Ergot to Anamycin -Biosynthesis

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158 J. Nat. Prod. 2006, 69, 158-169 ReViews From Ergot to Ansamycinss45 Years in Biosynthesis† Heinz G. Floss* Department of Chemistry, Box 351700, UniVersity of Washington, Seattle, Washington 98195-1700 ReceiVed October 5, 2005 In this review the author traces his scientific career from its beginnings in Germany to his moves to, successively, Purdue University, The Ohio State University, and finally University of Washington. During this time his research progressed from extensive studies on
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   Re V iews From Ergot to Ansamycins s 45 Years in Biosynthesis † Heinz G. Floss*  Department of Chemistry, Box 351700, Uni V ersity of Washington, Seattle, Washington 98195-1700 Recei V ed October 5, 2005 In this review the author traces his scientific career from its beginnings in Germany to his moves to, successively,Purdue University, The Ohio State University, and finally University of Washington. During this time his researchprogressed from extensive studies on ergot alkaloids, the stereochemistry of enzyme reactions, and tracer studies onantibiotic biosynthesis to its latest emphasis on the molecular biology of ansamycin antibiotics. The formative influenceof several mentors and colleagues is acknowledged.The year 2005 marks the end of my active involvement inscientific research. On such an occasion it is appropriate to look back and review where I came from, how I got to where I am now,and what some of the formative influences were along the way.However, I was cautioned not to become entirely enmeshed in asentimental journey, and hence, the second part of this review willsummarize some of the recent findings from our laboratory.I was born and raised in Berlin, Germany, finishing high schoolin 1953. How did I become a chemist? Well, as I prepared to entercollege, I was undecided between electrical engineering andchemistry. The Technical University Berlin at the time had cappedenrollments and required students to pass an entrance examination.I signed up for the exams in both subjects. The one for chemistrywas scheduled first; I passed it and never bothered to go to theother one. I have sometimes wondered what I would be doing hadthe electrical engineering exam been scheduled first, but I think,subconsciously, chemistry was my true preference.After the basic course of studies in chemistry, I joined theresearch group of organic chemistry professor Friedrich Weygandfor my “Diplomarbeit” (master’s thesis). Weygand was a studentof Richard Kuhn (Nobel Prize 1938), who was a student of RichardWillsta¨tter (Nobel Prize 1915), a student of Adolf v. Baeyer (NobelPrize 1905), who in turn was a student of August v. Kekule´ of benzene fame s not bad for pedigree. I studied a rearrangement of diazoketones using radioactive substrates that I synthesized. 1 Mywork was supervised by one of Weygand’s assistants, Dr. HelmutSimon, just returned from a postdoctorate with Melvin Calvin atUC Berkeley. Simon was later appointed to the faculty of theTechnical University Munich and became a lifelong friend.How did I get involved in natural products biosynthesis? Halfwayinto my M.S. research, Weygand accepted an offer from theTechnical University Munich, and in good German fashion mycollegues and I all migrated with him to Munich. When I arrivedthere after completion of my M.S. thesis, Weygand was very busyand, given my prior experience, asked me to synthesize severalradiolabeled versions of mevalonic acid while he thought about aproper Ph.D. thesis topic for me. Mevalonic acid had just beenidentified as the precursor of biological isoprene units and wasneeded for a collaboration with the group of Prof. Kurt Mothes inHalle, East Germany, on the biosynthesis of the ergot alkaloids.One year later, when I had finished all these syntheses, the idea of switching to a new topic for my Ph.D. thesis was rather unappealing,and I asked Weygand whether I could join the collaboration withthe Mothes group for my thesis work.Feeding experiments with the radiolabeled precursors establishedthe biosynthetic building blocks of the ergoline ring system astryptophan, the methyl group of methionine, and an isoprene unitderived from mevalonic acid (Figure 1). 2 This involvement of anamino acid and an isoprene unit represented a new paradigm, be- † Based on the opening lecture presented at the 46th Annual Meeting of the American Society of Pharmacognosy, Corvallis, OR, July 23 - 27, 2005.* To whom correspondence should be addressed. Tel: (206) 543-0310.Fax: (206) 685-8665. E-mail: floss@chem.washington.edu. Figure 1. Biosynthetic srcin of the ergoline ring system of ergotalkaloids. Figure 2. Two possibilities for attachment of the isoprenoid sidechain. 158 J. Nat. Prod. 2006, 69, 158 - 169 10.1021/np058108l CCC: $33.50 © 2006 American Chemical Society and American Society of PharmacognosyPublished on Web 12/15/2005  Figure 3. Biosynthetic pathway to the ergot alkaloids. Figure 4. Mechanism of cis - trans isomerization during D-ring closure.  Re V iews Journal of Natural Products, 2006, Vol. 69, No. 1 159  cause until then, an axiom of plant physiology had been that alka-loids and terpenoids did not co-occur in nature; subsequently, of course, many other classes of compounds, such as the indole alka-loids, were found to be of mixed amino acid and isoprenoid srcin.The next question was how the two main building blocks,tryptophan and the isoprenoid precursor dimethylallyl diphosphate,were initially connected. Two plausible possibilities are shown inFigure 2. The direct prenylation at C-4 of tryptophan had the Figure 5. Examples of microbial metabolites studied. Figure 6. First demonstration of genetic engineering of hybrid antibiotics (Hopwood et al., 1985). 160 Journal of Natural Products, 2006, Vol. 69, No. 1 Re V iews  problem that the 4-position is not the most nucleophilic site in anindole. The alternative, prenylation at the R -position of the sidechain, with simultaneous decarboxylation, circumvents this problem,because in the subsequent attack of a newly generated allylic cation,formation of a six-membered ring would favor the 4-position. Weplanned to test these two possibilities by synthesizing both potentialproducts in labeled form. We obtained compound II first and uponfeeding it to the ergot fungus found radioactivity in the elymoclavine Figure 7. Ansamycin antibiotics with mC 7 N units derived from 3-amino-5-hydroxybenzoic acid (AHBA). Figure 8. Rifamycin biosynthetic gene cluster and pathway.  Re V iews Journal of Natural Products, 2006, Vol. 69, No. 1 161
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