Neocarzinostatin (NCS) is a

macromolecular A macromolecule is a very large molecule important to biophysical processes, such as a protein or nucleic acid. It is composed of thousands of covalently bonded atoms. Many macromolecules are polymers of smaller molecules called monomers. The ...

chromoprotein A chromoprotein is a conjugated protein that contains a pigmented prosthetic group (or cofactor). A common example is haemoglobin, which contains a heme cofactor, which is the iron-containing molecule that makes oxygenated blood appear red. Other e ...

enediyne In organic chemistry, enediynes are organic compounds containing two triple bonds and one double bond. Enediynes are most notable for their limited use as antitumor antibiotics (known as enediyne Chemotherapy, anticancer antibiotics). They are ...

antitumor antibiotic Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

secreted by ''

Streptomyces ''Streptomyces'' is the largest genus of Actinomycetota and the type genus of the family Streptomycetaceae. Over 500 species of ''Streptomyces'' bacteria have been described. As with the other Actinomycetota, streptomycetes are gram-positive, ...

macromomyceticus''. It consists of two parts, a labile

chromophore A chromophore is the part of a molecule responsible for its color. The color that is seen by our eyes is the one not absorbed by the reflecting object within a certain wavelength spectrum of visible light. The chromophore is a region in the molec ...

(the non-protein molecular entity shown at right) and a 113 amino acid

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

to which the chromophore is tightly and non- covalently bound with high affinity (K_d ~ 10⁻¹⁰ M). The non-protein component is a very potent DNA-damaging agent; However it is extremely unstable and the role of the protein is to protect it and release it to the target DNA. Opening of the epoxide under reductive conditions present in cells creates favorable conditions for a Masamune-Bergman cyclization, leading to formation of benzyne, followed by DNA strand cleavage. Another important member of the

group of

natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical syn ...

s is

kedarcidin Kedarcidin is a chromoprotein antitumor antibiotic first isolated from an Actinomycete in 1992, comprising an ansa-bridged enediyne chromophore (shown) as well as an apoprotein that serves to stabilize the toxin in the Actinomycete. Like other ...

. As a medicine it is among the most potent, and in Japan only it has been used against

liver cancer Liver cancer (also known as hepatic cancer, primary hepatic cancer, or primary hepatic malignancy) is cancer that starts in the liver. Liver cancer can be primary (starts in liver) or secondary (meaning cancer which has spread from elsewhere to th ...

clinically. __TOC__

Biosynthesis of NCS Chromophore

The biosynthesis of neocarzinostatin takes place through a convergence of the activities of a gene cluster, which includes two separate iterative type I

polyketide synthase Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...

(PKS) and

deoxy sugar Deoxy sugars are sugars that have had a hydroxyl group replaced with a hydrogen atom. Examples include: * Deoxyribose, or 2-deoxy-D-ribose, a constituent of DNA * Fucose, or 6-deoxy-L-galactose, main component of fucoidan of brown algae, and p ...

biosynthetic pathways. The first type I PKS gene, NcsE, codes for the

moiety. The second type I PKS gene, NcsB, codes for the naphthoic acid moiety. Additionally, a cluster of ''NcsC'' genes are responsible for coding enzymes for the synthesis of the deoxyamino sugar moiety of NCS chromophore. The biosynthesis can be divided into three preliminary steps with a final convergence of the three moieties: 1. Synthesis of deoxyaminosugar moiety: This part is carried out by the enzymes encoded by a cluster of seven genes, named ''NcsC'' through ''Ncs6''. Since, these enzymes have similarity to dNDP-D-mannose synthases, it has been proposed that, the synthesis starts from D-

mannose-1-phosphate Mannose 1-phosphate is a molecule involved in glycosylation. See also

* Congenital disorder of glycosylation * Mannose-6-phosphate Organophosphates Monosaccharide derivatives {{organic-compound-stub ...

. Since the C-2 hydroxyl group (-OH) is ultimately eliminated, the possibility of having D-

glucose-1-phosphate Glucose 1-phosphate (also called cori ester) is a glucose molecule with a phosphate group on the 1'-carbon. It can exist in either the α- or β-anomeric form. Reactions of α-glucose 1-phosphate Catabolic In glycogenolysis, it is the direct pro ...

cannot also be ruled out. However, additional studies indicate that, D-mannose-1-phosphate is the more likely starting point. 2. Synthesis of naphthoic acid moiety: ''NcsB'', ''NcsB1'', ''NcsB2'' and ''NcsB3'' are enzymes responsible for the synthesis of the naphthoic acid moiety. This is similar to other enediyne natural products, the genes involved in construction of the aromatic moiety are an iterative type I PKS rather than a type II PKS system. The methyl group on the phenol group is added by SAM. 3. Synthesis of enediyne moiety and convergent assembly: The enediyne is synthesized by 14 enzymes encoded by ''NcsE'' to ''NcsE11'' plus ''NcsF1'' and ''NcsF2''. ''NcsE'' to ''NcsE11'' constitute another iterative type I PKS, while ''NcsF1'' and ''NcsF2'' have epoxide hydrolase activity. Finally, the building blocks are assembled in a convergent fashion. Ncs6 glycosyltransferase catalyzes the coupling between the enediyne core and the dNDP-deoxyaminosugar. The naphthoyl group is attached to the enediyne core by the enzyme NcsB2 CoA ligase. There is an additional carbonate functionality added, probably originating from CO₂ (or bicarbonate), however, it remains to be determined whether this step is truly enzymatic.

References

{{Enediynes Antineoplastic drugs Cancer research Enediynes Epoxides Carbonate esters Experimental cancer drugs Naphthalenes Nine-membered rings