Alamethicin

Alamethicin biosynthesis is hypothesized to be catalyzed by alamethicin synthase, a Nonribosomal peptide synthase (NRPS) first isolated in 1975.{{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| doi-access = free}} Although there are several sequences of the alamethicin peptide accepted,{{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}} evidence suggests these all follow the general NRPS mechanism {{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}} with small variations at select amino acids.{{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}} Beginning with the acylation of the N terminal of the first aminoisobutiric acid on the ALM synthase enzyme by Acetyl-CoA,{{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}} this is followed by the sequential condensation of amino acids by each modular unit of the synthetase.{{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}} 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.{{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}} 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.

File:NRPS basics corrected2.jpg

Assembly is completed by the addition of phenylalaninol, an unusual amino acid-like substrate.{{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 }} 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}}

File:Alamethicinbiosynth corrected2.jpg

{{reflist}}

• {{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