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-​D-​leucyl-​2-​methylalanyl-​L-​prolyl-​L-​valyl-​2-​methylalanyl-​2-​methylalanyl-​L-​α-​glutamyl-​N1-​[(1S)-​1-​benzyl-​2-​hydroxyethyl]-​L-​glutamamide
Identifiers
27061-78-5 N
ChEMBL ChEMBL438243 YesY
ChemSpider 17288702 YesY
Jmol-3D images Image
Image
PubChem 16132042
Properties
C92H150N22O25
Molar mass 1964.31 g/mol
Appearance Off 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).
 N verify (what isYesY/N?)
Infobox references

Alamethicin is a 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:

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[edit]

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]

alt text
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.

alt text
A diagram of the individual modules and elongation of alamethicin biosynthesis. The growing peptide chain is shown for each module, ending in the clevage 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

References[edit]

  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. Retrieved 2015-06-09. 
  3. ^ Kirschbaum, Jochen; Krause, Corina; Winzheimer, Ruth K.; Brückner, Hans (2003-12). "Sequences of alamethicins F30 and F50 reconsidered and reconciled". Journal of Peptide Science: An Official Publication of the European Peptide Society 9 (11-12): 799–809. doi:10.1002/psc.535. ISSN 1075-2617. PMID 14658799.  Check date values in: |date= (help)
  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. Retrieved 2015-06-09. 
  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 526 (2): 375–386. ISSN 0006-3002. PMID 568941. 
  7. ^ Weber, Thomas; Marahiel, Mohamed A (2001-01). "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. Retrieved 2015-06-09.  Check date values in: |date= (help)
  8. ^ a b Fischbach, Michael A.; Walsh, Christopher T. (2006-08). "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.  Check date values in: |date= (help)
  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. doi:10.1021/ma00069a031. ISSN 0024-9297. Retrieved 2015-06-09. 

Further reading[edit]

  • LR Jones, SW Maddock and HR Besch Jr. Unmasking effect of alamethicin on the (Na+,K+)-ATPase, beta-adrenergic receptor-coupled adenylate cyclase, and cAMP-dependent protein kinase activities of cardiac sarcolemmal vesicles. J. Biol. Chem., Vol. 255, Issue 20, 9971-9980, Oct, 1980.
  • Explore structures of Alamethicin at the protein data bank
  • Alamethicin in Norine
    • From "A voltage-gated ion channel model inferred from the crystal structure of alamethicin at 1.5-A resolution." Fox Jr, RO; Richards, FM (1982). "A voltage-gated ion channel model inferred from the crystal structure of alamethicin at 1.5-A resolution". Nature 300 (5890): 325–30. Bibcode:1982Natur.300..325F. doi:10.1038/300325a0. PMID 6292726.  edit
  • The History of Alamethicin: A Review of the Most Extensively Studied Peptaibol [1]
  1. ^ Leitgeb, Balázs; Szekeres, András; Manczinger, László; Vágvölgyi, Csaba; Kredics, László (2007-06-01). "The History of Alamethicin: A Review of the Most Extensively Studied Peptaibol". Chemistry & Biodiversity 4 (6): 1027–1051. doi:10.1002/cbdv.200790095. ISSN 1612-1880. Retrieved 2015-06-09.