Echinomycin is a

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

. It is a dimer of two peptides creating a cyclic structure. It contains a bicyclic aromatic chromophore that is attached to the dimerized cyclic peptide core and a thioacetal bridge. It intercalates into

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

at two specific sites, thereby blocking the binding of

hypoxia inducible factor Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. They also respond to instances of pseudohypoxia, such as thiamine deficiency. Both hypoxia an ...

1 alpha (HIF1alpha).

Biosynthesis

Echinomycin is a bis-intercalator

and is biosynthesized by a unique

nonribosomal peptide Nonribosomal peptides (NRP) are a class of peptide secondary metabolites, usually produced by microorganisms like bacterium, bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be ma ...

synthetase (NRPS). Echinomycin is isolated from various bacteria such as ''Streptomyces'' ''lasalienis''. It belongs to a family of quinoxaline

antibiotics An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

. There is great interest in this group of compounds because they have very potent antibacterial, anticancer, and antiviral activities. The biosynthesis of echinomycin starts with molecule QC. L-tryptophan is the precursor for QC and its biosynthesis parallels the first stage of

nikkomycin Nikkomycins are a group of antifungal medications. They work by interfering with the building of the fungal cell wall which results in the fungal cell breaking open. They were discovered in 1976. The specific agent nikkomycin Z has weak activity a ...

biosynthesis. After QC is biosynthesized, the adenylation domain-containing Ecm1 activates and transfers QC to FabC using the fatty acid biosynthesis

acyl carrier protein The acyl carrier protein (ACP) is a cofactor of both fatty acid and polyketide biosynthesis machinery. It is one of the most abundant proteins in cells of ''E. coli.'' In both cases, the growing chain is bound to the ACP via a thioester derived fr ...

(ACP). The first module, Ecm6 accepts the QC-SFabC as the starter unit. Emc7 contains a terminal

thioesterase In biochemistry, thioesterases are enzymes which belong to the esterase family. Esterases, in turn, are one type of the several hydrolases known. Thioesterases exhibit esterase activity (splitting of an ester into an acid and an alcohol, in the ...

domain which allows the peptide to dimerize and then release. This cyclized product then goes on to Ecm17, an oxidoreductase, creating a

disulfide In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inorg ...

bond. The last step in this biosynthesis transforms the disulfide bond into a

thioacetal In organosulfur chemistry, thioacetals are the sulfur (''thio-'') analog (chemistry), analogues of acetals (). There are two classes: the less-common monothioacetals, with the formula , and the dithioacetals, with the formula (symmetric dithio ...

bridge. This transformation takes place within Ecm18, a

S-adenosyl-L-methionine ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...

(SAM)-dependent

methyltransferase Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Ro ...

. The mechanism is proposed to proceed through two steps. Initially Emc18 transfers the activated methyl group from SAM to one of the sulfur atoms in the disulfide bond. Secondly deprotonation of the alpha proton to the tertiary sulfonium cation promotes the rearrangement for the formation of the thioacetal bond. QXC biosynthesis

References

{{Reflist Antibiotics Quinoxalines