whom it is
used to treat these and other primary conditions. This article
will review the pharmacology and formulations of botulinum
toxins as well as data from clinical trials demonstrating
their efficacy for numerous conditions based on their effects
on cholinergic synapses outside the motor nervous system.
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[PMID:
19925420 PubMed - indexed for MEDLINE]
It Takes Two to Tango: The Structure and Function
of LIM, RING, PHD and MYND Domains
J.M. Matthews, M. Bhati, E. Lehtomaki, R.E. Mansfield,
L. Cubeddu and J.P. Mackay
LIM (Lin-11, Isl-1, Mec-3), RING (Really interesting new
gene), PHD (Plant homology domain) and MYND (myeloid, Nervy,
DEAF-1) domains are all zinc-binding domains that ligate two
zinc ions. Unlike the better known classical zinc fingers,
these domains do not bind DNA, but instead mediate interactions
with other proteins. LIM-domain containing proteins have diverse
functions as regulators of gene expression, cell adhesion
and motility and signal transduction. RING finger proteins
are generally associated with ubiquitination; the presence
of such a domain is the defining feature of a class of E3
ubiquitin protein ligases. PHD proteins have been associated
with SUMOylation but most recently have emerged as a chromatin
recognition motif that reads the methylation state of histones.
The function of the MYND domain is less clear, but MYND domains
are also found in proteins that have ubiquitin ligase and/or
histone methyltransferase activity. Here we review the structure-function
relationships for these domains and discuss strategies to
modulate their activity.
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[PMID:
19925421 PubMed - indexed for MEDLINE]
Ring Finger Ubiquitin Protein Ligases and Their
Implication to the Pathogenesis of Human Diseases
Helen C. Ardley
The ubiquitin proteasome system (UPS) plays a fundamental
role in maintaining the correct balance of protein levels
inside all living cells. Degradation of proteins by this pathway
is essential for most cellular processes including cell signalling,
DNA repair, apoptosis and gene transcription. Any disruption
to the system is likely to have severe consequences which
may lead to disorders including neurodegeneration and cancer.
Ubiquitin protein ligases are a group of UPS proteins of particular
importance because these proteins determine targeting specificity
via recognition of a ‘target’
protein and its’
subsequent ‘tagging’
with ubiquitin. The 26S proteasome recognises these mutli-ubiquitylated
proteins, allowing the correct protein to be degraded at the
correct time and place within each cell.
Several types of ubiquitin protein ligase have now been identified,
however, the largest group by far are those proteins containing
a ‘RING’
motif. In this review, examples will be given whereby abnormal
protein ubiquitylation due to absence or inefficiency of a
RING protein ligase is proposed to be a key regulator of the
disease process. Ways in which we may be able to reverse these
effects or manipulate these proteins to restore function will
be discussed.
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[PMID:
19925422 PubMed - indexed for MEDLINE]
RING Finger E3
Ubiquitin Ligases: Structure and Drug Discovery
Christos T. Chasapis and Georgios A. Spyroulias
The RING (Really Interesting New Gene) family is the largest
type of E3 ubiquitin ligases. RING finger domains bind two
zinc ions in a unique ‘‘cross-brace’’
arrangement through a defined motif of cysteine and histidine
residues. This arrangement endows the RING domain with a globular
conformation, characterized by a central α-helix
and variable-length loops separated by several small β-strands.
RING E3 ubiquitin ligases, play an essential role in the regulation
of many biologic processes and defects in some of them are
involved in cancer development. Furthermore, some RING E3
ligases are frequently overexpressed in human cancers. Today,
RING ligases represent potentially molecular targets for disease
intervention and could act as prognostic biomarkers. Targeting
specific RING E3 ligases could lead to the development of
a novel class of anticancer drugs. However RING fingers exhibit
remarkable variations in their sequence and their topology
characteristics. Structure determination of new RING finger
domain is in the core of the design of new pharmaceuticals
and what is presented in this article is a thorough review
of achievements on the NMR or Xray structure determinations.
Protein preparation protocols along with analysis of the structural
features of known RING finger are also presented.
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