ssibly peroxisomes. The biosynthesis of the 27-carbon molecule from the initial 2-carbon acetyl-CoA building block involves the formation of mevalonate in the rate-determining step of the reaction leading to the formation of IPP. IPP is the substrate for the synthesis of sterols such as cholesterol and of non-sterol isoprenoids used in a variety of cellular functions. Briefly described, Acat2 interconverts acetyl-CoA and acetoacetyl-CoA which are condensed into HMG-CoA by Hmgcs1. The reduction of HMG-CoA to mevalonate is catalyzed by Hmgcr. The enzyme is the target of statin drugs acting as competitive inhibitors. Mevalonate is phosphorylated twice sequentially by Mvk and Pmvk, respectively; the mevalonate-PP product is decarboxylated and then dehydrated by Mvd to yield IPP. IPP is kept in equilibrium with DMAPP by Idi1. Fdps catalyzes the head-to-tail condensation of IPP and DMAPP to form GPP first, and then of GPP and IPP to form FPP. Two molecules of FPP are condensed and then reduced to form squalene by Fdft1 in the first committed sterol step in the pathway. An oxygen-dependent step requiring FAD and NADPH followed by cyclization reactions carried out by Sqle and Lss respectively, convert squalene to lanosterol. Fdft1, Sqle and Lss enzymes are also targets for the development of cholesterol-lowering drugs. As these enzymes act downstream of Hmgcr, drugs that inhibit their function would not interfere with the production of IPP-derived non-sterol compounds, as explained above (eg. dolichol, ubiquinone). The pathway from lanosterol to cholesterol involves a series of demethylation, reduction and oxidation reactions which may proceed via two alternative routes; the exact sequence of events is still to be established. The availability of cholesterol is tightly regulated by post-translational modifications, at the transcriptional level and by feedback mechanisms - the role of the SREBP signaling pathway in the control of cholesterol synthesis and transport is a notable example. High levels of cholesterol are associated with cardiovascular diseases, hence the targeting of biosynthetic enzymes for the development of drugs. On the other hand, defects in some of the enzymes have been associated with a variety of disorders and syndromes. To see the Ontology Report for annotations, GViewer and download click here

[Click here to see the ontology report for associated GO term - GO:0006695 and entry at Reactome - REACT_9405.2]...(less)