Current Chemical Biology

ISSN: 1872-3136

Current Chemical Biology
Volume 2, Number 2, May 2008

Contents


Prolyl-Specific Peptidases and Their Inhibitors in Biological Processes Pp. 97-109
Lucienne Juillerat-Je
[Abstract]


Peptide Nucleic Acids: A Novel Approach Pp. 110-121
Nitendra Sahu, Gyati Shilakari, Amit Nayak and Dharm Veer Kohli
[Abstract]


Synthesis of Polynuclear Complexes with an Amino Acid or Peptide as a Bridging Ligand Pp. 122-139
Takashi Komiyama, Satoshi Igarashi and Yasuhiko Yukawa
[Abstract]


Rationalizing the Study of Plants for the Treatment of Ora Pain Pp. 140-152
Michael D. Colvard and Geoffrey A. Cordell
[Abstract]


Cause of Chirality Consensus Pp. 153-158
Salla Jaakkola, Vivek Sharma and Arto Annila
[Abstract]


An Integrated Look at Metallonuclease Mechanism Pp. 159-173
Cynthia M. Dupureur
[Abstract]


Phytochemical Studies and Biological Activity of Teucrium pilosum Pp. 174-177
Usama W. Hawas, Mohamed Sharaf and Mohamed A. El-Ansari
[Abstract]


New Frontiers in Hydrogenase Structure and Biosynthesis Pp. 178-199
Matthew C. Posewitz, David W. Mulder and John W. Peters
[Abstract]




Abstracts


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Prolyl-Specific Peptidases and Their Inhibitors in Biologica Processes
Lucienne Juillerat-Jeanneret

Proteases are major targets to treat human diseases. Many biologically active peptides are protected from general proteolytic degradation by evolutionary conserved prolines (Pro), due to conformational constraints imposed by the Pro residue, pointing to the biological importance and a high potential for drug discovery of prolyl-specific peptidases. Of the known human proteases only a few Pro-specific proteases have been described which include exopeptidases and endopeptidases. Dipeptidylpeptidase IV (DPP IV)/CD26, DPP8, DPP9 and fibroblast activation protein-α (FAP-α) /seprase are able to release X-Pro dipeptides from the N-terminus of peptides. DPP8 and FAP-α are also capable of prolyl-specific endoproteolytic activity. Prolyl oligopeptidase (POP) is a post-prolyl-cleaving endopeptidase. Several families of inhibitors have been synthesized and evaluated on purified enzymes and their effects determined in a few biological models, suggesting the inhibition of families of enzymes with similar activities. DPP IV inhibitors are under clinical evaluation for type 2 diabetes. Inhibitors of POP-like activities ameliorate cognitive functions in animal models and may be protective and/or therapeutic in neurodegenerative disorders. In this review, the expression of prolyl-specific enzymes in mammalians is reviewed, their potential functions and their enzymatic and biological characteristics, as well as the inhibitors developed for these enzymes, are discussed.


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Peptide Nucleic Acids: A Novel Approach
Nitendra Sahu, Gyati Shilakari, Amit Nayak and Dharm Veer Kohli

Peptide nucleic acid (PNA), an oligonucleotide mimic, has a non-charged achiral polyamide backbone to which the nucleobases are attached. This structure gives PNAs the capacity to hybridize with high affinity and specificity to complementary sequences of DNA and RNA and also confers remarkable resistance to DNAses and proteinases. PNAs can be conveniently delivered into cells in complex with DNA and cationic lipid. However, as with other high molecular mass drugs, the delivery of PNA, involving passage through the cell membrane, appears to be a general problem. New chemical modifications of the original PNA backbone may contribute to increasing the potentialities of PNAs and lead to the development of novel applications and PNA-dependent projects in many areas of biology and therapy. The unique physico-chemical characteristics of PNAs have led to the development of a wide range of research and diagnostic assays. Studies indicate that PNA is capable of inhibiting transcription as well as translation, so it can be used as a new tool for antigene and antisense therapy. Due to its superior properties, PNA could replace DNA as a probe for many investigation purposes. This review discusses the synthesis, chemical modifications of PNA, its important properties, cellular delivery and its major applications.


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Synthesis of Polynuclear Complexes with an Amino Acid or a Peptide as a Bridging Ligand
Takashi Komiyama, Satoshi Igarashi and Yasuhiko Yukawa

Metal complexes of amino acids or small peptides interest biochemists. Some studies about their structures have therefore been carried out on the assumption that such complexes will act as models for the metal-binding sites on proteins. From the point of view of coordination chemistry, an amino acid can be regarded as a typical multidentate ligand which has different ligating atoms, a nitrogen atom of an amino group and an oxygen atom of a carboxyl group. The different ligating atoms can be coordinated to different metal ions such as metals having different hardness. The advantages of amino acid of being able to form a chelate ring and/or be coordinated to different metals can be used to synthesize heteronuclear and/or polynuclear complexes. Such syntheses of heteronuclear and/or polynuclear complexes continue to be an intensive and challenging area of investigation. In this article, some examples of polynuclear complexes with amino acids or peptides as a bridging ligand will be introduced and the possibility of using amino acidato complexes as potential building blocks in the formation of more complicated polynuclear arrays will be explored.


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Rationalizing the Study of Plants for the Treatment of Oral Pain
Michael D. Colvard and Geoffrey A. Cordell

Oral and maxillofacial pain, inflammation, and associated pathologies have been documented since the beginning of recorded human history, and the use of plant materials from certain families for the relief of these disorders has paralleled this health care need. Humans discovered, through personal experimentation, that numerous plants and plant-based products placed into the oral cavity had the capacity to deliver diverse secondary metabolites and thereby elicit a variety of stimulant, medicinal, and hallucinogenic effects. Recent pharmacognostic research has confirmed the presence of medicinal compounds in several of these plants. Contemporary neurobiological and pathophysiologic research has illuminated the mechanisms and actions of numerous tissues, cell structures, TRP channels, mammalian peripheral and CNS receptors, actions responsive to plant-based and other natural compounds. Consequently, theories have emerged that propose a co-evolutionary relationship and functionality between natural products and the various mammalian cell membrane channels, receptors, and tissues.

In this brief review, we will indicate some of the background relating to the contemporary views of the use of various plant-based products as analgesic and anesthetic agents for oral pain and inflammations and briefly discuss their mechanisms of action. An overview of the need for new, plant-based oral analgesic agents and for new experimental models for the discovery process from plant extracts will be described and some discussion will be offered regarding the potential for future research developments in this area of pharmacognosy.


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Cause of Chirality Consensus
Salla Jaakkola, Vivek Sharma and Arto Annila

Biological macromolecules, proteins and nucleic acids are composed exclusively of chirally pure monomers. The chirality consensus appears vital for life and it has even been considered as a prerequisite of life. However the primary cause for the ubiquitous handedness has remained obscure. We propose that the chirality consensus is a kinetic consequence that follows from the principle of increasing entropy, i.e. the 2^nd law of thermodynamics. Entropy increases when an open system evolves by decreasing gradients in free energy with more and more efficient mechanisms of energy transduction. The rate of entropy increase is the universal fitness criterion of natural selection that favors diverse functional molecules and drives the system to the chirality consensus to attain and maintain high-entropy non-equilibrium states.


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An Integrated Look at Metallonuclease Mechanism
Cynthia M. Dupureur

Metal-dependent nucleases are hydrolytic enzymes which perform phosphodiester cleavage of RNA and DNA. An entire host of nucleic acid enzymes possess this function, ranging from restriction enzymes and ribozymes to enzymes involved in DNA repair and recombination. While the advantages of metal ion-dependent mechanisms are often clear, exactly how these metal ions contribute to this reaction remains actively debated. The ways in which systems are both different and similar can provide important clues regarding mechanistic requirements. To this end, this review will examine current issues in this area within the broad context of protein and nucleic acid catalysts. These include important bioinorganic properties of metal ion cofactors, theories of nucleophile activation, the one vs multiple metal ion mechanism debate, metal ion movement during catalysis, and the coupling between conformation and catalysis. Approaches to these issues began with mutagenesis and x-ray crystallography, both of which have been used to identify important structural features. Recently, more interdisciplinary approaches have evolved. Quantitative thermodynamic studies of both metal ion and DNA binding have been invaluable to the discussion of proposed mechanisms. In a number of systems, a wide variety of spectroscopic, kinetic, and computational analyses are being increasingly utilized.


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Phytochemical Studies and Biological Activity of Teucrium pilosum
Usama W. Hawas, Mohamed Sharaf and Mohamed A. El-Ansari

Vicenine-2, cirsimaritin, salvigenin, diosmetin, desmethoxycentaureidin, 6-methoxy-luteolin 7,3´,4´-trimethylether, apigenin and luteolin, eight flavonoids were isolated for the first time from the aqueous methanolic extract of the aerial parts of Teucrium pilosum, The structures were established on the basis of chemical and spectroscopic (UV, ¹ H-, ¹³ C-NMR) analyses. Biological activity was studied using agar diffusion and cytotoxicity tests.


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New Frontiers in Hydrogenase Structure and Biosynthesis
Matthew C. Posewitz, David W. Mulder and John W. Peters

The [NiFe]- and [FeFe]- hydrogenases have convergently evolved to efficiently catalyze the reversible oxidation of molecular H_². Extensive research efforts are currently aimed at using these enzymes to generate H₂ for use as a renewable energy carrier, and at using these enzymes as a platinum substitute in fuel cells. Hydrogenases are found in taxonomically diverse microorganisms and function to either couple H₂ oxidation to energy yielding processes or reduce protons as a mechanism to recycle reduced electron carriers that accumulate during fermentation. Microbial genome sequencing continues to demonstrate the ubiquitous occurrence and diversity of the hydrogenases. In recent years, significant strides have been made in elucidating the structure, catalytic properties, spectroscopic characteristics, and assembly of these intriguing enzymes. The [NiFe]- and [FeFe]- hydrogenases differ in active site composition and structural polypeptides but are unified by the presence of CN- and CO as ligands to the active site Fe atoms. These biologically unusual ligands are responsible for the unique electronic properties of the hydrogenase active site and are necessary to efficiently catalyze the reversible oxidation of H₂. Although the active sites of the [NiFe]- and [FeFe]- enzymes contain similar ligands, the assembly proteins for each class of enzyme are unique. Since the term hydrogenase was first coined over seventy years ago, substantial progress has been made in characterizing several enzymes. These data, combined with recent genomics data, are used to compare the unique chemical properties of distinct hydrogenase enzymes, as well as the novel chemistries required for active site synthesis.