Terpenoids are a large (estimated 60% of known natural products ) and diverse group of lipids derived from five-carbon isoprene units assembled in thousands of combinations. Technically a terpenoid contains oxygen, while a terpene is a hydrocarbon. Often the two terms are used to refer collectively to both groups.

ompounds classified as terpenes constitute what is arguably the largest and most diverse class of natural products. A majority of these compounds are found only in plants, but some of the larger and more complex terpenes (e.g. squalene & lanosterol) occur in animals. Terpenes incorporating most of the common functional groups are known, so this does not provide a useful means of classification. Instead, the number and structural organization of carbons is a definitive characteristic. Terpenes may be considered to be made up of isoprene (more accurately isopentane) units, an empirical feature known as the isoprene rule.

While we can identify isoprene units within a terpenoid structure and use that in its classification, the building block for terpenoid synthesis in nature is isopentenyl diphosphate (formerly called isopentenyl pyrophosphate and abbreviated IPP). There are two major routes to the synthesis of IPP; namely (1) the mevalonate pathway and (2) the 1-deoxyxylulose pathway.

Mevalonate Pathway

Claisen Condensation: An early step in the biosynthesis of cholesterol and other ‘isoprenoid’ compounds is a Claisen condensation between two acetyl CoA molecules. An initial trans-thioesterase process transfers the acetyl group of the first acetyl CoA to an enzymatic cysteine (Reaction 1). In the Claisen condensation phase of the reaction, the alpha-carbon of a second acetyl CoA is deprotonated, forming an enolate.

The enolate carbon attacks the electrophilic thioester carbon, forming a tetrahedral intermediate (Reaction 3) which quickly collapses to expel the cysteine thiol (Reaction 4) and produce acetoacetyl CoA.

Aldol Condensation: Acetyl CoA then reacts with the acetoacetyl CoA in an aldol-like addition. Subsequent hydrolysis produces (3S)-3-hydroxy-3-methylglutaryl CoA (HMG-CoA).

Reduction of the Thioester: The thioester is reduced first to an aldehyde, then to a primary alcohol by two equivalents of NADPH producing (R)-mevalonate. The enzyme catalyzing this reaction is the target of the statin family of cholesterol-lowering drugs.

Mevalonate Phosphorylation: Two phsophorylations by adenosine triphosphate (ATP) occur at the terminal hydroxyl/phosphorus group through nucleophilic substitution, followed by a third ATP phosphorylation of the tertiary hydroxyl group.

Decarboxylation: Finally isopentenyl diphosphate (IPP), the 'building block' for all isoprenoid compounds, is formed from a decarboxylation-elimination reaction.

Conversion of IPP to Terpenoids

The electrophilic double bond isomerization catalyzed by IPP isomerase is a highly reversible reaction, with an equilibrium IPP:DMAPP ratio of about 6:1. In the next step of isoprenoid biosynthesis, the two five-carbon isomers condense to form a 10-carbon isoprenoid product called geranyl diphosphate (GPP).

The first step is ionization of the electrophile - in other words, the leaving group departs and a carbocation intermediate is formed. In this case, the pyrophosphate group on DMAPP is the leaving group, and the electrophilic species is the resulting allylic carbocation.

In the condensation (addition) step, the C3-C4 double bond in IPP attacks the positively-charged C1 of DMAPP, resulting in a new carbon-carbon bond and a second carbocation intermediate, this time at a tertiary carbon. In the elimination phase, proton abstraction leads to re-establishment of a double bond in the GPP product. Notice that the enzyme specifically takes the pro-R proton in this step.

To continue the chain elongation process, another IPP molecule can then condense, in a very similar reaction, with C1 of geranyl diphosphate to form a 15-carbon product called farnesyl diphosphate (FPP).