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Current Enzyme Inhibition
ISSN: 1573-4080
Current Enzyme Inhibition
Volume 1, Number 3, November 2005
Contents
Enzyme Inhibition Based Biosensors for Environmental Monitoring
Pp.207
B. Kuswandi & M. Mascini
[Abstract]
Factors Affecting Nitroreductase Activity in the Biological
Reduction of Nitro Compounds Pp.223
F. Rafii, G.L. Hehman & A.R. Shahverdi
[Abstract]
Structural Consensus Rules for Cysteine Protease
Inhibition by NO(-Donors) Pp.231
Paolo Ascenzi, Alessio Bocedi, Fabio Polticelli &
Martino Bolognesi
[Abstract]
Effects of Renin-Angiotensin-Aldosterone System
Blockade on Diabetic Patients Pp.239
F.A.H. Fonseca, W.G.M. Relvas & M.C.O. Izar
[Abstract]
Angiotensin Converting Enzyme Inhibitors and Cardiopulmonary
Bypass: Is ACE Inhibitor Safe for Heart Surgery? Pp.253
Yasuyuki Shimada & Hideshi Itoh
[Abstract]
Role of DNA Repair Systems Inhibition in Carcinogenicity
of Metal Compounds Pp.257
D. Cavallo, C.L. Ursini & S. Iavicoli
[Abstract]
Multiple Signalling Transduction Mechanisms Differentially
Coupled to Somatostatin Receptor Subtypes: A Current View
Pp.265
Davide Cervia, Caroline Nunn & Paola Bagnoli
[Abstract]
Role of Redox Controls of Caspase Activities in
Regulation of Cell Death Pp.281
Yuko Ibuki & Rensuke Goto
[Abstract]
The Role of Proteasome Chemical Inhibitors in
Investigating the Mechanisms of Aneuploidy in Mammalian Oocytes
Pp.287
John B. Mailhes
[Abstract]
Cyanopeptides: A New and Nearly Inexhaustible
Natural Resource for the Design and Structure-Activity Relationship
Studies of New Inhibitors of Trypsin-like Serine Proteases
Pp.295
G. Radau
[Abstract]
Lipoxygenases (LOs): An Heterogenous Family of Lipid
Peroxidizing Enzymes Implicated in Cell Differentiation, Inflammation,
Asthma, Carcinogenesis, Atherogenesis-An Interesting Target
for the Development of Promising Drugs Pp.309
E. Pontiki & D. Hadjipavlou–Litina
[Abstract]
Pathogenesis of Diabetic Retinopathy and Diabetic
Macular Edema and Enzyme Inhibition Pp.329
Hideharu Funatsu & Hidetoshi Yamashita
[Abstract]
Abstracts
[Back to top]
Enzyme Inhibition Based Biosensors for Environmental Monitoring
B. Kuswandi & M. Mascini
A review of methods based on enzyme inhibition in environmental
monitoring is presented, which is mainly focussed on the detection
of pollutants, such as pesticides, heavy metal ions and other
toxic compounds. The sensing principles, design of the biosensor
and an evaluation of biosensors structures (i.e. electrochemical,
optical, piezoelectric and calorimetric) that have been developed
for environmental monitoring are also emphasised. Finally,
future prospects of the enzyme based biosensor are discussed,
particularly in term of novel strategies required for application
to the real samples.
[Back to top]
Factors Affecting Nitroreductase Activity in the Biological
Reduction of Nitro Compounds
F. Rafii, G.L. Hehman & A.R. Shahverdi
Nitro compounds are used in various industries, including
the pharmaceutical industry. These compounds have considerable
importance for human health for two distinctly different reasons.
Some nitro compounds are toxic environmental contaminants
and pose a serious threat to human health; others are used
as therapeutic agents. Nitro compounds are used as agents
for the treatment of infectious diseases caused by Gram-positive
and Gram-negative bacteria, as antifungal and antiparasitic
drugs, and as chemotherapeutic agents. To exert either beneficial
or adverse biological effects, nitro compounds require enzymatic
activation, either by nitroreduction alone or by ring oxidation
followed by nitroreduction. The mechanism of drug action relies
on the toxicity of the products generated by nitroreductases.
Nitroreductases differ in the range of specificity and levels
of activity with various nitro prodrugs. In this review, factors
affecting nitroreductase activity, especially compounds that
inhibit reduction, will be discussed.
[Back to top]
Structural Consensus Rules for Cysteine Protease Inhibition
by NO(-Donors)
Paolo Ascenzi, Alessio Bocedi, Fabio Polticelli
& Martino Bolognesi
Nitric oxide (NO) exerts its action in several physiological
and pathological events. The great propensity for Cys(NO)-(de)nitrosylation
represents a mechanism which modulates cysteine protease action.
Cys(NO)-(de)nitrosylation is assisted by basic and acid residues,
within the environment of the Cys catalytic residue. In particular,
Cys-nitrosylation is catalyzed by amino acid residues which
stabilize the reactive deprotonated form of the Cys Sγ
atom. By contrast, CysNO-denitrosylation is assisted by amino
acid residues which facilitate the protonation of the Cys
Sγ
atom with the concomitant NO release. Note that Cys-nitrosylated
residues may undergo oxidation giving rise to sulfenic, sulfinic
or sulfonic acid and lead to the formation of disulfide bridges.
These structural consensus rules apply not only to cysteine
proteases, but represent a generally accepted mechanism for
(macro)molecular Cys(NO)-(de)nitrosylation.
[Back to top]
Effects of Renin-Angiotensin-Aldosterone System Blockade on
Diabetic Patients
F.A.H. Fonseca, W.G.M. Relvas & M.C.O. Izar
Diabetes mellitus rate is rising worldwide and is now recognized
as the most common cause of end-stage renal disease and blindness
among adults, and a major risk factor for cardiovascular disease.
Diabetics present more extensive atherosclerosis, and particularly,
the type 2 diabetes mellitus patients are often obese, hypertensive,
and dyslipidaemic subjects, sharing the criteria of the metabolic
syndrome. Nowadays, the renin-angiotensin system (RAS) can
be considered a cascade of peptide hormones which play an
important role in the development of several cellular and
hemodynamic alterations among diabetics. Diabetes mellitus
is now considered an inflammatory disease, since its origin
in either type 1 or type 2, and there is growing evidence
that insulin resistance, nephropathy, increased thrombotic
risk, and endothelial dysfunction are all linked to RAS activation.
In recent years, several studies showed the clear efficacy
of angiotensin-converting enzyme inhibitors and angiotensin
receptor blocking agents in reducing vascular complications
and metabolic disorders. However, the precise role of the
RAS blockade, including aldosterone inhibition, in modifying
the morbidity and mortality associated with diabetes, is waiting
for large, randomized and controlled clinical trials.
[Back to top]
Angiotensin Converting Enzyme Inhibitors and Cardiopulmonary
Bypass: Is ACE Inhibitor Safe for Heart Surgery?
Yasuyuki Shimada & Hideshi Itoh
Ischemia/reperfusion injury is unavoidable during cardiopulmonary
bypass surgery because the surgery is conducted during ischemic
arrest of the heart. Animal studies have shown that the administration
of angiotensin converting enzyme (ACE) inhibitors can protect
against lethal arrhythmias, preserve ventricular function,
and improve coronary reserve after ischemia/reperfusion. Two
factors to consider when using ACE inhibitors are their temperature
dependency (because cardiopulmonary bypass surgery is usually
done under hypothermic conditions) and their direct effect
on the bypass material.
In this paper, we review studies of ACE inhibitors and discuss
both their temperature dependency and their effect on bypass
material, especially on the coating of the circuit tube and
artificial lung. Finally, we explore the potential clinical
applications of ACE inhibitors in cardiopulmonary bypass surgery,
taking into consideration the findings of our own preliminary
clinical study.
[Back to top]
Role of DNA Repair Systems Inhibition in Carcinogenicity of
Metal Compounds
D. Cavallo, C.L. Ursini & S. Iavicoli
Several metals have been shown to be carcinogenic to humans
and/or experimental animals. The mechanisms of their carcinogenicity
are not completely understood, even if DNA repair inhibition
seems to be the most probable. Current evidence suggests that
DNA repair systems are very sensitive target for nickel (II),
cadmium (II), cobalt (II) and arsenic (III) leading to a diminished
removal of endogenous and exogenously induced DNA damage,
which increase the risk of tumor formation. Metal compounds
inhibit DNA repair probably by oxidative damage and direct
interactions of metal-ions with reparative enzyme. Metals
carcinogenic potential depends from their solubility and oxidation
state. Oxidative DNA damage by metal compounds is due to ROS
generation by Fenton-type reactions and inactivation of anti-oxidative
enzymes. DNA repair inhibition seems to depend on the ability
of metal ions to compete with magnesium ions or to displace
zinc ions in zinc finger structures of DNA repair enzymes
with consequent their inactivation. The DNA repair inhibition
has been shown for low non-cytotoxic metal concentrations.
DNA repair systems inhibited by metal compounds include essentially
base-excision repair (BER) including Formamidopyrimidinglycosilase
(Fpg)-oxidized base excision repair and nucleotide excision
repair (NER). Several studies on metal inhibition activity
use prevalently the comet test, a rapid and sensitive technique,
to evaluate direct and oxidative DNA damage and its repair
in human cells. Comet test consents to study the influence
of metals on the different steps involved in DNA repair, evaluating
the recovery of DNA damage induced by exposure to different
genotoxic agents in absence or presence of metal compounds.
This technique and its modifications can clarify the mechanisms
of inhibitory processes of enzymes involved in carcinogenesis
and could be a useful tool in the development of new anticancer
drugs.
[Back to top]
Multiple Signalling Transduction Mechanisms Differentially
Coupled to Somatostatin Receptor Subtypes: A Current View
Davide Cervia, Caroline Nunn & Paola Bagnoli
Somatostatin (SRIF) is a cyclic peptide widely distributed
throughout the body with important physiological effects (mostly
inhibitory) on several organ systems. SRIF may act as a neurohormone,
neurotransmitter, neuromodulator or as a local factor, and
exhibits potent antiproliferative activity. SRIF effects have
formed the basis for the clinical use of SRIF analogues in
the treatment of endocrine tumours, acromegaly and gastrointestinal
disorders. Several data suggest that SRIF may also be a therapeutic
target in a number of different diseases.
The binding of SRIF to its five G-protein coupled receptors
leads to modulation of multiple transduction pathways, including
adenylyl cyclase, guanylyl cyclase, phospholipase C, K+
and Ca2+ channels, phospholipase A2,
nitric oxide, Na+/H+ exchanger, protein
phosphatases and MAP kinases. The diversity of the transduction
pathways reflects the pleiotropic actions of SRIF. However,
our current understanding depicts a rather complicated picture
and conflicting results have also been reported. Data are
mostly based on in vitro experiments, and parallels
with the real in vivo conditions are not so obvious.
Due to the clinical relevance of the SRIF system, the elucidation
of the intracellular role of endogenous SRIF receptors may
offer new therapeutic perspectives. These will enable development
of specific pharmacological signalling modulators which can
be incorporated into the therapeutic arsenal.
The present review represents a detailed and exhaustive summary
which covers the latest advances in the transduction pathways
of SRIF receptors.
[Back to top]
Role of Redox Controls of Caspase Activities in Regulation
of Cell Death
Yuko Ibuki & Rensuke Goto
Caspases are a family of aspartate-specific cysteine p1roteinases
that play a critical role in the execution phase of apoptosis.
They are normally present in cells in a proenzyme form that
requires limited proteolysis for enzymatic activity. The processing
of caspases needs the reduction of a cysteine residue as well
as other cysteine residues around the catalytic site for enzymatic
activity and dimerization via sulfhydryl groups.
Therefore, both processing and activity are inhibited in the
presence of an excess of an oxidant such as hydrogen peroxide
or nitric oxide and thiol-oxidizing agents, and enhanced in
the presence of an anti-oxidant such as dithiothreitol or
glutathione. On the other hand, reactive oxygen species (ROS)
released from mitochondria decrease the concentration of cellular
glutathione during apoptosis. Under physiological conditions,
ROS are needed for survival. The redox valance decides the
fate of cells, survival or death involving apoptosis and necrosis.
In this review, we discussed the relationship between the
redox control of caspase activity and cell death.
[Back to top]
The Role of Proteasome Chemical Inhibitors in Investigating
the Mechanisms of Aneuploidy in Mammalian Oocytes
John B. Mailhes
Very little is known about the numerous causes and molecular
mechanisms of aneuploidy in any cell type. However, recent
data suggest that alterations in proteasome activity may be
one of several potential mechanisms that predispose cells
to faulty chromosome segregation. Proteasomes represent multicatalytic
26S proteases consisting of a 20S central catalytic core bordered
by two 19 S components that hydrolyze the C-terminal peptide
bonds to acidic, basic, and hydrophobic amino acid residues
of unwanted proteins in eukaryotic cells. Key cell-cycle regulatory
proteins such as cyclins, cyclin-dependent kinase inhibitors,
and anaphase-inhibitory proteins that have been ubiquinated
by the anaphase promoting complex are subject to degradation
by proteasomes. An association between proteasomes and chromosome
segregation exists because proteasomes are responsible for
proteolyzing subunits of the securin-cohesin protein complex
which helps bind homologues together prior to meiotic anaphase
I and sister chromatids during meiosis II and mitosis. This
association suggests that if cohesins are not timely removed
from chromosomes at anaphase onset, the probability of abnormal
chromosome segregation will be increased. Recent data obtained
from fission yeast and rodent cells exposed to proteasome
inhibitors have revealed that faulty proteasome activity can
lead to aberrant chromosome segregation. Certain peptide aldehydes
that function as transition-state analogues can readily enter
cells and inhibit 26S proteasome activity. The ability to
alter the function of the proteasome/ubiquitin pathway in
regulating cell-cycle control, chromosome segregation, and
apoptosis provides a venue for addressing aneuploidy and underlies
the current interest in the use of proteasome inhibitors as
chemotherapeutic agents.
[Back to top]
Cyanopeptides: A New and Nearly Inexhaustible Natural
Resource for the Design and Structure-Activity Relationship
Studies of New Inhibitors of Trypsin-like Serine Proteases
G. Radau
As shown in several screenings, cyanobacteria (blue-green
algae) are sources of very interesting metabolites, many of
which possess significant biological activities [1]. Cyanopeptides,
as a rule, metabolites of a peptidic nature, show in addition
to hepato- and neurotoxic properties, a broad spectrum of
biological activities, including antitumour [2], immunosuppressive
[3] and antimicrobial effects [4], as well as angiotensin-converting
enzyme inhibitory action [5] and cardioactive effects [6].
Many of the isolated, non-toxic compounds inhibit serine
proteases, which play a central role in the human organism.
Trypsin-like serine proteases (e.g. thrombin, plasmin, factor
Xa, t-PA, or tryptase) are the leading factors in blood coagulation,
fibrinolysis, kinin-kallikrein and complement systems as well
as in inflammatory processes. Both the kinin-kallikrein and
complement systems are thought to be closely related to inflammation
and immune reactions. Failures of one or more of these enzymes
may cause a state of imbalance between protease and antiprotease
(endogenous protease inhibitors) and may lead to an excess
of proteolytic activity and to the development of diseases
such as thrombosis, heart failures, further thromboembolic
events, asthma, multiple sclerosis and pancreatitis. The discovery
and development of oral inhibitors of the above mentioned
enzymes therefore presents a notable measure for improving
the treatment of these disorders and remains a challenge for
each medicinal chemist.
This paper reviews the low-molecular weight, serine protease
inhibitory cyanopeptides published over the last decade and
reports on actual efforts and developments in establishing
structure-activity relationships concerning the inhibition
of trypsin-like serine proteases.
[Back to top]
Lipoxygenases (LOs): An Heterogenous Family of Lipid
Peroxidizing Enzymes Implicated in Cell Differentiation, Inflammation,
Asthma, Carcinogenesis, Atherogenesis-An Interesting Target
for the Development of Promising Drugs
E. Pontiki & D. Hadjipavlou–Litina
Lipoxygenases (LOs) constitute a family of dioxygenases
containing one non-heme iron atom per molecule, which oscillates
between Fe2+ (inactive enzyme) and Fe3+
(active form) during the catalytic cycle. They catalyze the
oxygenation of polyunsaturated fatty acids containing a (1Z,
4Z)-penta-1,4-diene system to the corresponding hydroxyperoxy
derivatives. Arachidonic acid, which contains four double
bonds in its configuration, is metabolised via lipoxygenases
to a number of products with the hydroperoxy group in different
positions. The LOs family includes several members which have
been identified according the recommendations of the nomenclature
committee of the international union of biochemistry and molecular
biology on the nomenclature and classification of the enzymes
by inserting oxygen into the 5-, 8-, 9-, 11-, 12- and 15-
positions of fatty acids with varying stereoconfiguration
(S or R). Four of these (5-LOs, 8-LOs, 12-LOs,
15-LOs) have been discovered in mammals to date. Although
the cyclooxygenases could be considered specialized in the
arachidonate pathway, the detailed mechanism of the LO reaction
still remains controversial.
It has been found that LOs are implicated in several processes
such as cell differentiation, inflammation, carcinogenesis.
Development of drugs that interfere with the formation or
effects of these metabolites would be important for the treatment
of various diseases like asthma, psoriasis, ulcerative colitis,
rheumatoid arthritis, atherosclerosis, cancer and blood vessel
disorders. Asthma consists the only pathological case in which
improvement has been shown by LO inhibitors.
The most widely studied isoform of the enzyme is 5-LO, which
is involved in the biosynthesis of potent inflammatory mediators.
Accordingly research efforts have been directed towards the
development of drugs that interfere with the formation of
leukotrienes. Zileuton (Zyflo) is the only 5-LO inhibitor
on the market in the USA for the treatment of asthma.
[Back to top]
Pathogenesis of Diabetic Retinopathy and Diabetic
Macular Edema and Enzyme Inhibition
Hideharu Funatsu & Hidetoshi Yamashita
Diabetic retinopathy and diabetic macular edema (DME) remain
important causes of visual loss worldwide despite the adoption
of intensive glycemic control for the management of diabetes.
Several interacting and mutually perpetuating abnormal biochemical
systems, such as non-enzymatic glycation, protein kinase C
(PKC) β
activation, the polyol pathway, and oxidative stress, may
be activated by sustained hyperglycemia in patients with diabetes.
These abnormal systems may in turn influence several vasoactive
factors, which are probably instrumental in the development
of functional and morphological changes in the retina. Among
the known vasoactive factors, vascular endothelial growth
factor (VEGF), angiotensin II, and interleukin-6, are thought
to be important in mediating the functional and structural
alterations that occur in diabetic retinopathy and DME. Complex
and interacting regulatory mechanisms, as well as enzyme inhibition,
which are included advanced glycation end product inhibitor,
PKC β
inhibitor, aldose reductase inhibitor, antioxidant, angiotensin
converting enzyme inhibitor, angiotensin II type 1 receptor
blocker, and anti-VEGF, may modulate the ability of these
molecules to produce biologically significant effects. Better
understanding of these factors and their interactions should
be of assistance in the development of new therapies for the
treatment of diabetic retinopathy and DME.
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