Curacin A is a hybrid

polyketide synthase Polyketide synthases (PKSs) are a family of multi- domain enzymes or enzyme complexes that produce polyketides, a large class of secondary metabolites, in bacteria, fungi, plants, and a few animal lineages. The biosyntheses of polyketides share ...

(PKS)/ nonribosomal peptide synthase (NRPS) derived

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 s ...

produced isolated from the

cyanobacterium Cyanobacteria ( ) are a group of autotrophic gram-negative bacteria that can obtain biological energy via oxygenic photosynthesis. The name "cyanobacteria" () refers to their bluish green (cyan) color, which forms the basis of cyanobacteria' ...

Lyngbya majuscula ''Lyngbya majuscula'' is a species of filamentous cyanobacteria in the genus '' Lyngbya''. It is named after the Dane Hans Christian Lyngbye. As a result of recent genetic analyses, several new genera were erected from the genus ''Lyngbya'': ...

''. Curacin A belongs to a family of natural products including jamaicamide, mupirocin, and

pederin Pederin is a vesicant toxic amide with two tetrahydropyran rings, found in the haemolymph of the beetle genus ''Paederus'', including the Nairobi fly, belonging to the family Staphylinidae. It was first characterized by processing 25 million field ...

that have an unusual

terminal alkene In organic chemistry, terminal alkenes (alpha-olefins, α-olefins, or 1-alkenes) are a family of organic compounds which are alkenes (also known as olefins) with a chemical formula , distinguished by having a double bond at the primary, alpha ( ...

. Additionally, Curacin A contains a notable

thiazoline Thiazolines (; or dihydrothiazoles) are a group of isomeric 5-membered heterocyclic compounds containing both sulfur and nitrogen in the ring. Although unsubstituted thiazolines are rarely encountered themselves, their derivative (chemistry), der ...

ring and a unique

cyclopropyl A cyclopropyl group is a chemical structure derived from cyclopropane; it is typically produced in a cyclopropanation reaction. The group has an empirical formula of C3H5 and chemical bonds from each of the three carbons to both of the other tw ...

moiety, which is essential to the compound's

biological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...

. Curacin A has been characterized as potent antiproliferative

cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of dr ...

compound with notable anticancer activity for several

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

lines including renal, colon, and breast cancer. Curacin A has been shown to interact with colchicine binding sites on

tubulin Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytosk ...

, which inhibits

microtubule polymerization Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...

, an essential process for cell division and proliferation.

Biosynthesis

The synthetic

enzymes An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as pro ...

for Curacin A are found in a gene cluster with 14

open reading frame In molecular biology, reading frames are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible reading frames ...

s (ORFs) with the nomenclature CurA through CurN. Analysis of the pathway demonstrated the presence of one NRPS/PKS hybrid module located on CurF, one

HMG-CoA β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl coenzyme A, is an intermediate in the mevalonate pathway, mevalonate and ketogenesis pathways. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase ...

synthase cassette located on CurD, and seven monomodular PKS modules. CurA contains a unique GCN5-related ''N''-acetyltransferase (GNAT) loading domain and an associated acyl carrier protein (ACP). The loading module tethers an acetyl group to the ACP that then condenses with one of three tandem ACPs present in the adjacent module of CurA. An hydroxymethylglutaryl-CoA synthase cassette (mevalonate pathway) catlyzes the formation of hydroxymethylglutaryl acid by the addition of an malonyl-CoA unit to the terminal ketide of the aceto-acetyl-ACP moiety of ACP1,ACP2, or ACP3. subsequent enzymes, including a unique heme independent halogenase (HaI) catalyze the formation of a cyclopropyl ring. A cysteine specific NRPS module located on CurF follows after cyclopropyl ring formation, and due to the activity of a cyclizing condensation domain, forms a thiazole ring attached to the cylcopropyl moiety from previous reactions in the pathway. Seven standalone PKS modules follow to extend the growing

polyketide In organic chemistry, polyketides are a class of natural products derived from a Precursor (chemistry), precursor molecule consisting of a Polymer backbone, chain of alternating ketone (, or Carbonyl reduction, its reduced forms) and Methylene gro ...

chain with ''S''-adenosyl methionine (SAM) dependent methylations occurring at positions 10 and 13. A rare offloading strategy involving a sulfotransferase is employed by the final curacin synthase module. The sulfotransferase sulfates the hydroxyl group of carbon 15, which activates the molecule for decarboxylation and terminal alkene formation.

Cyclopropyl ring formation

The CurB (ACP), CurC (ketosynthase), and CurD (HMG-CoA reductase) are responsible for the formation of (S)HMG-ACP3. HaI, from the CurA gene, is a unique non-heme halogenase that goes through a purported Fe(IV)=O intermediate to add a chlorine atom onto an unactivated carbon atom. After chlorination, ECH1 acting as a dehydratates HMG-ACP3 to 3-methylgultaconyl-ACP3 and ECH2 performs the required decarboxylation. Finally,an unusual ER catalyzed cyclization reaction, purported to go through a substitution like mechanism, forms the cyclopropane ring. The added chlorine atom assists in the decarboxylation step and likely serves as the leaving group during cyclopropane ring formation.

References

{{reflist , 2 Polyketides Cyclopropanes Alkene derivatives