Thursday, November 5, 2009

Lovastatin-synthesizing enzyme successfully reconstituted...

Lovastatin is a member of the drug class of statins, used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. Lovastatin is a naturally occurring drug found in food such as oyster mushrooms and red yeast rice. When I was working with a Banglore based company (Biocon), they did try this compound and I think the company is marketing this drug now. As for as my knowledge goes there were two ways to synthesise 'biosynthesis using Dield-Alder catalyzed cyclization' & 'biosyntheis using broadly specific acyltransferase'

Dield-Alder catalysed cyclisation : In vitro formation of a triketide lactone using a genetically-modified protein derived from 6-deoxyerythronolide B synthase has been demonstrated. The stereochemistry of the molecule supports the intriguing idea that an enzyme-catalyzed Diels-Alder reaction may occur during assembly of the polyketide chain. It thus appears that biological Diels-Alder reactions may be triggered by generation of reactive triene systems on an enzyme surface.

Biosynthesis using broadly specific acyltransferase : It has been found that a dedicated acyltransferase, LovD, is encoded in the lovastatin biosynthetic pathway. LovD has a broad substrate specificity towards the acyl carrier, the acyl substrate and the decalin acyl acceptor. It efficiently catalyzes the acyl transfer from coenzyme A thoesters or N-acetylcysteamine (SNAC) thioesters to monacolin J. The biosynthesis of lovastatin is coordinated by two iterative type I polyketide syntheses and numerous accessory enzymes. Nonketide, the intermediate biosynthetic precursor of lovastatin, is assembled by the upstream megasynthase LovB (also known as lovastatin nonaketide synthase), enoylreductase LovC, and CYP450 oxygenases.

Recently more interesting out come from a group of UCLA researchers is that, for the first time thy have successfully reconstituted in the laboratory the enzyme responsible for producing the blockbuster cholesterol-lowering drug lovastatin. As per the claim by the researchers, the lovastatin-synthesizing enzyme is one of the most interesting but least understood of the polyketide synthases, which are found in filamentous fungi and which play a crucial role in the synthesis of "small molecule natural products" — pharmacologically or biologically potent compounds produced by living organisms, many of which are the active ingredients in pharmaceuticals.

This finding is of great significance because commonly used antibiotics, such as tetracycline, are produced by polyketide synthases. Polyketides represent a class of 7,000 known structures, of which more than 20 are commercial drugs, including the immunosuppressant rapamycin, the antibiotic erythromycin and the anticancer drug doxorubicin. In their study studied the enzyme that makes a small-molecule precursor to lovastatin. The real difference about this enzyme, is its extraoridnarily large size in comparison to all other enzymes so for studied. As per the claim by the lead researcher Dr. Yi Tang, "It's one of the largest enzymes ever to be reconstituted in a test tube. It is 10 times the size of most enzymes people study & the enzyme has seven active sites and catalyzes more than 40 different reactions that eventually result in an important precursor to lovastatin. Hope with this remarkable achievement, one can prepare many natural products in the lab in the days to come.

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