| Current
Enzyme Inhibition
ISSN: 1573-4080
Current Enzyme Inhibition
Volume 1, Number 1, January 2005
Contents
Editorial Pp.1-2
[Editorial
In PDF]
Role of Integrin-Linked Kinase in Neuronal
Cells Pp.3-10
Toshiaki Ishii
[Abstract] [Full
text article]
Sesamin and Sesamolin: Nature’s Therapeutic
Lignans Pp.11-20
K.C.G. Jeng & R.C.W. Hou
[Abstract] [Full
text article]
Carbonyl–Induced Enzyme Inhibition:
Mechanisms and New Perspectives Pp.21-27
Norbert W. Seidler
[Abstract] [Full
text article]
Current Inhibition Concepts of Zinc Metallopeptidases
Involved in Blood Pressure Regulation Pp.29-42
Georgios A. Spyroulias & Paul Cordopatis
[Abstract] [Full
text article]
Role of Caspases in Activation-Induced Cell Death
of Neuroglia Pp.43-50
Kyoungho Suk
[Abstract] [Full
text article]
ACE2; an ACE up the Sleeve? Pp.51-63
M.C. Thomas & C. Tikellis
[Abstract] [Full
text article]
Inhibition of Dipeptidyl Peptidase-4 (DPP-4)
– A Novel Approach to Treat Type 2 Diabetes Pp.65-73
Bo Ahren
[Abstract] [Full
text article]
Translating MAPK Inhibitors To Anti-Inflammatory
Compounds Pp.75-84
C. Ropert
[Abstract] [Full
text article]
Monoamine Oxidase Inhibition In the Light
of New Structural Data Pp.85-95
M. Reyes-Parada, A. Fierro, P. Iturriaga-Vasquez
& B.K. Cassels
[Abstract] [Full
text article]
Abstracts
[Back to top]
Editorial
[Editorial
In PDF]
The present copy of the journal Current Enzyme Inhibition
(CEI) is the inaugural issue of the journal. CEI is a review
journal which has been started to provide the scientific community
involved in the studies of structure, function, and inhibition
of the enzymes with a comprehensive coverage of the inhibitory
aspects of the different enzymes. Inhibitors of enzymic reactions
have acquired a very vast dimension in biochemical, biophysical,
medical, and pharmaceutical research and in the treatment
of a large number of diseases. They are used to study specific
intracellular functions and related processes and provide
tools by which the mechanisms of ligand binding, enzymic catalysis,
and other aspects of enzyme chemistry can be elucidated. Blockades
of the functions of various enzymes act as the favored targets
for the development of drugs against several diseases. The
inhibition study thus has become a very fascinating area of
research for biochemists, medicinal chemists, and pharmaceutical
scientists. Consequently, a huge number of papers are being
published every year on enzyme inhibition-related studies
in different journals. It has made difficult to have a track
of all developments on a particular enzyme of one’s
interest, and thus a need was felt to provide a comprehensive
and cohesive coverage on all inhibitory studies related to
a particular enzyme. With this aim, Bentham Science has started
the Current Enzyme Inhibition, wherein the leading scientists
from all over the world are invited to contribute the review
articles on the topics in which they have expertise. Each
issue would aim to publish a series of timely in-depth reviews
written by leaders in the fields on some important topics
related to enzyme inhibition. The present issue contains nine
articles, covering a variety of interesting topics.
In article 1, Toshiaki Ishii has reviewed the role of integrin-linked
kinase (ILK) in neuronal cells. Recent studies demonstrated
that ILK interacts with and regulates many different signaling
pathways in neuronal cells, which implies an important role
for ILK in a variety of neuronal functions. This article discusses
the role of ILK in neuronal cells and also the possible involvement
of ILK in neuronal disorders. In article 2, Jeng and Hou discuss
about sesamin and sesamolin-nature’s therapeutic lignans.
Sesamin (SA) and sesamolin (SO) are major lignans (a non-fat
constituent) in sesame seed oil, inhibit D5-desaturase activity
and cause accumulation of dihomo-g -linolenic acid (DGLA),
a precursor of 1-series prostaglandins. In article 3, Norbert
Seidler presents an account of carbonyl-induced enzyme inhibition
in which he describes the way carbonyl-containing (and particularly
glycating) agents react with protein residues elucidating
mechanisms that include two broad categories: direct reaction
(1) with active site residues and (2) with residues distinct
from the active site. Article 4, which has been written by
Spyroulias and Cordopatis, presents current inhibition concepts
of zinc metallopeptidases involved in blood pressure regulation.
Certain zinc metallopeptidases, such as angiotensin converting
enzyme (ACE), neutral endopeptidase (NEP) and endothelin converting
enzyme (ECE), play a key role in vascular homeostasis through
their proteolytic activity in various vasoactive peptides.
Spyroulias and Cordopatis discuss a new class of promising
compounds, namely vasopeptidase inhibitors, which represent
a new concept in hypertension and cardiovascular disease therapeutics.
They contemporarily inhibit the catalytic function of more
than one of the above enzymes and are undergoing extensive
clinical trials exhibiting increased efficacy in hypertension
treatment and higher risk for side-effects such as angioedema
when compared to ACE inhibitors. In the next article, Suk
describes the role of caspases in the activation-induced cell
death (AICD) of neuroglia. Caspases may be a target for the
modulation of neuroglial AICD that has implications in neurodegenerative
diseases. In article 6, Thomas and Tikellis present an account
of angiotensin converting enzyme 2 (ACE2) and discuss that
ACE2 may also have important functional consequences in heart
failure and pre-eclampsia and that its selective inhibitors
may provide important tools for exploring the physiology and
pathology of the enzyme in both health and disease states.
Bo Ahrén describes, in article 7, the inhibition of
dipeptidyl peptidase-4 (DPP-4), a novel approach to treat
type 2 diabetes. The novel approach for the treatment of type
2 diabetes is based on the gut hormone glucagon-like peptide-1
(GLP-1), which is antidiabetic due to its combined action
to stimulate insulin secretion, increase beta-cell mass, inhibit
glucagon secretion, reduce the rate of gastric emptying and
induce satiety. The inhibition of DPP-4 can increase the level
of endogenous active GLP-1 and prolong its half-life. Recently,
a considerable interest has developed in the study of inhibitors
of protein kinase. Mitogen activated protein kinases (MAPKs),
a group of Ser/Thr protein kinases, are activated by a wide
spectrum of extracellular stimuli. Extensive literature reports
have indicated the key role of these kinases in inflammatory
processes and in immune response. A review by Ropert ( article
8) outlines relevant aspects on the development of MAPK inhibitors
that could form the molecular basis for a new class of anti-inflammatory
and immunoregulatory agents. Lastly, an article by Reyes-Parada
et al. discusses monoamine oxidase (MAO) inhibition in the
light of new structural data. The recent description of the
crystal structures of rat MAO-A and human MAO-B provides an
unprecedented framework to elucidate the mechanisms underlying
the selective interactions between these proteins and their
ligands. Reyes-Parada et al. present a detailed account of
this. I thank all the authors of this issue for their excellent
stimulating contributions and hope that readers will greatly
enjoy reading these articles as I did and that these contributions
will be of great value to those involved in the studies of
enzyme inhibition.
S. P. Gupta
Editor-in-Chief
Department of Chemistry
Birla Institute of Technology and Science
Pilani-333031, India
Tel: +91-1596-242126, ext. 414 (O); +91-1596-242816 (R)
Fax: +91-1596-244183
E-mail: spg@bits-pilani.ac.in
[Back to top]
Role of Integrin-Linked Kinase in Neuronal Cells
Toshiaki Ishii
[Full text
article]
Integrin-linked kinase (ILK) is a focal adhesion serine/threonine
protein kinase that binds to the cytoplasmic domain of β1
integrin and has an important role in integrin and growth
factor signaling pathways. Clustering of integrins on the
cell surface in contact with the extracellular matrix induces
focal adhesion that recruits numerous mitogenic signaling
proteins other than ILK, such as growth factor receptors,
mitogenactivated protein kinase, and small GTP-binding proteins,
to integrin receptors and forms signaling centers where adhesive
and mitogenic pathways can integrate. ILK is highly expressed
in neuronal cells and its enzyme activity is activated by
cell adhesion on the extracellular matrix in a phosphatidylinositol
3-kinasedependent manner. Recent studies demonstrated that
ILK interacts with and regulates many different signaling
pathways in neuronal cells, which implies an important role
for ILK in a variety of neuronal functions. This article discusses
the role of ILK in neuronal cells and also the possible involvement
of ILK in neuronal disorders.
[Back to top]
Sesamin and Sesamolin: Nature’s Therapeutic
Lignans
K.C.G. Jeng & R.C.W. Hou
[Full text
article]
Sesame oil is commonly used as antioxidant. Sesamin (SA)
and sesamolin (SO) are major lignans (a non-fat constituent)
in sesame seed oil, inhibit D 5-desaturase activity and cause
accumulation of dihomo-γ-linolenic
acid (DGLA), a precursor of 1-series prostaglandins, and the
decreasing production of proinflammatory 2-series prostaglandins
and 4-series leukotrienes. Diets supplemented with SA and/or
SO, lower serum levels of interleukin (IL)-1β,
IL-6 but elevate IL-10 in mice after lipopolysaccharide (LPS)
exposure. Mice fed with sesame seed oil have a 65% survival
rate after cecal ligation and puncture as compared with the
20% survival in the controls. SA and SO inhibit the IL-6,
tumor necrosis factor (TNF)-α
and nitric oxide (NO) productions from microglia under LPS
stimulation. The protective effects of SA/SO to stroke-prone
spontaneously hypertensive rats and hepatic ischemia-reperfusion
injury have been attribute to their antioxidant and anti-inflammatory
activities. The antioxidant activities of SA/SO are identified
in their methylenedioxyphenyl moieties that can be changed
into dihydrophenyl (catechol) moieties. Since reactive oxygen
species (ROS) are mediators of a variety of pathological processes,
including inflammation and ischemic/hypoxic injury, the ROS
scavenging moiety may contribute as an important component
to prevent cells from the free radical injury. Hypoxia or
H2O2-induced cell injury are related
with activated MAPKs and caspase-3 activities. Evidence suggests
that the protective effects of SA and SO on hypoxic neuronal
cells are related to suppression of ROS generation and mitogen-activated
protein kinases (MAPKs). In addition, SA/SO significantly
reduce LPS-activated p38 MAPK. Specific inhibitors of MAPKs
dose-dependently inhibit NO and cytokine productions in LPS-stimulated
microglia. Therefore, the inhibition of NO and cytokine productions
may partly due to the reduction of LPS-induced p38 MAPK signal
pathway by SA and SO.
[Back to top]
Carbonyl–Induced Enzyme Inhibition: Mechanisms and New
Perspectives
Norbert W. Seidler
[Full text
article]
While agents that cause carbonyl-induced modification include
sugars, lipids and industrial and pyrogenic compounds, much
of the existing literature describes the process of glycation.
Protein glycation is recognized as a major post-translational
modification that attends the pathogenesis of diverse diseases.
Glycation arises from the reactivity of common carbohydrates,
their metabolic intermediates and their oxidized byproducts.
The hyperglycemia associated with diabetes and the life-long
exposure to pro-glycating agents bring about an environment
that favors the modification of diverse proteins resulting
in macro- and microangiopathy and the neuropathy of misfolding
disorders such as Alzheimer’s disease. Numerous structural
and catalytic proteins have been shown to be targets of glycation.
The literature documents the potent inhibitory effects of
glycation with very insightful suggestions on mechanisms of
action. The current review describes the way carbonyl-containing
(and particularly glycating) agents react with protein residues
elucidating mechanisms that include two broad categories:
direct reaction (1) with active site residues and (2) with
residues distinct from the active site. The consequence of
active site modification involves obvious steric and chemical
changes that are likely to be prohibitive. The modification
of residues distinct from the active site suggests inhibitory
mechanisms more subtle and complex. The current review presents
new perspectives in this emerging field that has implications
beyond enzyme inhibition, such as the cellular impact of protein
insolubility and aggregation.
[Back to top]
Current Inhibition Concepts of Zinc Metallopeptidases Involved
in Blood Pressure Regulation
Georgios A. Spyroulias & Paul Cordopatis
[Full text
article]
Certain Zinc Metallopeptidases, such as Angiotensin Converting
Enzyme (ACE), Neutral Endopeptidase (NEP) and Endothelin Converting
Enzyme (ECE), play a key role in vascular homeostasis through
their proteolytic activity in various vasoactive peptides.
Effective inhibitors for these enzymes were until recently
designed in the absence of the X-ray structure of these enzymes,
and a variety of ACE inhibitors are commercially available.
A new class of promising compounds, namely vasopeptidase inhibitors,
have emerged and they represent a new concept in hypertension
and cardiovascular disease therapeutics. They contemporarily
inhibit the catalytic function of more than one of the above
enzymes and they are undergoing extensive clinical trials
exhibiting increased efficacy in hypertension treatment and
higher risk for side effects such as angioedema when compared
to ACE inhibitors. The determination of the substrate-free
and substrateloaded X-ray models of NEP and ACE provides valuable
insight of the structure determinants in enzymesubstrate interaction
and it is believed that new more selective inhibitors could
be afforded through structurebased drug design process. Selectivity
towards target enzyme even in simultaneous inhibition could
modify the breakdown of vasodilator and vasoconstrictor peptides
and could therefore modulate the balance of the risk-benefit
profile.
[Back to top]
Role of Caspases in Activation-Induced Cell Death of Neuroglia
Kyoungho Suk
[Full text
article]
Activation-induced cell death (AICD) is an active process.
T and B lymphocytes undergo AICD as an auto-regulatory mechanism
for the body to remove unwanted activated cells after making
appropriate use of them. Recent studies have shown that brain
microglia and astrocytes also undergo apoptosis upon inflammatory
activation. Caspase-11 has been demonstrated to play a central
role in the apoptosis of both microglia and astrocytes following
inflammatory activation; inflammatory stimuli induce neuroglial
apoptosis through caspases-11, -1, and -3. Thus, inflammatory
signals that activate neuroglia may also initiate internal
death program, in which caspases play a crucial role. Caspases
may be a target for the modulation of neuroglial AICD that
has implications in neurodegenerative diseases.
[Back to top]
ACE2; an ACE up the Sleeve?
M.C. Thomas & C. Tikellis
[Full text
article]
The traditional linear model of the RAS has now been replaced
by a dynamic system than includes a number of new components.
Among them the angiotensin converting enzyme type 2 has recently
become recognized as an important homeostatic factor and counterbalance
to ACE, modulating the balance between vasoconstrictors and
vasodilators within the heart and kidney, and playing a significant
role in regulating cardiovascular and renal function. However,
ACE2 also has a number of important independent actions as
evidence by its differential distribution in both development
and in adult tissues. Studies from knockout mice suggest that
ACE2 is involved in both cardiac and renal development. ACE2
is also involved in a number of disease processes, most notably
ACE2 has been reported recently to be the functional receptor
for the severe acute respiratory syndrome (SARS) coronavirus.
A reduction in ACE2 in diabetes may also contribute to endorgan
damage. ACE2 may also have important functional consequences
in heart failure and pre-eclampsia. In this context, selective
inhibitors of ACE2 will provide important tools for exploring
the physiology and pathology of the enzyme in both heath and
disease states.
[Back to top]
Inhibition of Dipeptidyl Peptidase-4 (DPP-4) –
A Novel Approach to Treat Type 2 Diabetes
Bo Ahren
[Full text
article]
A novel approach for treatment of type 2 diabetes is based
on the gut hormone glucagon-like peptide-1 (GLP-1), which
is antidiabetic due to its combined action to stimulate insulin
secretion, increase beta-cell mass, inhibit glucagons secretion,
reduce the rate of gastric emptying and induce satiety. A
problem is, however, that the peptide is rapidly inactivated
by the enzyme dipeptidyl peptidase-4 (DPP-4), resulting in
a half-life of active GLP-1 of only approximately 1-2 minutes.
To overcome this inconvenient drawback for the treatment of
diabetes, two strategies have been successful; one strategy
uses DPP-4 resistant GLP-1 receptor agonists whereas the other
strategy uses inhibition of DPP-4. Such inhibition will increase
the levels of endogenous active GLP-1 and prolong its half-life.
The rationale behind the strategy is evident from studies
in animals with genetic deletion of DPP-4, which have improved
glucose tolerance and increased insulin secretion in response
to oral glucose. Furthermore, in experimental animals, different
pharmacological DPP-4 inhibitors are antidiabetic. Recently
also studies in subjects with type 2 diabetes have shown that
prolonged DPP-4 inhibition for up to 1 year is antidiabetogenic
because fasting and postprandial glucose as well as HbA1c
levels are reduced. This is seen in association with good
tolerability and weight neutrality. Hence, DPP-4 inhibition
has the potential to be a novel, efficient and tolerable approach
to treat type 2 diabetes.
[Back to top]
Translating MAPK Inhibitors To Anti-Inflammatory Compounds
C. Ropert
[Full text
article]
Protein phosphorylation plays a central role in cellular
processes. Recently, a considerable interest in the development
of inhibitors of protein kinase has been taken. Mitogen activated
protein kinases (MAPKs), a group of Ser/Thr protein kinases,
are activated by a wide spectrum of extracellular stimuli.
Extensive literature reports have indicated the key role of
these kinases in inflammatory processes and in immune response.
This review outlines relevant aspects on the development of
MAPK inhibitors that could form the molecular basis for a
new class of anti-inflammatory and immunoregulatory agents.
Particular focus is given to their role in regulating the
dysfunction of innate immunity. Also, concepts as docking
interactions, participation of scaffold proteins in MAPK cascades
and its importance in the design of more specific inhibitors
are discussed.
[Back to top]
Monoamine Oxidase Inhibition In the Light of New Structural
Data
M. Reyes-Parada, A. Fierro, P. Iturriaga-Vasquez
& B.K. Cassels
[Full text
article]
The recent description of the crystal structures of rat MAO-A
and human MAO-B provides an unprecedented framework to elucidate
the mechanisms underlying the selective interactions between
these proteins and their ligands. The analysis of previous
and emerging data, in the light of the structural similarities
and differences between both isozymes, allows a better understanding
of the requirements that determine the affinity and selectivity
of substrates and inhibitors. This augurs a new impulse for
the rational design of potent and selective MAO inhibitors
with therapeutic potential.
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