Isoprenoid Biosynthesis Intermediates Analysis Service


Isoprenoids are a large, diverse class of naturally occurring organic chemicals that are essential for  cell survival. Over 35000 isoprenoid molecules have been identified to date in  the three domains of life (bacteria, archaea and eukaryotes), and they are  involved in a wide variety of vital biological functions.

The isoprenoid biosynthesis pathway is an important  metabolic pathway that produces a range of sterol and non-sterol isoprenoids,  vital for multiple cellular functions. Cholesterol is an important sterol end  product of the pathway and functions not only as a structural component of the plasma  membrane, but also as the precursor for steroid hormones, bile acids and  oxysterols. In addition, the pathway synthesizes non-sterol isoprenoids (such as  the side chains of ubiquinone-10 and heme A, dolichol, isopentenyl tRNA and the  farnesyl and geranylgeranyl groups of isoprenylated proteins) which are  incorporated into diverse classes of end products that participate in processes  relating to cell growth, differentiation, cytoskeletal function and vesicle  trafficking.

The  isoprenoid biosynthesis pathway.  Figure 1. The isoprenoid biosynthesis pathway.

The  mevalonate pathway is the non-sterol, pre-squalene part of the isoprenoid  biosynthesis and is involved in the synthesis of all isoprenoids. This pathway  starts with three acetyl-CoAs, which are converted into  3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) in two consecutive enzyme steps.  HMG-CoA is then converted into mevalo-nate (MVA) by the rate-limiting enzyme of  the pathway, HMG-CoA reductase. Subsequently, MVA is phosphorylated twice,  which produces 5-pyrophosphomevalonate (MVAPP). Decarboxylation of this latter  compound yields isopentenyl pyrophosphate (IPP). After isomerization of IPP to  dimethylallyl pyrophosphate (DMAPP), a head-to-tail condensation of IPP to  DMAPP results in the formation of geranyl pyrophosphate (GPP). Addition of  another IPP gives farnesyl pyrophosphate (FPP), the branch point metabolite of  the pathway, which is the precursor of geranylgeranyl pyrophosphate (GGPP); GGPP is produced by the condensation of one FPP with one IPP  molecule.

It  is significant that human/mammalian isoprenoid biosynthesis is the target of  several FDA-approved drugs, including those used in the treatment of cancer  (taxol), bone disease (bisphosphonates) and hypercholesterolaemia (statins). In  humans, cholesterol biosynthesis proceeds via the mevalonate pathway, which is  responsible for the production of the IPP precursor molecule. Some of the  best-characterized and most effective inhibitors of IPP biosynthesis are the  cholesterol-lowering statins. Statins disrupt a reaction in the mevalonate  pathway by binding to and inhibiting HMGR, the rate-limiting enzyme for  cholesterol biosynthesis in mammals. Nitrogenous bisphosphonates (NBPs) such as  pamidronate and zoledronate, which are predominantly used to treat bone  disease, also target the mevalonate pathway by inhibiting farnesyl  pyrophosphate synthase. The IPP isomerases have been considered as potential  targets; however, as humans possess the type I isomerase, specific inhibitors  of the type II enzyme could function to target pathogenic bacteria such as  multidrug-resistant Staphylococcus.

Since  the isoprenoid biosynthesis pathway is an important target in many areas of  ongoing research, new inhibitors to block this pathway are being developed.  Inhibition of this pathway is already applied in the treatment of cardiovascular  disease, hypercholesterolemia and metabolic bone disease and is a possible new  therapy in cancer treatment. Therefore, Creative Proteomics developed a  sensitive and specific method for the detection and quantification of nearly  all intermediates of the isoprenoid  biosynthesis pathway using UPLC–MS/MS, which can be used to investigate  the specificity of inhibitors of this pathway.

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Isoprenoid  Biosynthesis Intermediates Quantified  in This Service

With  integrated set of separation, characterization, identification and  quantification systems featured with excellent robustness &  reproducibility, high and ultra-sensitivity, Creative Proteomics provides  reliable, rapid and cost-effective isoprenoid biosynthesis intermediates targeted  metabolomics services.

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