Alamethicin

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Alamethicin [1]
Alamethicin.png
Names
IUPAC name
N-acetyl-2-methylalanyl-L-prolyl-2-methylalanyl-L-alanyl-2-methylalanyl-L-alanyl-L-glutaminyl-2-methylalanyl-L-valyl-2-methylalanylglycyl-L-leucyl-2-methylalanyl-L-prolyl-L-valyl-2-methylalanyl-2-methylalanyl-L-α-glutamyl-N1-[(1S)-1-benzyl-2-hydroxyethyl]-L-glutamamide
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.121.626 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C92H150N22O25/c1-47(2)43-58(72(127)108-92(24,25)84(139)113-41-29-33-59(113)73(128)103-65(48(3)4)75(130)111-90(20,21)82(137)112-89(18,19)80(135)102-56(37-40-64(120)121)70(125)101-55(35-38-61(93)117)69(124)98-54(46-115)44-53-31-27-26-28-32-53)99-63(119)45-95-77(132)85(10,11)110-76(131)66(49(5)6)104-81(136)88(16,17)107-71(126)57(36-39-62(94)118)100-67(122)50(7)96-78(133)86(12,13)106-68(123)51(8)97-79(134)87(14,15)109-74(129)60-34-30-42-114(60)83(138)91(22,23)105-52(9)116/h26-28,31-32,47-51,54-60,65-66,115H,29-30,33-46H2,1-25H3,(H2,93,117)(H2,94,118)(H,95,132)(H,96,133)(H,97,134)(H,98,124)(H,99,119)(H,100,122)(H,101,125)(H,102,135)(H,103,128)(H,104,136)(H,105,116)(H,106,123)(H,107,126)(H,108,127)(H,109,129)(H,110,131)(H,111,130)(H,112,137)(H,120,121)/t50-,51-,54-,55-,56-,57-,58-,59-,60-,65-,66-/m0/s1 Yes check.svgY
    Key: LGHSQOCGTJHDIL-UTXLBGCNSA-N Yes check.svgY
  • InChI=1/C92H150N22O25/c1-47(2)43-58(72(127)108-92(24,25)84(139)113-41-29-33-59(113)73(128)103-65(48(3)4)75(130)111-90(20,21)82(137)112-89(18,19)80(135)102-56(37-40-64(120)121)70(125)101-55(35-38-61(93)117)69(124)98-54(46-115)44-53-31-27-26-28-32-53)99-63(119)45-95-77(132)85(10,11)110-76(131)66(49(5)6)104-81(136)88(16,17)107-71(126)57(36-39-62(94)118)100-67(122)50(7)96-78(133)86(12,13)106-68(123)51(8)97-79(134)87(14,15)109-74(129)60-34-30-42-114(60)83(138)91(22,23)105-52(9)116/h26-28,31-32,47-51,54-60,65-66,115H,29-30,33-46H2,1-25H3,(H2,93,117)(H2,94,118)(H,95,132)(H,96,133)(H,97,134)(H,98,124)(H,99,119)(H,100,122)(H,101,125)(H,102,135)(H,103,128)(H,104,136)(H,105,116)(H,106,123)(H,107,126)(H,108,127)(H,109,129)(H,110,131)(H,111,130)(H,112,137)(H,120,121)/t50-,51-,54-,55-,56-,57-,58-,59-,60-,65-,66-/m0/s1
    Key: LGHSQOCGTJHDIL-UTXLBGCNBC
  • CC(C)C[C@@H](C(=O)NC(C)(C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)NC(C)(C)C(=O)NC(C)(C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC2=CC=CC=C2)CO)NC(=O)CNC(=O)C(C)(C)NC(=O)[C@H](C(C)C)NC(=O)C(C)(C)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C)NC(=O)C(C)(C)NC(=O)[C@H](C)NC(=O)C(C)(C)NC(=O)[C@@H]3CCCN3C(=O)C(C)(C)NC(=O)C
  • CC(C)CC(C(=O)NC(C)(C)C(=O)N1CCCC1C(=O)NC(C(C)C)C(=O)NC(C)(C)C(=O)NC(C)(C)C(=O)NC(CCC(=O)O)C(=O)NC(CCC(=O)N)C(=O)NC(Cc2ccccc2)CO)NC(=O)CNC(=O)C(C)(C)NC(=O)C(C(C)C)NC(=O)C(C)(C)NC(=O)C(CCC(=O)N)NC(=O)C(C)NC(=O)C(C)(C)NC(=O)C(C)NC(=O)C(C)(C)NC(=O)C3CCCN3C(=O)C(C)(C)NC(=O)C
Properties
C92H150N22O25
Molar mass 1964.31 g/mol
AppearanceOff white solid
Melting point 255 to 270 °C (491 to 518 °F; 528 to 543 K)
Insoluble
Solubility in DMSO, methanol, ethanol Soluble
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Alamethicin is a channel-forming peptide antibiotic, produced by the fungus Trichoderma viride . It belongs to peptaibol peptides which contain the non-proteinogenic amino acid residue Aib (2-aminoisobutyric acid). This residue strongly induces formation of alpha-helical structure. The peptide sequence is:

Contents

Ac-Aib-Pro-Aib-Ala-Aib-Ala-Gln-Aib-Val-Aib-Gly-Leu-Aib-Pro-Val-Aib-Aib-Glu-Gln-Phl

(Ac = acetyl, Phl = phenylalaninol, Aib = 2-Aminoisobutyric acid)

In cell membranes, it forms voltage-dependent ion channels by aggregation of four to six molecules.

Biosynthesis

Alamethicin biosynthesis is hypothesized to be catalyzed by alamethicin synthase, a Nonribosomal peptide synthase (NRPS) first isolated in 1975. [2] Although there are several sequences of the alamethicin peptide accepted, [3] evidence suggests these all follow the general NRPS mechanism [4] with small variations at select amino acids. [5] Beginning with the acylation of the N terminal of the first aminoisobutiric acid on the ALM synthase enzyme by Acetyl-CoA, [6] this is followed by the sequential condensation of amino acids by each modular unit of the synthetase. [7] Amino acids are initially adenylated by an “adenylylation” (A) domain before being attached by a thioester bond to an Acyl Carrier Protein-like Peptidyl carrier protein. [8] The growing chain is attached to the amino acid bearing PCP by the "condensation" (C) domain, followed by another round of the same reactions by the next module. [8]

The general mechanism of NRPS synthesis in alamethicin, showing the condensation of amino acid substrates from module to module. Ac=Acetyl Aib=aminoisobutyric acid. Module components: A= Adenylylation PCP= Peptidyl Carrier Protein C=Condensation NRPS basics corrected2.jpg
The general mechanism of NRPS synthesis in alamethicin, showing the condensation of amino acid substrates from module to module. Ac=Acetyl Aib=aminoisobutyric acid. Module components: A= Adenylylation PCP= Peptidyl Carrier Protein C=Condensation

Assembly is completed by the addition of phenylalaninol, an unusual amino acid-like substrate. [9] Following addition of phenylalaninol the completed peptide chain is cleaved by the thioesterase domain, cleaving the thioester bond and leaving an alcohol.[ citation needed ]

A diagram of the individual modules and elongation of alamethicin biosynthesis. The growing peptide chain is shown for each module, ending in the cleavage of the thioester and generation of linear alamethicin. Ac=Acetyl Aib=Aminoisobutyric acid Pheol=Phenylalaninol. Module components: A=Adenylylation PCP= Peptidyl Carrier Protein C=Condensation Alamethicinbiosynth corrected2.jpg
A diagram of the individual modules and elongation of alamethicin biosynthesis. The growing peptide chain is shown for each module, ending in the cleavage of the thioester and generation of linear alamethicin. Ac=Acetyl Aib=Aminoisobutyric acid Pheol=Phenylalaninol. Module components: A=Adenylylation PCP= Peptidyl Carrier Protein C=Condensation

Related Research Articles

Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides which have a molecular weight of 10000 or more are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.

<span class="mw-page-title-main">Polymyxin</span>

Polymyxins are antibiotics. Polymyxins B and E are used in the treatment of Gram-negative bacterial infections. They work mostly by breaking up the bacterial cell membrane. They are part of a broader class of molecules called nonribosomal peptides.

Nonribosomal peptides (NRP) are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacteria inside these organisms. While there exist a wide range of peptides that are not synthesized by ribosomes, the term nonribosomal peptide typically refers to a very specific set of these as discussed in this article.

<span class="mw-page-title-main">Acyl carrier protein</span>

The acyl carrier protein (ACP) is a cofactor of both fatty acid and polyketide biosynthesis machinery. It is one of the most abundant proteins in cells of E. coli. In both cases, the growing chain is bound to the ACP via a thioester derived from the distal thiol of a 4'-phosphopantetheine moiety.

<span class="mw-page-title-main">Viomycin</span> Chemical compound

Viomycin is a member of the tuberactinomycin family, a group of nonribosomal peptide antibiotics exhibiting anti-tuberculosis activity. The tuberactinomycin family is an essential component in the drug cocktail currently used to fight infections of Mycobacterium tuberculosis. Viomycin was the first member of the tuberactinomycins to be isolated and identified, and was used to treat TB until it was replaced by the less toxic, but structurally related compound, capreomycin. The tuberactinomycins target bacterial ribosomes, binding RNA and disrupting bacterial protein synthesis and certain forms of RNA splicing. Viomycin is produced by the actinomycete Streptomyces puniceus.

<span class="mw-page-title-main">Gramicidin S</span> Chemical compound

Gramicidin S or Gramicidin Soviet is an antibiotic that is effective against some gram-positive and gram-negative bacteria as well as some fungi.

<span class="mw-page-title-main">2-Aminoisobutyric acid</span> Chemical compound

2-Aminoisobutyric acid (also known as α-aminoisobutyric acid, AIB, α-methylalanine, or 2-methylalanine) is the non-proteinogenic amino acid with the structural formula H2N-C(CH3)2-COOH. It is rare in nature, having been only found in meteorites, and some antibiotics of fungal origin, such as alamethicin and some lantibiotics.

<span class="mw-page-title-main">Tyrocidine</span> Chemical compound

Tyrocidine is a mixture of cyclic decapeptides produced by the bacteria Bacillus brevis found in soil. It can be composed of 4 different amino acid sequences, giving tyrocidine A–D. Tyrocidine is the major constituent of tyrothricin, which also contains gramicidin. Tyrocidine was the first commercially available antibiotic, but has been found to be toxic toward human blood and reproductive cells. The function of tyrocidine within its host B. brevis is thought to be regulation of sporulation.

<span class="mw-page-title-main">Phosphopantetheine</span> Chemical compound

Phosphopantetheine, also known as 4'-phosphopantetheine, is a prosthetic group of several acyl carrier proteins including the acyl carrier proteins (ACP) of fatty acid synthases, ACPs of polyketide synthases, the peptidyl carrier proteins (PCP), as well as aryl carrier proteins (ArCP) of nonribosomal peptide synthetases (NRPS). It is also present in formyltetrahydrofolate dehydrogenase.

<span class="mw-page-title-main">Long-chain-fatty-acid—CoA ligase</span> Class of enzymes

The long chain fatty acyl-CoA ligase is an enzyme of the ligase family that activates the oxidation of complex fatty acids. Long chain fatty acyl-CoA synthetase catalyzes the formation of fatty acyl-CoA by a two-step process proceeding through an adenylated intermediate. The enzyme catalyzes the following reaction,

<span class="mw-page-title-main">Holo-(acyl-carrier-protein) synthase</span>

In enzymology and molecular biology, a holo-[acyl-carrier-protein] synthase is an enzyme that catalyzes the chemical reaction:

Peptaibols are biologically active peptides containing between seven and twenty amino acid residues, some of which are non-proteinogenic amino acids. In particular, they contain α-aminoisobutyric acid along with other unusual aminoacids such as ethylnorvaline, isovaline and hydroxyproline; the N-terminus is acetylated, and the C-terminal amino acid is hydroxylated to an acid alcohol. They are named pebtaibols due to them being peptides containing α-aminoisobutyric acid (Aib) and ending in an alcohol. They are produced by certain fungi, mainly in the genus Trichoderma, as secondary metabolites which function as antibiotics and antifungal agents. Some are referred to as trichorzianines. They are amphipathic which allows them to form voltage-dependent ion channels in cell membranes which create holes in the membrane making them leaky and leading to the death of the cells. As of 2001, over 317 peptaibols had been identified. The most widely known peptaibol is alamethicin.

<span class="mw-page-title-main">Codinaeopsin</span> Chemical compound

Codinaeopsin is an antimalarial isolated from a fungal isolate found in white yemeri trees (Vochysia guatemalensis) in Costa Rica. It is reported to have bioactivity against Plasmodium falciparum with an IC50 = 2.3 μg/mL (4.7 μM). Pure codinaeopsin was reported to be isolated with a total yield of 18 mg/mL from cultured fungus. The biosynthesis of codinaeopsin involves a polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) hybrid.

<span class="mw-page-title-main">Atromentin</span> Chemical compound

Atromentin is a natural chemical compound found in Agaricomycetes fungi in the orders Agaricales and Thelephorales. It can also be prepared by laboratory synthesis. Chemically, it is a polyphenol and a benzoquinone.

<span class="mw-page-title-main">Efrapeptin</span>

Efrapeptins are peptides produced by fungi in the genus Tolypocladium that have antifungal, insecticidal, and mitochondrial ATPase inhibitory activities. They are produced via a biosynthetic pathway similar to but simpler than the Ciclosporin pathway, with nonribosomal peptide synthase (NRPS) and/or polyketide synthase (PKS) being the key elements.

The nonribosomal code refers to key amino acid residues and their positions within the primary sequence of an adenylation domain of a nonribosomal peptide synthetase used to predict substrate specificity and thus (partially) the final product. Analogous to the nonribosomal code is prediction of peptide composition by DNA/RNA codon reading, which is well supported by the central dogma of molecular biology and accomplished using the genetic code simply by following the DNA codon table or RNA codon table. However, prediction of natural product/secondary metabolites by the nonribosomal code is not as concrete as DNA/RNA codon-to-amino acid and much research is still needed to have a broad-use code. The increasing number of sequenced genomes and high-throughput prediction software has allowed for better elucidation of predicted substrate specificity and thus natural products/secondary metabolites. Enzyme characterization by, for example, ATP-pyrophosphate exchange assays for substrate specificity, in silico substrate-binding pocket modelling and structure-function mutagenesis helps support predictive algorithms. Much research has been done on bacteria and fungi, with prokaryotic bacteria having easier-to-predict products.

<span class="mw-page-title-main">Leinamycin</span> Chemical compound

Leinamycin is an 18-membered macrolactam produced by several species of Streptomyces atroolivaceus. This macrolactam has also been shown to exhibit antitumor properties as well as antimicrobial properties against gram-positive and gram-negative bacteria. The presence of a spiro-fused 1,3-dioxo-1,2-dithiolane moiety was a unique structural property at the time of this compound's discovery and it plays an important role in leinamycin's antitumor and antibacterial properties due to its ability to inhibit DNA synthesis.

Cyclodipeptide synthases (CDPSs) are a newly defined family of peptide-bond forming enzymes that are responsible for the ribosome-independent biosynthesis of various cyclodipeptides, which are the precursors of many natural products with important biological activities. As a substrate for this synthesis, CDPSs use two amino acids activated as aminoacyl-tRNAs (aa-tRNAs), therefore diverting them from the ribosomal machinery. The first member of this family was identified in 2002 during the characterization of the albonoursin biosynthetic pathway in Streptomyces noursei. CDPSs are present in bacteria, fungi, and animal cells.

Andrimid is an antibiotic natural product that is produced by the marine bacterium Vibrio coralliilyticus. Andrimid is an inhibitor of fatty acid biosynthesis by blocking the carboxyl transfer reaction of acetyl-CoA carboxylase (ACC).

<span class="mw-page-title-main">Halovir</span> Group of chemical compounds

Halovir refers to a multi-analogue compound belonging to a group of oligopeptides designated as lipopeptaibols which have membrane-modifying capacity and are fungal in origin. These peptides display interesting microheterogeneity; slight variation in encoding amino acids gives rise to a mixture of closely related analogues and have been shown to have antibacterial/antiviral properties.

References

  1. ↑ Alamethicin product page from Fermentek
  2. ↑ Rindfleisch, H.; Kleinkauf, H. (1976-03-01). "Biosynthesis of alamethicin". FEBS Letters. 62 (3): 276–280. doi: 10.1016/0014-5793(76)80074-9 . ISSN   0014-5793. PMID   945191.
  3. ↑ Kirschbaum, Jochen; Krause, Corina; Winzheimer, Ruth K.; Brückner, Hans (November–December 2003). "Sequences of alamethicins F30 and F50 reconsidered and reconciled". Journal of Peptide Science. 9 (11–12): 799–809. doi:10.1002/psc.535. ISSN   1075-2617. PMID   14658799. S2CID   25076336.
  4. ↑ Marahiel, Mohamed A.; Stachelhaus, Torsten; Mootz, Henning D. (1997-11-01). "Modular Peptide Synthetases Involved in Nonribosomal Peptide Synthesis". Chemical Reviews. 97 (7): 2651–2674. doi:10.1021/cr960029e. ISSN   0009-2665. PMID   11851476.
  5. ↑ Kleinkauf, H.; Rindfleisch, H. (1975). "Non-ribosomal biosynthesis of the cyclic octadecapeptide alamethicin". Acta Microbiologica Academiae Scientiarum Hungaricae. 22 (4): 411–418. ISSN   0001-6187. PMID   1241650.
  6. ↑ Mohr, H.; Kleinkauf, H. (1978-10-12). "Alamethicin biosynthesis: acetylation of the amino terminus and attachment of phenylalaninol". Biochimica et Biophysica Acta (BBA) - Enzymology. 526 (2): 375–386. doi:10.1016/0005-2744(78)90129-8. ISSN   0006-3002. PMID   568941.
  7. ↑ Weber, Thomas; Marahiel, Mohamed A (January 2001). "Exploring the Domain Structure of Modular Nonribosomal Peptide Synthetases". Structure. 9 (1): –3–R9. doi: 10.1016/S0969-2126(00)00560-8 . ISSN   0969-2126. PMID   11342140.
  8. 1 2 Fischbach, Michael A.; Walsh, Christopher T. (August 2006). "Assembly-line enzymology for polyketide and nonribosomal Peptide antibiotics: logic, machinery, and mechanisms". Chemical Reviews. 106 (8): 3468–3496. doi:10.1021/cr0503097. ISSN   0009-2665. PMID   16895337.
  9. ↑ Turner, S. Richard; Voit, Brigitte I.; Mourey, Thomas H. (1993-08-01). "All-aromatic hyperbranched polyesters with C-phenylalaninol and N-acetate end groups: synthesis and characterization". Macromolecules. 26 (17): 4617–4623. Bibcode:1993MaMol..26.4617T. doi:10.1021/ma00069a031. ISSN   0024-9297.

Further reading

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