Aspergillus Terreus Isolated from the Brazillian Diversity: Genomic Variability Associated to Lovastatin Production

The World Health Organization (WHO) has determined that cardiovascular diseases are the leading cause of deaths worldwide. In 2008, about 17.3 million people died from cardiovascular disease accounting for about 30% of total world deaths. This number is expected to increase 34% by 2030 (OMS 2008). According to the Brazilian Society of Cardiology, in Brazil, it has been estimated that 300-400mil people die of cardiovascular disease being the leading cause of mortality in the country (SBC 2012)
One of the causes that may lead to cardiovascular disease is hypercholesterolemia which represents high blood cholesterol levels (> 200mg/dL). In U.S. one in every six Americans has high cholesterol level in the blood (CDC 2012) and in Brazil a study including Brazillians from different cities  had showed that about 40% of this population had cholesterol above normal levels(Martinez, Santos et al. 2003).

Statins are the most used drugs for hypercholesterolemia treatment. These are inhibitors of HMG-CoA reductase, the first enzyme in the cholesterol biosynthesis pathway, which catalyzes the reduction of HMG-CoA to mevalonate. Statin treatment reduces cholesterol synthesis preventing the buildup of plaque inside the arteries (Barrios-Gonzalez and Miranda 2010). Among naturally occuring statins, Lovastatin is the active principle of drugs such as Mevacor, Altocor and Altoprev. Also, is the precursor of Simvastatin, the second best-selling statin world being the active drug like Zocor and Lipex (Barrios-Gonzalez and Miranda 2010). Simvastatin is produced chemically from the direct alkylation of lovastatin. However, the chemical conditions are not environmentally friendly and the final product is difficult to be purified (Barrios-Gonzalez and Miranda 2010).The fermentation process was then developed and patented where the simvastatin is produced by fermentation of genetically modified strains of Aspergillus terreus (Van Den Berg, Hans et al. 2009). Thus strains that hyper produce lovastatin allow the production not only of this statin but its derivatives.

Up to now a single strain of the fungus Aspergillus terreus (ATCC20542) is used for industrial lovastatin production. Additionally strains producing different amounts of lovastatin allow a comparative study in order to improve knowledge on the biosynthetic pathway of this compound. Therefore the present study aimed at isolation of A. terreus strains that superproduce lovastatin. Screening results enabled identification of strains with similar production as control strain ATCC20542 (~300mg/L) and isolates that produced traces amount of lovastatin (~6mg/L). Those strains were further identified as A. terreus using both molecular and protein finger printing profile. Genomic sequences from lovastatin cluster were obtained from strains producing different lovastatin levels and are correlated to statin production. Up to date this is the first time that A. terreus strains are compared in genomic level and correlated to lovastatin production.

References

Barrios-Gonzalez, J. and R. U. Miranda (2010). "Biotechnological production and applications of statins." Applied Microbiology and Biotechnology 85(4): 869-883.

 CDC, C. f. D. C. a. P. (2012). "(http://www.cdc.gov/cholesterol/facts.htm) ".

 Martinez, T. L., R. D. Santos, D. Armaganijan, K. P. Torres, A. Loures-Vale, M. E.

 Magalhaes, J. C. Lima, E. Moriguchi, C. Amodeo and J. Ortiz (2003). "National alert campaign about increased cholesterol: determination of cholesterol levels in 81,262 Brazilians." Arq Bras Cardiol 80(6): 635-638, 631-634.

 OMS. (2008). "http://www.who.int/mediacentre/factsheets/fs317/en/." from http://www.who.int/mediacentre/factsheets/fs317/en/.

 SBC, S. B. d. C. (2012). "(http://socios.cardiol.br/noticias/colesterol.asp."

 Van Den Berg, M., M. Hans and H. Streekstra (2009). METHOD FOR THE PRODUCTION OF SIMVASTATIN. US 2009/019731.