Current
Chemical Biology
ISSN: 1872-3136
Current
Chemical Biology
Volume 1, Number 1, January 2007
Contents
Editorial Pp. 1
[Editorial
in PDF]
New Emergent Nanotechnologies in Medical and Biochemical
Applications: Advanced Fluorescence Protein-Based Nanosensors
Pp. 3-9
Maria Staiano, Marcella de Champdoré, Stefano Borini,
Andrea M. Rossi, Mosè Rossi and Sabato D’Auria
[Abstract] [Full
Text Article]
Supramolecularly Organized Lanthanide Complexes for
Efficient Metal Excitation and Luminescence as Sensors in
Organic and Biological Applications Pp. 11-39
Ernesto Brunet, Olga Juanes and Juan C. Rodriguez-Ubis
[Abstract] [Full
Text Article]
Possible Origins of Biohomochirality Pp.
41-52
Daniel Fitz, Hannes Reiner, Kristof Plankensteiner and
Bernd Michael Rode
[Abstract] [Full
Text Article]
Energy Utilization, Catalysis and Evolution-Emergent
Properties of Life Pp. 53-57
Abraham Szoke, David van der Spoel and Janos Hajdu
[Abstract] [Full
Text Article]
Folding, Assembly, and Stability of Transmembrane
Cytochromes Pp. 59-74
Hans-Georg Koch and Dirk Schneider
[Abstract] [Full
Text Article]
Structure, Substrate Complexation and Reaction Mechanism
of Bacterial Asparaginases Pp. 75-86
Mario Sanches, Sandra Krauchenco and Igor Polikarpov
[Abstract] [Full
Text Article]
Store-Operated Ca2+ Entry in Muscle Physiology
Pp. 87-95
Marco Brotto, Noah Weisleder and Jianjie Ma
[Abstract] [Full
Text Article]
Synthesis of Poison-Frog Alkaloids and Their Pharmacological
Effects at Neuronal Nicotinic Acetylcholine Receptors
Pp. 97-114
Naoki Toyooka, Hiroshi Tsuneki, Soushi Kobayashi, Zhou
Dejun, Masashi Kawasaki, Ikuko Kimura, Toshiyasu Sasaoka and
Hideo Nemoto
[Abstract] [Full
Text Article]
Properties and Architecture of Drugs and Natural
Products Revisited Pp. 115-127
Kristina Grabowski and Gisbert Schneider
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Editorial
[Editorial in PDF]
Current Chemical Biology represents an exciting new journal
which will publish full-length and mini reviews on recent
developments at the chemistry-biology interface. It will cover
a wide range of topics relating to the synthesis of biologically
important molecules including macromolecules such as proteins,
polypeptides, oligonucleotides, oligosaccharides etc. It will
also include areas such as asymmetric synthesis, combinatorial
synthesis and biomimetic synthesis. The reviews focusing on
science at the chemistry-biology interface will include such
fields as chemical informatics, macromolecular biosynthesis,
receptor chemistry and cell signaling chemistry. Reviews are
also to be published on chemical mechanisms of biological
systems, including mechanisms of drug design, molecular recognition,
enzyme inhibition mechanisms, chemical mechanisms of biological
functions, molecular machines and chemical ecology.
This inaugural issue of Current Chemical Biology
presents a number of reviews written by the leading experts
in their respective fields. These include reviews on metal
excitation and luminescence as sensors in organic and biological
applications, emergent nanotechnologies in medical and biochemical
applications, bacterial asparaginases, origins of biohomochirality,
folding assembly and stability of transmembrance cytochromes,
and energy utilization, catalysis and evolution — emergent
properties of life.
It is hoped that this journal will soon become a leading international
journal in this exciting area.
Atta-ur-Rahman, FRS
HEJ Research Institute of Chemistry
University of Karachi
Karachi-75270
Pakistan
E-mail: ccb@bentham.org
[Back to top]
New Emergent Nanotechnologies in Medical and Biochemical
Applications: Advanced Fluorescence Protein-Based Nanosensors
Maria Staiano, Marcella de Champdoré, Stefano Borini,
Andrea M. Rossi, Mosè Rossi and Sabato D’Auria
[Full
Text Article]
In this review we explore the advantages deriving from the
use of either enzymes or binding proteins to develop non-consuming
substrate fluorescence biosensors. We report on a novel approach
to address the consumption of substrate by enzyme-based biosensors,
namely the utilization of apo-enzymes as non-active forms
of proteins, which through still able to bind the ligand yet
cannot transform it into product. We also report recent studies
in which fluorescence labelling of a naturally thermostable
binding protein by a fluorescent probe allows a quantitative
monitoring of glucose. Finally, we will illustrate a novel
methodology based on the utilization of porous silicon chips
that allows a nanotechnological approach to the realization
of protein arrays for analyses of high medical and biochemical
interest.
[Back to top]
Supramolecularly Organized Lanthanide Complexes for
Efficient Metal Excitation and Luminescence as Sensors in
Organic and Biological Applications
Ernesto Brunet, Olga Juanes and Juan C. Rodriguez-Ubis
[Full
Text Article]
Using molecular shape for the functional control of multicomponent
systems is one of the challenges in the field of supramolecular
chemistry. The well-known emission in the visible region of
certain lanthanide (III) salts has found a new dimension by
the controlled assembly of supramolecular architectures to
enshroud and excite the metal. The emission properties of
these systems find applications as luminescent probes in sensing
schemes, interaction with biomolecules, or light conversion
systems.
Complexes of Tb(III) and Eu(III) can in some cases be highly
luminescent and typically exhibit emission lifetimes in the
millisecond range. These long lifetimes provide a facile means
to detect biomolecules labeled with lanthanide from the short-lived
background emission of biosystems.
The strongly ionic nature of the bonding in solid lanthanide
complexes results in coordination geometries that reveal a
balance between electrostatic and steric demands. The inclusion
of lanthanide guests into macrocycles, cryptands, cavitands
and spherands had the purpose of shielding the metals from
solvent molecules whose OH, NH or CH groups are able to heavily
quench lanthanide luminescence (intensity and lifetime) by
deactivation of their emissive levels by vibronic coupling.
The literature on the various chemical systems, based on nitrogen
heteroaromatic rings, used to sensitize lanthanides will be
thoroughly reviewed including those molecules synthesized
by the authors which displayed high quantum yield of lanthanide
emission.
[Back to top]
Possible Origins of Biohomochirality
Daniel Fitz, Hannes Reiner, Kristof Plankensteiner and
Bernd Michael Rode
[Full Text Article]
The origin of biohomochirality and the reasons, why this form
of homochirality (L-amino acids, D-sugars, etc.) and not the
mirror image case was preferred have been the subject of numerous
hypotheses, but a definitive solution to this riddle that
might be strongly correlated with the origin of life itself
has not been found to date.
In this paper different pathways trying to explain the origin
of biohomochirality are reviewed, inter alia the chance hypothesis,
spontaneous resolution mechanisms, preferential adsorption
on chiral surfaces, the interaction of interstellar organic
dust clouds with circularly polarised light and subsequent
transport to earth via meteorites, and a possible preference
for one enantiomeric form due to parity violation in weak
nuclear interactions.
In the Salt-Induced Peptide Formation (SIPF) reaction a preference
for the L-form of several amino acids was observed. The active
complex in this reaction contains a central copper ion which,
due to its high atomic number, provides larger parity violating
energy differences (PVED's). In combination with the geometry
of this complex that features a central chirality at this
copper ion and further chiral influence through chiral amino
acid ligands a completely new aspect to explain biohomochirality
is presented.
[Back to top]
Energy Utilization, Catalysis and Evolution-Emergent
Properties of Life
Abraham Szoke, David van der Spoel and Janos Hajdu
[Full Text Article]
Life is fueled by available energy. In fact, life is organized
around the utilization of available energy, either from photons
or from chemicals. The basic architecture of life can be understood
from the following propositions: catalysts are able to control
the path of chemical reactions and influence their rate by
transient and reversible exchange of high-grade energy between
themselves and reactants, while conserving the total energy.
That, in turn, enables the synthesis of essential chemicals
as well as the duplication of templates. We argue in this
paper that energy utilization and evolution are emergent properties
in life that are based on a small number of well-established
laws of physics and chemistry governing catalysis. We propose
that the relevant laws constitute a framework for biology
on a level intermediate between quantum chemistry and cell
biology.
[Back to top]
Folding, Assembly, and Stability of Transmembrane
Cytochromes
Hans-Georg Koch and Dirk Schneider
[Full Text Article]
Heme cofactors of transmembrane cytochromes are crucial for
mediating charge transfer across membranes during aerobic
and anaerobic electron transport reactions. In addition, several
in vivo observations indicate that heme cofactors
directly or indirectly impact the folding, assembly, and stability
of individual transmembrane cytochromes and also of oligomeric
cytochrome complexes. In this article, we review the function
of heme molecules for the formation of transmembrane cytochromes
in vivo and in vitro, and discuss distinct
steps during the assembly of cytochromes and cytochrome complexes.
We furthermore highlight the need of in vitro studies
using isolated apo-cytochromes for analyzing the role of the
heme cofactor for folding and stability of single proteins
or larger cytochrome complexes. In combination with in
vivo studies, this approach holds the potential to obtain
a comprehensive picture on how binding of the heme co-factor
to its apoprotein determines not only the biological function
of a heme protein but also its three-dimensional structure.
[Back to top]
Structure, Substrate Complexation and Reaction Mechanism
of Bacterial Asparaginases
Mario Sanches, Sandra Krauchenco and Igor Polikarpov
[Full Text Article]
Asparaginases and glutaminases are enzymes that catalyze the
hydrolysis of asparagine or glutamine to the correspondent
acid and ammonia. Based on their biochemical properties and
sequence homology, this group of proteins, common to various
organisms, can be divided into three families: bacterial asparaginases,
plant asparaginases and enzymes similar to Rhizobium etli
asparaginase. Bacterial L-asparaginases can be further subdivided
into two types: type I, which are expressed constitutively
and display enzymatic activity towards both L-asparagine and
L-glutamine, and type II, induced by anaerobic conditions,
which have high specific activity towards L-asparagine. Type
II L-asparaginases (e.g. E. coli L-asparaginase)
have been used in the treatment of acute lymphoblastic leukemia
for many years, but their medical applications are limited
by severe side effects and by the development of resistant
tumors in a fraction of the patients. In this paper we review
available structural and biochemical information on bacterial
L-asparaginases, and focus on a detailed mechanistic description
of their reaction mechanism, including the structural basis
for the preference of these enzymes for threonine residues
as the primary nucleophiles. The L-asparaginase enzymatic
mechanism involves two catalytic triads operating at distinct
steps of the reaction pathway. The first triad, Thr12-Tyr25-Glu283
(E. coli asparaginase numbering), acts during the
acylation step starting with a nucleophilic attack of the
primary nucleophile (Thr12) on the substrate, which results
in an intermediate covalently bound to the enzyme. The second
triad, Thr89-Lys162-Asp90, acts by activating a water molecule,
which releases the product through a second nucleophilic attack.
A detailed comprehension of the enzymatic mechanism of these
bacterial enzymes in structural terms might open the way to
design modified L-asparaginases with improved biomedical and
biotechnological properties.
[Back to top]
Store-Operated Ca2+ Entry in Muscle Physiology
Marco Brotto, Noah Weisleder and Jianjie Ma
[Full Text Article]
Store-operated Ca2+ entry (SOCE) represents a unique
Ca2+ entry mechanism, where Ca2+ channels
located on the plasma membrane sense the Ca2+ filling
status of intracellular Ca2+ stores and gate the
entry of Ca2+ from the extracellular reservoir
to replenish intracellular Ca2+ storage. This pathway
has received great interest not only because of its unusual
nature as a retrograde signal, but also due to its wide occurrence
in both excitable and non-excitable cells and its potential
role in various physiological and pathophysiological situations.
In skeletal muscle, contractility is contingent upon the maintenance
of intracellular Ca2+ homeostasis, which requires
the preservation of low levels of resting cytosolic Ca 2+
, readily available releasable pool of Ca2+ from
the sarcoplasmic reticulum, as well as functional Ca2+
uptake and extrusion mechanisms. Recent studies have demonstrated
that SOCE is present in skeletal muscle, and may play a significant
role in muscle physiology. While the need for SOCE is increased
during strenuous muscle exercise and fatigue, disruption of
this process can lead to pathophysiological conditions. Repressed
SOCE activity has been linked to aging related dysfunction.
Elevated SOCE could lead to elevated intracellular Ca2+
in dystrophic muscle cells and progression of muscular dystrophy.
The role of SOCE in the physiology and pathophysiology of
skeletal muscle is a subject of increasing interest in the
muscle biology field. Manipulation of SOCE by chemical, pharmacological
and genetic approaches should have great potential in the
treatment of muscle disorders that involve dysfunctional Ca2+
homeostasis.
[Back to top]
Synthesis of Poison-Frog Alkaloids and Their Pharmacological
Effects at Neuronal Nicotinic Acetylcholine Receptors
Naoki Toyooka, Hiroshi Tsuneki, Soushi Kobayashi, Zhou
Dejun, Masashi Kawasaki, Ikuko Kimura, Toshiyasu Sasaoka and
Hideo Nemoto
[Full
Text Article]
The flexible and efficient enantioselective synthesis of poison-frog
alkaloids has been described using the highly stereoselective
conjugate addition reactions as the key step. Several 5,8-disubstituted
indolizidines and 1,4-disubstituted quinolizidines have been
synthesized according to this strategy. Furthermore, 5,6,8-trisubstituted
indolizidne type of poison-frog alkaloid 223A
and unique tricyclic poison-frog alkaloid 205B
have also been synthesized by sequential use of the above
key conjugate addition reaction. Investigations of inhibitory
effects of synthetic poison-frog alkaloids on neuronal nicotinic
acetylcholine receptors have been conducted, and we found
that most of the synthetic compounds showed inhibitory effects
on the neuronal nicotinic acetylcholine receptors. Especially,
the 5,8-disubstituted indolizidine 235B'
inhibited the α4β2-neuronal
nicotinic acetylcholine receptors in highly subtype-selective
manner. These results suggested that the synthetic alkaloid
235B' is a promising lead compound for the
drugs designed to treat cholinergic disorders such as autosomal
dominant nocturnal frontal lobe epilepsy (ADNFLE).
[Back to top]
Properties and Architecture of Drugs and Natural
Products Revisited
Kristina Grabowski and Gisbert Schneider
[Full Text Article]
Computer-based analysis revealed that natural products exhibit
a remarkable structural diversity of molecular frameworks
and scaffolds that could be systematically exploited for combinatorial
synthesis. Natural products offer a rich pool of unique molecular
frameworks that complement “drug space”. They
possess desirable druglike properties rendering them ideal
starting points for molecular design considerations. This
review provides an overview of chemotype diversity and molecular
properties of collections of drugs and druglike molecules,
pure natural products, and natural product-derived compounds.
Compared to druglike molecules, pure natural products contain
more oxygen atoms and chiral centers, and have less aromatic
atoms on average. Among the natural product library we identified
more than one thousand scaffolds that were not contained in
any other compound set analyzed. This outcome provides a basis
for the design of new natural product-derived compound libraries.
Our study demonstrates that computational chemical biology
can assist in finding suitable molecular entities in collections
of natural products for drug discovery.
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