(+)-Costunolide is a naturally occurring

sesquiterpene lactone Sesquiterpene lactones (SLs) are a class of sesquiterpenoids that contain a lactone ring. They are most often found in plants of the family Asteraceae (daisies, asters). Other plant families with SLs are Umbelliferae (celery, parsley, carrots) ...

, first isolated in ''

Saussurea costus ''Dolomiaea costus'', formerly known as ''Saussurea costus'', commonly known as costus, Indian costus, kuth, or putchuk, is a species of thistle in the genus '' Dolomiaea'' native to South Asia and China. Rishi (Hindu) mystics of Kashmir especial ...

'' roots in 1960. It is also found in

lettuce Lettuce (''Lactuca sativa'') is an annual plant of the family Asteraceae mostly grown as a leaf vegetable. The leaves are most often used raw in Green salad, green salads, although lettuce is also seen in other kinds of food, such as sandwiche ...

Synthesis

It is synthesized through the

mevalonate pathway The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl ...

, seen in Figure 1. The synthesis begins with the

cyclization A cyclic compound (or ring compound) is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where ...

of compound 1,

farnesyl pyrophosphate Farnesyl pyrophosphate (FPP), also known as farnesyl diphosphate (FDP), is the precursor to all sesquiterpenes, which comprises thousands of compounds. These include all sesquiterpenes as well as sterols and carotenoids. It is also used in the syn ...

(FPP), which is mediated by a

sesquiterpene Sesquiterpenes are a class of terpenes that consist of three isoprene units and often have the molecular formula C15H24. Like monoterpenes, sesquiterpenes may be cyclic or contain rings, including many combinations. Biochemical modifications s ...

cyclase A cyclase is an enzyme, almost always a lyase, that catalyzes a chemical reaction to form a cyclic compound. Important cyclase enzymes include: * Adenylyl cyclase, which forms cyclic AMP from adenosine triphosphate (EC 4.6.1.1) ** ADCY1 ** ADCY2 ** ...

, (+)-germacrene A synthase, to form compound 2, cation. Inside this same

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

, a

proton A proton is a stable subatomic particle, symbol , Hydron (chemistry), H+, or 1H+ with a positive electric charge of +1 ''e'' (elementary charge). Its mass is slightly less than the mass of a neutron and approximately times the mass of an e ...

is lost to form 3, (+)-

germacrene A Germacrenes are a group of five naturally occurring volatile organic hydrocarbons of the sesquiterpene and cycloalkene class. Germacrenes are typically produced in a number of plant species for their antimicrobial and insecticidal properties, th ...

. The isoprenyl side chain of (+)-germacrene A is then

hydroxylated In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...

by (+)-germacrene A

hydroxylase In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate Alcohol (chemistry), alcohols and phenols, which are very common functional groups. Hydroxylation confers some degre ...

, which is a

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

enzyme, to form 4. NAD(P)⁺ dependent

hydrogenase A hydrogenase is an enzyme that Catalysis, catalyses the reversible Redox, oxidation of molecular hydrogen (H2), as shown below: Hydrogen oxidation () is coupled to the reduction of electron acceptors such as oxygen, nitrate, Ferric, ferric i ...

(s) then

oxidize Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

4, germacra-1(10),4,11(13)-trien-12-ol, through the intermediate 5, germacra-1(10),4,11(13)-trien-12-al to form compound 6, germacrene acid. The cytochrome P450 enzyme, (+)-costunolide synthase, which is a

NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require N ...

and O₂ dependent enzyme, then oxidizes germacrene acid to give the

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

intermediate, 7, which then cyclizes to form the

lactone Lactones are cyclic carboxylic esters. They are derived from the corresponding hydroxycarboxylic acids by esterification. They can be saturated or unsaturated. Lactones are formed by lactonization, the intramolecular esterification of the corresp ...

8, (+)-costunolide. :

References

{{Reflist Sesquiterpene lactones Vinylidene compounds