{{chembox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 477316294 | Reference =<ref>[https://www.fermentek.com/alamethicin Alamethicin product page] from Fermentek</ref> | ImageFile =Alamethicin.png | ImageSize =250px | IUPACName =''N''-acetyl-2-methylalanyl-<small>L</small>-prolyl-2-methylalanyl-<small>L</small>-alanyl-2-methylalanyl-<small>L</small>-alanyl-<small>L</small>-glutaminyl-2-methylalanyl-<small>L</small>-valyl-2-methylalanylglycyl-<small>L</small>-leucyl-2-methylalanyl-<small>L</small>-prolyl-<small>L</small>-valyl-2-methylalanyl-2-methylalanyl-<small>L</small>-α-glutamyl-''N''<sup>1</sup>-[(1''S'')-1-benzyl-2-hydroxyethyl]-<small>L</small>-glutamamide | OtherNames = |Section1={{Chembox Identifiers | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 17288702 | 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 | SMILES1 = 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 | InChIKey = LGHSQOCGTJHDIL-UTXLBGCNBC | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 438243 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 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 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = LGHSQOCGTJHDIL-UTXLBGCNSA-N | CASNo_Ref = {{cascite|correct|CAS}} | CASNo =27061-78-5 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 0LT1I1B7S8 | PubChem =16132042 | SMILES =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 }} |Section2={{Chembox Properties | Formula =C<sub>92</sub>H<sub>150</sub>N<sub>22</sub>O<sub>25</sub> | MolarMass =1964.31 g/mol | Appearance =Off white solid | Density = | MeltingPtC = 255 to 270 | MeltingPt_notes = | BoilingPt = | Solubility =Insoluble | SolubleOther = Soluble | Solvent = DMSO, methanol, ethanol
}} |Section3={{Chembox Hazards | MainHazards = | FlashPt = | AutoignitionPt = }} }} '''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>{{Cite journal| doi = 10.1016/0014-5793(76)80074-9| pmid = 945191| issn = 0014-5793| volume = 62| issue = 3| pages = 276–280| last1 = Rindfleisch| first1 = H.| last2 = Kleinkauf| first2 = H.| title = Biosynthesis of alamethicin| journal = FEBS Letters| date = 1976-03-01| bibcode = 1976FEBSL..62..276R| doi-access = free}}</ref> Although there are several sequences of the alamethicin peptide accepted,<ref>{{Cite journal| doi = 10.1002/psc.535| issn = 1075-2617| volume = 9| issue = 11–12| pages = 799–809| last1 = Kirschbaum| first1 = Jochen| last2 = Krause| first2 = Corina| last3 = Winzheimer| first3 = Ruth K.| last4 = Brückner| first4 = Hans| title = Sequences of alamethicins F30 and F50 reconsidered and reconciled| journal = Journal of Peptide Science| date = November–December 2003| pmid = 14658799| s2cid = 25076336}}</ref> evidence suggests these all follow the general NRPS mechanism <ref>{{Cite journal| doi = 10.1021/cr960029e| issn = 0009-2665| volume = 97| issue = 7| pages = 2651–2674| last1 = Marahiel| first1 = Mohamed A.| last2 = Stachelhaus| first2 = Torsten| last3 = Mootz| first3 = Henning D.| title = Modular Peptide Synthetases Involved in Nonribosomal Peptide Synthesis| journal = Chemical Reviews| date = 1997-11-01| pmid=11851476}}</ref> with small variations at select amino acids.<ref>{{Cite journal| issn = 0001-6187| volume = 22| issue = 4| pages = 411–418| last1 = Kleinkauf| first1 = H.| last2 = Rindfleisch| first2 = H.| title = Non-ribosomal biosynthesis of the cyclic octadecapeptide alamethicin| journal = Acta Microbiologica Academiae Scientiarum Hungaricae| date = 1975| pmid = 1241650}}</ref> Beginning with the acylation of the N terminal of the first aminoisobutiric acid on the ALM synthase enzyme by Acetyl-CoA,<ref>{{Cite journal| issn = 0006-3002| volume = 526| issue = 2| pages = 375–386| last1 = Mohr| first1 = H.| last2 = Kleinkauf| first2 = H.| title = Alamethicin biosynthesis: acetylation of the amino terminus and attachment of phenylalaninol| journal = Biochimica et Biophysica Acta (BBA) - Enzymology| date = 1978-10-12| pmid = 568941| doi=10.1016/0005-2744(78)90129-8}}</ref> this is followed by the sequential condensation of amino acids by each modular unit of the synthetase.<ref>{{Cite journal| doi = 10.1016/S0969-2126(00)00560-8| issn = 0969-2126| volume = 9| issue = 1| pages = –3–R9| last1 = Weber| first1 = Thomas| last2 = Marahiel| first2 = Mohamed A| title = Exploring the Domain Structure of Modular Nonribosomal Peptide Synthetases| journal = Structure| date = January 2001| pmid = 11342140| doi-access = free}}</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>{{Cite journal| doi = 10.1021/cr0503097| issn = 0009-2665| volume = 106| issue = 8| pages = 3468–3496| last1 = Fischbach| first1 = Michael A.| last2 = Walsh| first2 = Christopher T.| title = Assembly-line enzymology for polyketide and nonribosomal Peptide antibiotics: logic, machinery, and mechanisms| journal = Chemical Reviews| date = August 2006| pmid = 16895337}}</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 />
thumb|center|550px|alt=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.<ref>{{Cite journal| doi = 10.1021/ma00069a031| issn = 0024-9297| volume = 26| issue = 17| pages = 4617–4623| last1 = Turner| first1 = S. Richard| last2 = Voit| first2 = Brigitte I.| last3 = Mourey| first3 = Thomas H.| title = All-aromatic hyperbranched polyesters with C-phenylalaninol and N-acetate end groups: synthesis and characterization| journal = Macromolecules| date = 1993-08-01|bibcode = 1993MaMol..26.4617T }}</ref> Following addition of phenylalaninol the completed peptide chain is cleaved by the thioesterase domain, cleaving the thioester bond and leaving an alcohol.{{cn|date=March 2023}}
thumb|center|550px|alt=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 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
== References == {{reflist}}
== Further reading == * {{cite journal | last1 = Jones | first1 = LR | last2 = Maddock | first2 = SW | last3 = Besch | first3 = HR Jr | year = 1980 | title = 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 | journal = J. Biol. Chem. | volume = 255 | issue = 20| pages = 9971–9980 | doi = 10.1016/S0021-9258(18)43488-6 | pmid = 6253461 | doi-access = free }} * Explore structures of [http://www.ebi.ac.uk/pdbe/searchResults.html?display=both&term=NOR00010 Alamethicin] at the protein data bank * [http://bioinfo.lifl.fr/norine/result.jsp?ID=NOR00010 Alamethicin] in Norine ** From "A voltage-gated ion channel model inferred from the crystal structure of alamethicin at 1.5-A resolution." {{Cite journal | last1 = Fox Jr | first1 = RO | last2 = Richards | first2 = FM | title = A voltage-gated ion channel model inferred from the crystal structure of alamethicin at 1.5-A resolution | journal = Nature | volume = 300 | issue = 5890 | pages = 325–30 | year = 1982 | pmid = 6292726 |bibcode = 1982Natur.300..325F |doi = 10.1038/300325a0 | s2cid = 4278453 }} * {{Cite journal| doi = 10.1002/cbdv.200790095| pmid = 17589875| issn = 1612-1880| volume = 4| issue = 6| pages = 1027–1051| last1 = Leitgeb| first1 = Balázs| last2 = Szekeres| first2 = András| last3 = Manczinger| first3 = László| last4 = Vágvölgyi| first4 = Csaba| last5 = Kredics| first5 = László| title = The History of Alamethicin: A Review of the Most Extensively Studied Peptaibol| journal = Chemistry & Biodiversity| date = 2007-06-01| s2cid = 40886688}}
{{Non-ribosomally synthesized channels}}
Category:Polypeptide antibiotics Category:Antimicrobial peptides