The biosynthesis of fungal bicyclo[2.2.2]diazaoctane indole alkaloids with a wide spectrum of biological activities have attracted increasing interest. Their intriguing mode of assembly has long been proposed to feature a non-ribosomal peptide synthetase, a presumed intramolecular Diels-Alderase, a variant number of prenyltransferases, and a series of oxidases responsible for the diverse tailoring modifications of their cyclodipeptide-based structural core. Until recently, the details of these biosynthetic pathways have remained largely unknown due to lack of information on the fungal derived biosynthetic gene clusters. Herein, we report a comparative analysis of four natural product metabolic systems of a select group of bicyclo[2.2.2]diazaoctane indole alkaloids including (+)/(−)-notoamide, paraherquamide and malbrancheamide, in which we propose an enzyme for each step in the biosynthetic pathway based on deep annotation and on-going biochemical studies.

AbstractsA method recently developed for the calculation of intramolecular nonbonded interactions based on experimental bond polarisabilities and atomic charges and transition m-charges obtained from MO calculations has been applied to the alanyl dipeptide. The potential energy contours in the 4,+ plane obtained by this method compare favourably with those derived from the frequency of occurrence of conformations in globular proteins. An analysis of the various components of the nonbonded interaction energy indicates that the fairly frequent occurrence of conformations around (b = -SO", t+b = 0" is presumably due to a favourable interaction of the Ir-polarisation.Une mCthode dtveloppCe rCcemment pour calculer les interactions intramolCculaires non-likes et bake soit sur des polarisabilitCs de liaison exp6rimentales soit sur des charges atomiques et des charges de transition m obtenues de calculs MO a Ct C appliqute au dipeptide d'alanyle. Les contours de 1'Cnergie potentielle dans le plan 4, + obtenuspar cette mCthode sont en bon accord avecceux obtenus de la frCquence de conformations diffkrentes dans les protkines globulaires. Une analyse des composantes diffkrentes de I'knergie d'interaction non-liCe indique que la frkquence relativement grande de conformations autour de 4 = -SO", t+b = 0" peut 6tre due ? i une interaction favorable de la polarisation m Eine vor kurzem entwickelte Methode fur die Berechnung von intramolekularen nichtbindenden Wechselwirkungen ist auf Alanyldipeptid angewandt worden. Diese Methode basiert teils auf experimentalle Bindungspolarisierbarkeiten teils auf Atomladungen und m-Ubergangsladungen, die von MO-Berechnungen erhalten werden. Die n i t dieser Methode erhaltenen Potentialenergiekurven in der (+,$)-Ebene stimmen wohl mit denen iiberein, die von der Konformationsfrequenz in Globularproteinen hergeleitet werden. Eine Analyse der verschiedenen Komponenten in der nichtbindenden Wechselwirkungsenergie deutet an, dass das ziemlich haufige Vorkommen von Konformationen um (b = -SO", t+b = O", vermutlich von einer giinstigen Wechselwirkung der T-Polarisierung herriihrt.