Chimeric Yeast Pumps Out Steroids

By mixing and matching a menagerie of genes, scientists have reprogrammed yeast to churn out a human steroid. This new approach, unveiled in this month's Nature Biotechnology, might be used to produce steroids--natural substances that can fight cancer and inflammation and are a key ingredient in some contraceptives--at a lower cost than traditional chemical synthesis.

The steroid progesterone helps maintain pregnancy; given to nonpregnant women, it dupes the body into not ovulating. Although the body's assembly line of progesterone-building enzymes has been reproduced in the test tube and in mammalian cell culture, these approaches are inefficient and costly. Now, in a three-way collaboration with Hoechst-Marion-Roussel and Transgene, Denis Pompon and colleagues at the Center for Molecular Genetics at the French national research agency CNRS in Paris have overcome these problems by reprogramming baker's yeast to cook up progesterone and its precursor, pregnenolone.

By inactivating a yeast gene, the researchers stopped the production of a yeast steroid called ergosterol and instead allowed its precursors to accumulate. They also inserted a plant gene that makes an enzyme that converted these precursors into a compound resembling cholesterol, a progesterone precursor. Three cow genes added enzymes and cofactors that shuffled electrons and cleaved part of the cholesterol-like compound to produce pregnenolone. As a final touch, an enzyme coded by a human gene converted pregnenolone to progesterone.

Within 4 days, the yeasty enzyme broth was producing 60 to 100 milligrams of pregnenolone per liter and lesser amounts of progesterone. "They have achieved one milestone in the effort to produce steroid hormones in microorganisms," says Michael Waterman, a biochemist at the Vanderbilt University Medical Center in Nashville, Tennessee. With an additional step, Pompon says, this yield could be upped to meet "the industrial requirement for economic competition with chemical synthesis."