[5,6]-spiroketal formation in griseorhodin A biosynthesis

Rubromycins (incl. griseorhodin A) are complex molecules, particularly interesting for drug industry, as recent studies have shown that these compounds could serve as potent antimicrobials and anticancer agents. However, for that purpose, great amounts of these molecules are needed, precluding the isolation of these compounds from their natural producers (certain bacteria). Instead, chemical synthesis strategies need to be employed, but, due to the complex chemical nature of the molecules classical synthetic chemistry, so far, has failed to produce these interesting compounds. This problem, nevertheless, could be overcome by using a combined chemical and enzymatic synthesis. In this case, relatively simple rubromycin precursors could be synthesized in the wet lab and would later be converted to the desired final products using enzymes naturally involved in rubromycin formation. Such an approach, however, requires a very detailed understanding of the enzymes considered to be employed in this reaction cascade, because enzymes are quite particular and do not convert every molecule provided to them. To better understand the structural prerequisites for compounds to be converted to the desired rubromycins, I will investigate three enzymes (GrhO1, GrhO5 and GrhO6) that, only recently, have been postulated to be involved in the key steps in griseorhodin A biosynthesis. The information gained from the analysis of their 3D structures and from studying their mode of action, will certainly help to get one step closer to the ultimate goal of establishing an artificial synthesis route for rubromycin-like compounds, required for their application as pharmaceuticals.