Fungal Cell Factories - Food and Industrial Bioproducts and Bioprocessing - page 208

A (HMG-CoA) reductase inhibitors that block the HMG-CoA reductase (HMGR) conversion
of HMG-CoA into mevalonic acid, an early and rate-limiting step in de novo cholesterol
biosynthesis. The lactone ring of the statin molecule is reversibly converted to an open acid
that resembles the HGM portion of HMG-CoA (Figure 8.2), the substrate of the reaction
catalyzed by the HMGR enzyme (Endo, 2004). The mechanism by which statins lower
cholesterol is an important factor in its success. Previous attempts to reduce cholesterol
biosynthesis, such as the Triparanol compound that blocks a late step in the pathway, were
ultimately unsuccessful due to accumulation of potentially toxic precursors and adverse
effects.
The first identified HMGR inhibitor mevastatin, also known as compactin and
ML-236B, was isolated from Penicillium citrinum in 1971 by Japanese microbiologist
Endo Akira at Sankyo (Endo, 1979). However, the chemically distinct lovastatin, isolated
from the soil fungus Aspergillus terreus in 1978 by Alberts and colleagues at Merck
Research Laboratories, became the first statin developed for human drug use (Alberts
et al ., 1980). Lovastatin proved to be slightly more effective in lowering total serum cho-
lesterol than mevastatin (Alberts et al ., 1980 ; Endo, 1980 ), and Merck patented lovastatin
in 1980 (Monaghan et al ., 1980 ; Tobert, 2003 ). The US Food and Drug Administration
approved lovastatin in 1987, and it became the first prescribed statin used in humans for
lowering cholesterol. Lovastatin was a blockbuster for Merck, with over $1 billion of
sales at its peak (Tobert, 2003).
The discovery of these early statins paved the way for the worldwide development of
other drugs based on the statin chemical structure (Figure 8.2). Sankyo and Merck directed
their later efforts at manufacturing synthetic analogs. Many different statins are currently
available for therapeutic use, but lovastatin and mevastatin remain the only fermentation-
derived statins. The lovastatin biosynthetic pathway in A. terreus is well understood. This
pathway was the first example of a polyketide synthetic pathway in which two fungal type
I polyketide synthases work in combination to produce a product (Hendrickson et al .,
1999 ; Kennedy et al ., 1999). Since then several statins, including simvastatin, pravastatin,
fluvastatin and atorvastatin, have been approved in many countries and are currently used
by millions.
8.4 GENOMICS AND THE FUTURE
8.4.1 Citric acid and Aspergillus niger
Current A. niger industrial strain development combines information garnered from
the reported genome sequences and targeted reverse genetic engineering to boost enzyme
and acid production. Pel and colleagues reported the genome sequence of A. niger CBS
513.88, a predecessor to the now widely used workhorse strain for industrial enzyme
and organic acids production, including citric acid (Pel et al ., 2007 ). The authors integrated
the annotated genome data into a model of central carbon metabolism to better understand
the metabolic processes behind the organism's high productivity. Genetic redundancy
may be one factor that influences citric acid overflow; the model highlights the involve-
ment of multiple copies of citrate synthases, aconitases and malate dehydrogenase-like
sequences.