Researchers learn how nature produces cholesterol-lowering agent

Scientists know that a fuzzy fungus similar to the mold that grows on stale bread and over-ripe fruit produces lovastatin, the natural substance that lowers cholesterol in humans. Now researchers at the School of Pharmacy have learned how the fungus makes it.

The UW researchers, who in the past decade have made key discoveries about the way microorganisms produce related substances such as antibiotics and certain cancer-fighting agents, reported their findings in the May 21 Science.

The discovery may prove useful to pharmaceutical companies, which currently manufacture nearly $4 billion of cholesterol-lowering drugs each year, by providing a more efficient, less costly approach. The findings may also be used to genetically alter fungus metabolism to yield more potent drugs. Bacteria and fungi produce hundreds of substances like lovastatin, designed to improve the odds of their own survival. Many of the substances, called polyketides, appear as attractive or repellent aromas, flavors, colors or toxins. Some, like tetracycline and erythromycin, have been found to be medically useful for humans.

Ten years ago UW pharmacy professor C. Richard Hutchinson and scientists in England discovered one process by which microorganisms produce polyketides. The scientists found that six enzymes work together with two or three carbon building blocks to produce a series of biochemical reactions leading ultimately to a complex molecule, a structure that makes a colored pigment. Other scientists at Cambridge University and Abbott Laboratories in Chicago later found a second way microbes make polyketides, utilizing three enzymes and four variations of building blocks. Products of this process are never pigmented, but they can result in erythromycin, which is widely used as an antibacterial drug.

But the UW researchers suspected a third process might exist when they looked closely at one gene associated with lovastatin production. “When we analyzed the gene, we found it behaved differently than it should have based on the earlier standards,” he said.

Examining a second gene they found near the first, the UW researchers observed to their surprise that both were required to make two enzymes that produced lovastatin. The process entailed a pathway of 35 steps and seven major activities. What’s more, the scientists saw that lovastatin’s actual cholesterol-reducing capability didn’t materialize until the end of the process where it was governed by two additional genes. “Polyketides are very complex so it’s challenging and expensive to alter them by existing chemical means,” Hutchinson said. “With this new information we now can genetically engineer fungi to produce lovastatin in a less complicated and less costly way.”

The new discovery also greatly increases potential ways novel drugs can be made through genetic engineering of polyketide-forming genes. Hutchinson estimates that 10 to 15 percent of all polyketides may be made this unique way.