Prediction of the secondary structure of proteins from their amino acid sequence.

Publisher Summary Turns are a fundamental class of polypeptide structure and are defined as sites where the peptide chain reverses its overall direction. In the past 20 years, the peptide field has witnessed major development, stimulated by the discovery of a host of bioactive peptides. Turn structures have been proposed and implicated in the bioactivity of several of these naturally occurring peptides. In addition, many structural details of turns have been derived from conformational studies of model peptides. During this same period, more than 100 complete protein structures have been elucidated in single-crystal X-ray studies. These examples document the rich diversity of structural patterns in the chain folds of native proteins. Turns are intrinsically polar structures with backbone groups that pack together closely and side chains that project outward. Such an array of atoms may constitute a site for molecular recognition, and indeed, the literature abounds with suggestions that turns serve as loci for receptor binding, antibody recognition, and post-translational modification. In peptides, turns are the conformations of choice for simultaneously optimizing both backbone–chain compactness (intramolecular nonbonded contacts) and side-chain clustering (to facilitate intermolecular recognition). Presence of turns in bioactive conformations may in fact also reflect the lack of alternative conformational possibilities. The aim of this chapter is to examine structural and functional roles of turns in peptides and proteins.

Turns in peptides and proteins.

The chemistry of copper is extremely rich because it can easily access Cu0, CuI, CuII, and CuIII oxidation states allowing it to act through one-electron or two-electron processes. As a result, both radical pathways and powerful two-electron bond forming pathways via organmetallic intermediates, similar to those of palladium, can occur. In addition, the different oxidation states of copper associate well with a large number of different functional groups via Lewis acid interactions or π-coordination. In total, these feature confer a remarkably broad range of activities allowing copper to catalyze the oxidation and oxidative union of many substrates.

Oxygen is a highly atom economical, environmentally benign, and abundant oxidant, which makes it ideal in many ways.1 The high activation energies in the reactions of oxygen require that catalysts be employed.2 In combination with molecular oxygen, the chemistry of copper catalysis increases exponentially since oxygen can act as either a sink for electrons (oxidase activity) and/or as a source of oxygen atoms that are incorporated into the product (oxygenase activity). The oxidation of copper with oxygen is a facile process allowing catalytic turnover in net oxidative processes and ready access to the higher CuIII oxidation state, which enables a range of powerful transformations including two-electron reductive elimination to CuI. Molecular oxygen is also not hampered by toxic byproducts, being either reduced to water, occasionally via H2O2 (oxidase activity) or incorporated into the target structure with high atom economy (oxygenase activity). Such oxidations using oxygen or air (21% oxygen) have been employed safely in numerous commodity chemical continuous and batch processes.3

However, batch reactors employing volatile hydrocarbon solvents require that oxygen concentrations be kept low in the head space (typically <5–11%) to avoid flammable mixtures, which can limit the oxygen concentration in the reaction mixture.4,5,6 A number of alternate approaches have been developed allowing oxidation chemistry to be used safely across a broader array of conditions. For example, use of carbon dioxide instead of nitrogen as a diluent leads to reduced flammability.5 Alternately, water can be added to moderate the flammability allowing even pure oxygen to be employed.6 New reactor designs also allow pure oxygen to be used instead of diluted oxygen by maintaining gas bubbles in the solvent, which greatly improves reaction rates and prevents the build up of higher concentrations of oxygen in the head space.4a,7 Supercritical carbon dioxide has been found to be advantageous as a solvent due its chemical inertness towards oxidizing agents and its complete miscibility with oxygen or air over a wide range of temperatures.8 An number of flow technologies9 including flow reactors,10 capillary flow reactors,11 microchannel/microstructure structure reactors,12 and membrane reactors13 limit the amount of or afford separation of hydrocarbon/oxygen vapor phase thereby reducing the potential for explosions.

Enzymatic oxidizing systems based upon copper that exploit the many advantages and unique aspects of copper as a catalyst and oxygen as an oxidant as described in the preceding paragraphs are well known. They represent a powerful set of catalysts able to direct beautiful redox chemistry in a highly site-selective and stereoselective manner on simple as well as highly functionalized molecules. This ability has inspired organic chemists to discover small molecule catalysts that can emulate such processes. In addition, copper has been recognized as a powerful catalyst in several industrial processes (e.g. phenol polymerization, Glaser-Hay alkyne coupling) stimulating the study of the fundamental reaction steps and the organometallic copper intermediates. These studies have inspiried the development of nonenzymatic copper catalysts. For these reasons, the study of copper catalysis using molecular oxygen has undergone explosive growth, from 30 citations per year in the 1980s to over 300 citations per year in the 2000s.

A number of elegant reviews on the subject of catalytic copper oxidation chemistry have appeared. Most recently, reviews provide selected coverage of copper catalysts14 or a discussion of their use in the aerobic functionalization of C–H bonds.15 Other recent reviews cover copper and other metal catalysts with a range of oxidants, including oxygen, but several reaction types are not covered.16 Several other works provide a valuable overview of earlier efforts in the field.17 This review comprehensively covers copper catalyzed oxidation chemistry using oxygen as the oxidant up through 2011. Stoichiometric reactions with copper are discussed, as necessary, to put the development of the catalytic processes in context. Mixed metal systems utilizing copper, such as palladium catalyzed Wacker processes, are not included here. Decomposition reactions involving copper/oxygen and model systems of copper enzymes are not discussed exhaustively. To facilitate analysis of the reactions under discussion, the current mechanistic hypothesis is provided for each reaction. As our understanding of the basic chemical steps involving copper improve, it is expected that many of these mechanisms will evolve accordingly.

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Aerobic Copper-Catalyzed Organic Reactions

Opiate drugs have potent analgesic and addictive properties. These drugs interact with receptors that also mediate the response to endogenous opioid peptide ligands. However, the receptors for opioids have eluded definitive molecular characterization. By transient expression in COS cells and screening with an iodinated analog of the opioid peptide enkephalin, a complementary DNA clone encoding a functional delta opioid receptor has been identified. The sequence shows homology to G protein-coupled receptors, in particular the receptors for somatostatin, angiotensin, and interleukin-8.

Cloning of a delta opioid receptor by functional expression

THIS REVIEW will deal with the biosynthesis of many of the members of the ACTH/lipotropin (LPH) family of peptides (Fig. 1). Peptides in this family fall into two groups: peptides related to ACTH include α-melanotropin (αMSH) and corticotropin-like intermediate lobe peptide (CLIP); peptides related to βLPH include γLPH, βMSH, and β-endorphin. In several species ACTH and βLPH each contain an identical heptapeptide segment located in the region of the molecule that is responsible for melanotropic bioactivity (1, 2). In this review we have taken a somewhat historical approach, and will therefore begin with a discussion of the biosynthesis of ACTH and the characterization of biosynthetic precursors to ACTH. When this work began, βLPH, γLPH, and βMSH were well-characterized pituitary peptides, but the opioid peptides (and β-endorphin in particular) had not yet been identified (3–5). Studies on the biosynthesis of ACTH were heavily influenced by prior work defining the biosynthetic pathways for insulin and para...

Structure and Biosynthesis of Pro-Adrenocorticotropin/Endorphin and Related Peptides*

The amino acid sequences of peptide hormones that terminate in an α-amide group seem usually to be followed by glycine in the sequence of their precursor molecules. Thus it has long been known that the sequence of α-melanotropin, which terminates in Lys-Pro-Val-CONH2 (ref. 1), occurs adjacent to glycine in the sequence of corticotropin2 and more recently it has been shown that the peptide hormone mellitin, which terminates in glutamine amide3, is synthesized as a prohormone that terminates in glutaminyl-glycine4. A similar relationship is suggested by comparison of the primary structures of adipokinetic hormone5 and red pigment-concentrating hormone6. These observations indicate that biosynthesis of the C-terminal amide may involve the action of a specific enzyme which has a requirement for C-terminal glycine. We present here direct evidence that porcine pituitary contains an enzyme with the ability to convert peptides that terminate in glycine to the corresponding des-glycine peptide amide. We have investigated the substrate specificity of the enzyme and with the aid of isotopic labelling have demonstrated that its mechanism of action involves dehydrogenation and hydrolysis of the glycine-containing substrate.

Mechanism of C-terminal amide formation by pituitary enzymes

RECENT reports have shown that the brain contains an endogenous peptide with opiate-like activity1–3 and similar peptides have been found in the pituitary4,5,13. One of the brain peptides, known as methionine enkephalin, was identified as a pentapeptide Tyr–Gly–Gly–Phe–Met6, and evidence was presented that a minor component may have leucine in place of methionine. The principal sequence is identical to that at the NH2-terminus of lipotropin C fragment, a peptide discovered in substantial quantity in porcine pituitary7,8. This suggests that methionine enkephalin is derived in vio by proteolytic cleavage of C fragment. Since enkephalin is thought to compete directly with opiates for the brain opiate receptor, while having no primary structure similarity to opiates, we have searched for and found a basis for the competition in a proposed secondary structure for the peptide.

A.F. Bradbury

Papers

Mechanism of C-terminal amide formation by pituitary enzymes

Biosynthetic origin and receptor conformation of methionine enkephalin.

Lipotropin: precursor to two biologically active peptides.

Substrate specificity of an amidating enzyme in porcine pituitary.

Comparison of the analgesic properties of lipotropin C-Fragment and stabilized enkephalins in the rat