User:Ksklwsk2/sandbox
Names | |
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Other names
cyclothiazomycin A, 5102-II
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Identifiers | |
3D model (
JSmol ) |
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PubChem CID
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Properties | |
C59H64N18O14S7 | |
Molar mass | 1473.71 g/mol |
Melting point | >210 °C (decomposes) |
Solubility | soluble in DMSO/water, methanol/water, acetone /water)
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Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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The cyclothiazomycins are a group of
History
Cylothiazomycin A was first isolated from Streptomyces sp. NR0516 in 1991.
Structural analogues cyclothiazomycin B1 and B2 were isolated from Streptomyces sp. A307 and solved in 2006 with the help of high-resolution mass spectrometry and NMR spectroscopy.[5]
A third analogue, cyclothiazomycin C, was discovered in 2014 with the aid of genome mining, nucleophilic 1,4-addition labeling reactions, high resolution mass spectrometry, and NMR spectroscopy.[6]
Structure
The cyclothiazomycins are thiazole-containing bicyclic and macrocyclic peptides that are structurally similar to thiostrepton and noshiheptide.[2] Formally classified as thiopeptides within the larger family of ribosomally synthesized and post-translationally modified peptides (RiPPs), the cyclothiazomycins are initially biosynthesized as peptides which subsequently undergo chemical modifications, including macrocyclization, aromization, cyclodehydration, and dehydrogenation. Cyclothiazomycins exist as three analogues that differ at two amino acid residues in the core peptide. The image below denotes in red the differences between the analogues as well as the amino acid sequence that becomes the final compounds.
The structure of cyclothiazomycin A was established primarily by two-dimensional nuclear magnetic resonance spectroscopy. Cyclothiazomycin A contains a dehydroalanine and two dehydrohomoalanine residues within a bicyclic, macrocyclic scaffold comprised of thiazolines, thiazoles, and a trisubstituted pyridine.[2]
Cyclothiazomycin B and C vary from cyclothiazomycin A at the second and third
Cyclothiazomycin C has a lysine in place of the second threonine residue found in cyclothiazomycin A and a serine residue in place of the third threonine residue, resulting in a dehydroalanine instead of the dehydrohomoalanine observed in cyclothiazomycin A.[6]
Biosynthesis
Cyclothiazomycin is part of a class of natural products that are ribosomally synthesized and post-translationally modified peptides (RiPPs). As such, cyclothiazomycin begins as a peptide that is synthesized in the bacterial ribosome. A series of chemical steps by biosynthetic
The gene encoding for cyclothiazomycin begins with a short open reading frame (ORF) ctmA (cltA). CtmD (cltB) encodes a "fused" TOMM cyclodehydratase believed to take part in the formation of thiazolines. The enzyme encoded by the ctmB (cltC) gene is believed to catalyze the dehydrogenation of thiazolines to thiazoles.CtmE and ctmF (ctlE and cltF) each encode a split lanthipeptide dehydratase which dehydrates serine and threonine to dehydroalanine and dehydrobutyrine.CtmG (cltG) is believed to aide in the production of the central pyridine. CtmI(cltD) encodes a ThiF-like protein. CtmH (cltH) is a LuxR-type regulatory gene. CtmJK are not present in the cycloythiazomycin A and C clusters; there is no known function. The cltN gene is believed to encode an enzyme that is involved in the formation of the tertiary thioether, however this has not been proven and cltN is not regulated by ctmH.CtmA,ctmD ,ctmF, and ctmG deletion leads to the disappearance of cyclothiazomycin A.[3][4][7]
CtmH is a LuxR-type regulatory gene that was shown to regulate ctmA-ctmL.[7]
Bioactivity
Each analogue of cyclothiazomycin is believed to interact with at least one biological target. Cyclothiazomycin A has been shown to inhibit