mevalonate pathway

The biosynthesis of isopentenyl pyrophosphate (IPP) occurs via two distinct routes: the mevalonate pathway (MVA pathway, this pathway) and the methylerythritol phosphate pathway (MEP pathway) .In the former, IPP is synthesized from the condensation of three acetyl-CoA molecules; in contrast the MEP pathway occurs via the condensation of pyruvate and D-glyceraldehyde 3-phosphate. For many years, the MVA pathway was considered to be the sole source of IPP in all living organisms, however, several inconsistencies led to the discovery of the MEP pathway in bacteria and plants. In the latter the MVA pathway is located in the cytosol whilst the MEP pathway is found in plastids.

In eukaryotic cells, the mevalonate pathway leads to plant sterol biosynthesis , superpathway of ergosterol biosynthesis and dolichols via the formation of farnesyl diphosphate (FPP). IPP from this pathway is also used to synthesize cytosolic geranylgeranyl diphosphate (GGPP) which is used (along with FPP) for the prenylation of proteins. In plants, the mevalonate pathway is also a source of isoprene units for the biosynthesis of a variety of terpenoids (cytokinins, brassinosteroids, sesquiterpenes, polyprenoids). However, the MVA pathway appears not to function independently from the MEP pathway but rather interacts through metabolic cross-talk.

This pathway described as mevalonat pathway displays the enzymatic steps that lead to mevalonate and the further conversion towards dimethylallyl pyrophosphate (DMPP) one of the crucial intermediates that give rise to several terpenoid and plant hormone pathways. Most of the enzymes characterized in Arabidopsis thaliana from this pathway have been demonstrated to be fully functional, largely through functional complementation of bacterial and yeast mutant strains.

The first enzyme of the pathway, i.e. acetoacetyl (AcAc)-CoA thiolase (AACT; EC 2.3.1.9) that catalyzes the condensation of two acetyl-CoA to form acetoacetyl-CoA has not yet been identified in Arabidopsis. The following enzyme hydroxymethylglutaryl-CoA synthase (HMGS) catalyzes the formation of the thermodynamically favourable aldol condensation of one molecule of AcAc-CoA with acetyl-CoA to form one molecule of S-HMG-CoA .The proposal that the conversion from acetyl-CoA to hydroxymethylglutaryl-CoA comprising two enzymatic steps is carried out by a single enzyme was not confirmed as the yeast mutant deficient in acetoacetyl-CoA thiolase could not be functionally complemented. The isolation and characterization of hydroxymethylglutaryl-CoA synthase from Brassica juncea indicates that those conversions are conducted by two independent proteins.

The last enzymatic step to form mevalonate is accomplished by hydroxymethylglutaryl-CoA (HMG-CoA) reductase, which are encoded in Arabidopsis by two genes HMG1 and HMG2 from which HMG1 forms two isoforms, HMGR1S and HMGR1L. The enzyme is located within the Endoplasmatic Reticulum (ER) but has also been found within new and so far unidentified vesicular structures in the cytoplasm and within the vacuole of differentiated cotyledon cells .

The remaining steps towards DMPP comprise two phosphorylation steps to convert mevalonate to mevalonate-5-diphosphate. Following the ATP-dependent decarboxylation of mevalonate-5-diphosphate to generate isopentenyl-pyrophosphate (IPP) the final enzyme of the pathway, isopentenyl-diphosphate delta-isomerase encoded by two genes (IPP1, IPP2) forms dimethylallyl pyrophosphate (DMPP)