(+)-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) an ...

, 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 especia ...

'' roots in 1960. It is also found in

lettuce Lettuce (''Lactuca sativa'') is an annual plant of the family Asteraceae. It is most often grown as a leaf vegetable, but sometimes for its stem and seeds. Lettuce is most often used for salads, although it is also seen in other kinds of food, ...

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 al ...

of compound 1,

farnesyl pyrophosphate Farnesyl pyrophosphate (FPP), also known as farnesyl diphosphate (FDP), is an intermediate in the biosynthesis of terpenes and terpenoids such as sterols and carotenoids. It is also used in the synthesis of CoQ (part of the electron transport cha ...

(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 unique combinations. Biochemical modificatio ...

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, (+)-germacryl cation. Inside this same

enzyme Enzymes () are proteins that act as biological catalysts 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 products. A ...

, a

proton A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...

is lost to form 3, (+)-

germacrene A Germacrenes are a class of volatile organic hydrocarbons, specifically, sesquiterpenes. Germacrenes are typically produced in a number of plant species for their antimicrobial and insecticidal properties, though they also play a role as insect ph ...

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

hydroxylated In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemistry, chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH gr ...

by (+)-germacrene A

hydroxylase In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a m ...

, which is a

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

enzyme, to form 4. NAD(P)⁺ dependent

hydrogenase A hydrogenase is an enzyme that catalyses the reversible oxidation of molecular hydrogen (H2), as shown below: Hydrogen uptake () is coupled to the reduction of electron acceptors such as oxygen, nitrate, sulfate, carbon dioxide (), and fumara ...

(s) then

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

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 cyctochrome 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 NAD ...

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

alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...

intermediate, 7, which then cyclizes to form the

lactone Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. Lactones are formed by intramolecular esterification of the co ...

8, (+)-costunolide. Figure 1. Biosynthesis of (+)-Costunolide.

References

{{Reflist Sesquiterpene lactones Vinylidene compounds