Synthesis of Linear Oligomers of (<i>R</i>)‐3‐Hydroxybutyrate and Solid‐State Structural Investigations by electron microscopy and X‐ray scattering

Seebàch, Dieter; Bürger, H.; Müller, Hans‐Martin; Lengweiler, Urs D.; Beck, Albert K.; Sykes, Kathy; Barker, P. A.; Barham, Peter

doi:10.1002/hlca.19940770423

Cited by 61 publications

(33 citation statements)

References 41 publications

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“…6 ä; investigations into lamellar crystal of OHB [64] and PHB [64 ± 67] are also consistent with a 2 1 -helix structure of the ester chains (Fig. 3).…”

Section: Louis Pasteursupporting

confidence: 80%

“…The 3 14 -helix has been detected by NMR spectroscopy in solution with a bpeptide consisting of only six acyclic amino acids [75], and in g-peptides a chain length of a mere four amino acids appears to suffice for a solution helix structure to be detectable [234] [350 ± 352]. Helix stability thus increases with homologation of the amino acids, even though the number of possible conformations becomes larger with each homologation step, with the introduction of an additional CÀC bond, while, at the same time, the number of H-bonds 64 ) per atom in the chain decreases.…”

Section: Helices Of A- B- and G-peptides Made Of Homologues Of The mentioning

confidence: 99%

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The World of β‐ and γ‐Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components

Seebàch

Beck

Bierbaum

2004

Chemistry & Biodiversity

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926

562

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The origins of our nearly ten-year research program of chemical and biological investigations into peptides based on homologated proteinogenic amino acids are described. The road from the biopolymer poly[ethyl (R)-3-hydroxybutanoate] to the beta-peptides was primarily a step from organic synthesis methodology (the preparation of enantiomerically pure compounds (EPCs)) to supramolecular chemistry (higher-order structures maintained through non-covalent interactions). The performing of biochemical and biological tests on the beta- and gamma-peptides, which differ from natural peptides/proteins by a single or two additional CH(2) groups per amino acid, then led into bioorganic chemistry and medicinal chemistry. The individual chapters of this review article begin with descriptions of work on beta-amino acids, beta-peptides, and polymers (Nylon-3) that dates back to the 1960s, even to the times of Emil Fischer, but did not yield insights into structures or biological properties. The numerous, often highly physiologically active, or even toxic, natural products containing beta- and gamma-amino acid moieties are then presented. Chapters on the preparation of homologated amino acids with proteinogenic side chains, their coupling to provide the corresponding peptides, both in solution (including thioligation) and on the solid phase, their isolation by preparative HPLC, and their characterization by mass spectrometry (HR-MS and MS sequencing) follow. After that, their structures, predominantly determined by NMR spectroscopy in methanolic solution, are described: helices, pleated sheets, and turns, together with stack-, crankshaft-, paddlewheel-, and staircase-like patterns. The presence of the additional C--C bonds in the backbones of the new peptides did not give rise to a chaotic increase in their secondary structures as many protein specialists might have expected: while there are indeed more structure types than are observed in the alpha-peptide realm - three different helices (10/12-, 12-, and 14-helix) if we include oligomers of trans-2-aminocyclopentanecarboxylic acid, for example - the structures are already observable with chains made up of only four components, and, having now undergone a learning process, we are able to construct them by design. The structures of the shorter beta-peptides can also be reliably determined by molecular-dynamics calculations (in solution; GROMOS program package). Unlike in the case of the natural helices, these compounds' folding into secondary structures is not cooperative. In beta- and gamma-peptides, it is possible to introduce heteroatom substituents (such as halogen or OH) onto the backbones or to incorporate heteroatoms (NH, O) directly into the chain, and, thanks to this, it has been possible to study effects unobservable in the world of the alpha-peptides. Tests with proteolytic enzymes of all types (from mammals, microorganisms, yeasts) and in vivo examination (mice, rats, insects, plants) showed beta- and gamma-peptides to be completely stable towards proteolysis and, as ...

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“…6 ä; investigations into lamellar crystal of OHB [64] and PHB [64 ± 67] are also consistent with a 2 1 -helix structure of the ester chains (Fig. 3).…”

Section: Louis Pasteursupporting

confidence: 80%

Section: Helices Of A- B- and G-peptides Made Of Homologues Of The mentioning

confidence: 99%

The World of β‐ and γ‐Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components

Seebàch

Beck

Bierbaum

2004

Chemistry & Biodiversity

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926

562

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“…5A). Seebach et al (34,35) proposed that the PHB molecules are oriented as 2 1 -helices of 6 Å pitch, as determined for the bulk polymer by fiber x-ray scattering measurements (36-39), and fold in the same lamellar morphology as PHB crystallites (40). Each molecule of ca.…”

Section: Resultsmentioning

confidence: 99%

Proof for a nonproteinaceous calcium-selective channel in Escherichia coli by total synthesis from ( R )-3-hydroxybutanoic acid and inorganic polyphosphate

Das

Lengweiler

Seebàch

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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111

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Traditionally, the structure and properties of natural products have been determined by total synthesis and comparison with authentic samples. We have now applied this procedure to the first nonproteinaceous ion channel, isolated from bacterial plasma membranes, and consisting of a complex of poly(3-hydroxybutyrate) and calcium polyphosphate. To this end, we have now synthesized the 128-mer of hydroxybutanoic acid and prepared a complex with inorganic calcium polyphosphate (average 65-mer), which was incorporated into a planar lipid bilayer of synthetic phospholipids. We herewith present data that demonstrate unambiguously that the completely synthetic complex forms channels that are indistinguishable in their voltage-dependent conductance, in their selectivity for divalent cations, and in their blocking behavior (by La 3؉ ) from channels isolated from Escherichia coli. The implications of our finding for prebiotic chemistry, biochemistry, and biology are discussed.Synthetic and naturally occurring ion channels are amphiphilic structures with an outer coat of nonpolar residues and a lining of polar and charged residues (1-7). In this report, we demonstrate the formation of synthetic nonproteinaceous ion channels from two structurally distinct polymers that share the above attributes in a cooperative fashion. The polymers in question, poly(3-hydroxybutyrate) (PHB) and inorganic polyphosphate (polyP), are ubiquitous constituents of biological cells (8)(9)(10)(11)(12). PHB is an amphiphilic homopolymer of (R)-3-hydroxybutanoic acid, which in bacteria is synthesized from acetyl-CoA in three steps: dimerization to form acetoacetyl-CoA, reduction by NADPH to form 3-hydroxybutyrylCoA, and polymerization to form PHB (13,14). Under growth-limiting conditions, some bacteria produce highmolecular-mass PHB (60,000 to Ͼ1,000,000 Da) in amounts of up to 90% of the cell dry weight. PolyP, a polyanion composed of phosphate residues linked by anhydride bonds, is formed by repetitive phosphoryl transfer from ATP or other high-energy phosphates (15-17).Both PHB and polyP have molecular characteristics that are consistent with a role in ion conduction. PHB has salt-solvating properties that derive from the recurrence of electrondonating ester carbonyl oxygens at regular and frequent intervals along its flexible backbone (18,19). The solvating abilities of PHB are illustrated by studies that demonstrate its capacity to transport cations across methylene chloride layers in U-tubes (20), form ion-conducting complexes with lithium perchlorate (21), or large-conductance nonselective ion channels in planar lipid bilayers (22). PolyP has a flexible backbone and high density of monovalent negative charges that create a large capacity for ion exchange and a stronger affinity for multivalent over monovalent cations (23).Plasma membrane vesicles of Escherichia coli contain complexes of PHB and polyP that function as calcium-selective channels in planar lipid bilayers (24). In vivo, such channels may control the influx of calcium to ma...

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“…[17] [18]. It was our initial aim to look for complexation properties of these 3-HB oligomers with synthetic Ca'PP, in order to obtain a completely synthetic analog of the naturally occurring P(3-HB)/Ca.…”

Section: Introduction -Poly[(r)-3-hydroxybutanoate] (P(3-hb)mentioning

confidence: 99%

Channel‐Forming Activity of 3‐Hydroxybutanoic‐Acid Oligomers in Planar Lipid Bilayers

Seebàch¹,

Brunner

Büger

et al. 1996

Helvetica Chimica Acta

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Dedicated to Prof. Dr. Edgar Heilbronner on the occasion of his 75th birthday (30.X.95)Monodisperse and polydisperse oligomers and polymers of 3-hydroxybutanoic acid (3-HB) containing 8, 16, ca. 28,32, ca. 60,64,96, and ca. 3000 monomer units were incorporated into palmitoyl-oleoyl-phosphatidyl choline (POPC) planar bilayers. At concentrations of 0.1-5% of oligo(3-HB), the resulting phospholipid bilayers showed typical single-channel behavior for Rb+ and Ba2+ ions, using the patch clamp technique. Thus, channel-forming activity of a pure polyester has been demonstrated for the first time (Figs. I, 3, and 6 ) . Single-channel activity depends upon the following structural parameters of the 3-HB derivatives: unprotected OH and COOH groups on the chain ends; chain length 2 16 monomer units; no high-molecular-weight as in P(3-HB). The results are discussed in view of the Ca2+-specific channel formed with the P(3-HP)/Ca .PP, complex from genetically competent Escherichiu coli and in view of the ubiquitous occurrence of low-molecular-weight P(3-HB) in prokaryotic and eukaryotic organisms. A simple model for the channel-causing structure is proposed, based on the proven tendency of oligo-and poly(3-HB) to form ca. 50-8, thick lamellar crystallites.

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Synthesis of Linear Oligomers of (R)‐3‐Hydroxybutyrate and Solid‐State Structural Investigations by electron microscopy and X‐ray scattering

Cited by 61 publications

References 41 publications

The World of β‐ and γ‐Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components

The World of β‐ and γ‐Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components

Proof for a nonproteinaceous calcium-selective channel in Escherichia coli by total synthesis from ( R )-3-hydroxybutanoic acid and inorganic polyphosphate

Channel‐Forming Activity of 3‐Hydroxybutanoic‐Acid Oligomers in Planar Lipid Bilayers

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