Alamethicin

Template:Chembox 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

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

where Ac = acetyl, Phl = phenylalaninol, and 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.<ref>Template:Cite journal</ref> Although there are several sequences of the alamethicin peptide accepted,<ref>Template:Cite journal</ref> evidence suggests these all follow the general NRPS mechanism <ref>Template:Cite journal</ref> with small variations at select amino acids.<ref>Template:Cite journal</ref> Beginning with the acylation of the N terminal of the first aminoisobutiric acid on the ALM synthase enzyme by Acetyl-CoA,<ref>Template:Cite journal</ref> this is followed by the sequential condensation of amino acids by each modular unit of the synthetase.<ref>Template:Cite journal</ref> 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.<ref name = Fischbach>Template:Cite journal</ref> 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.<ref name = Fischbach />

File: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.<ref>Template:Cite journal</ref> Following addition of phenylalaninol the completed peptide chain is cleaved by the thioesterase domain, cleaving the thioester bond and leaving an alcohol.Template:Cn

File: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

Further reading

• Template:Cite journal
• 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." Template:Cite journal
• Template:Cite journal