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.