Metabolic Engineering towards Simvastatin Biosynthesis
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Statins are extremely important drugs for treating cardiovascular diseases. Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR), which catalyzes the rate-limiting step in cholesterol biosynthesis. The importance of statins to atherosclerosis has been compared to that of penicillin to infectious diseases. One of the top selling statins is simvastatin, the active pharmaceutical ingredient of the blockbuster drug Zocor. The worldwide market of simvastatin, which become a generic drug in 2007, is ~ $2 billion USD. Simvastatin is currently chemically synthesized from lovastatin, which is naturally produced by the fungus Aspergillus terreus, as a semisynthetic drug. Within the structure of lovastatin is an alpha-methylbutyrate side chain that is important for binding to HMGR. At the same position in simvastatin is an alpha-dimethylbutyrate side chain, a subtle difference from lovastatin that results in more potent inhibition and decreased side effects. The synthesis from lovastatin to simvastatin requires multiple protection and deprotection steps and is highly inefficient despite a decade of process refinement. Therefore, new methods that can increase the efficiency of simvastatin synthesis, decrease the cost of production and operate under greener conditions will be of significant impact and commercial value. One attractive alternative to the current chemical modification is by using a carefully chosen/designed enzyme and an engineered microbe to yield a new process that is significantly more efficient, cost effective and environmentally friendly. We have previously discovered an enzyme that can synthesize simvastatin directly from a biosynthetic precursor of lovastatin. The industrial sponsor of this grant, Codexis Inc (Redwood City, CA) licensed the intellectual property on this enzyme from UCLA and has engineered the enzyme into a powerful biocatalyst towards simvastatin production from lovastatin. In this grant, we seek to join forces and genetically and metabolically engineer A. terreus towards direct production of simvastatin, without requiring first isolation of lovastatin. The targeted processes can be directly implemented using the current fermentation facilities that are used to produce lovastatin, thereby completely eliminating the chemical semisynthetic steps. The collaboration between the Tang lab at UCLA and Codexis is seamlessly complementary. While the Tang lab has expertise in natural product biosynthesis and fungal genetics, Codexis is the leader in protein engineering and the most successful company in applying biocatalysis to pharmaceutical synthesis. The two sides already have extensive collaboration. The UC DISCOVERY grant is therefore a perfect mechanism for both parties to work on this important, proposed project. From a broader impact perspective, this work proposed here is at the cutting edge of the emerging discipline of synthetic biology. The new process wil