Alamethicin

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

Alamethicin^[1]

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
CAS Number	27061-78-5 Y
3D model (JSmol)	Interactive image Interactive image
ChEMBL	ChEMBL438243 Y
ChemSpider	17288702 Y
ECHA InfoCard	100.121.626
PubChem CID	16132042
UNII	0LT1I1B7S8 Y
CompTox Dashboard (EPA)	DTXSID40893675
InChI 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 Y Key: LGHSQOCGTJHDIL-UTXLBGCNSA-N Y 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
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 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
Chemical formula	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)
Solubility in water	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 is YN ?) Infobox references

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.^[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

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

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. 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

• Jones, LR; Maddock, SW; Besch, HR Jr (1980). "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. 255 (20): 9971–9980. doi:10.1016/S0021-9258(18)43488-6. PMID 6253461.
• 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. S2CID 4278453.
• 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. PMID 17589875. S2CID 40886688.