Polyketide Synthase-Mediated O-Methyloxime Formation in the Biosynthesis of the Oximidine Anticancer Agents

Bacterial trans-acyltransferase polyketide synthases (trans-AT PKSs) are modular megaenzymes that employ unusual catalytic domains to assemble diverse bioactive natural products. One such PKS is responsible for the biosynthesis of the oximidine anticancer agents, oxime-substituted benzolactone enamides that inhibit vacuolar H⁺-ATPases. Here, we describe the identification of the oximidine gene cluster in Pseudomonas baetica and the characterization of four novel oximidine variants, including a structurally simpler intermediate that retains potent anticancer activity. Using a combination of in vivo, in vitro and computational approaches, we experimentally elucidate the oximidine biosynthetic pathway and reveal an unprecedented mechanism for O-methyloxime formation. We show that this process involves a specialized monooxygenase and methyltransferase domain and provide insight into their activity, mechanism and specificity. Our findings expand the catalytic capabilities of trans-AT PKSs and identify potential strategies for the production of novel oximidine analogues.     

Spin Structures on Flat Manifolds

The aim of this paper is to present some results about spin structures on flat manifolds. We prove that any finite group can be the holonomy group of a flat spin manifold. Moreover, we shall give some methods of constructing spin structures related to the holonomy representation.     

Polynomial structures on polycyclic groups

We know, by recent work of Benoist and of Burde & Grunewald, that there exist polycyclic-by-finite groups , of rank (the examples given were in fact nilpotent), admitting no properly discontinuous affine action on . On the other hand, for such , it is always possible to construct a properly discontinuous smooth action of on . Our main result is that any polycyclic-by-finite group of rank contains a subgroup of finite index acting properly discontinuously and by polynomial diffeomorphisms of bounded degree on . Moreover, these polynomial representations always appear to contain pure translations and are extendable to a smooth action of the whole group .

     

The Anosov Relation for Nielsen Numbers of Maps of Infra-Nilmanifolds

The relative ranks of the monoid of endomorphisms of a strong independence algebra of infinite rank modulo two distinguished subsets are calculated. These subsets are the group of automorphisms and the endomorphisms α satisfying α² = α. The extra generators are characterised in each case.     

The uniqueness of polynomial crystallographic actions

Let be a polycyclic-by-finite group. It is proved in [8] that admits a polynomial action of bounded degree on which is properly discontinuous and such that the quotient is compact. We prove here that such an action is unique up to conjugation by a polynomial transformation of . Received: 30 October 2000 / Revised version: 12 July 2001 / Published online: 18 January 2002     

The finiteness of the Reidemeister number of morphisms between almost-crystallographic groups

We give a practical criterion to determine whether a given pair of morphisms between almost-crystallographic groups has a finite Reidemeister coincidence number. As an application, we determine all two- and three-dimensional almost-crystallographic groups that have the R _∞ property. We also show that for a pair of continuous maps between oriented infra-nilmanifolds of equal dimension, the Nielsen coincidence number equals the Reidemeister coincidence number when the latter is finite.     

Direct molecular-level Monte Carlo simulation of Joule—Thomson processes

We present an application of the recently developed constant enthalpy-constant pressure Monte Carlo method [SMITH, W. R., and LÍSAL, M., 2002, Phys. Rev. E, 66, 01114] for the direct simulation of Joule-Thomson expansion processes using a molecular-level system model. For the alternative refrigerant HFC-32 (CH_{2F 2}), we perform direct simulations of the isenthalpic integral Joule-Thomson effect (temperature drop) resulting from Joule-Thomson expansion from an initial pressure to the representative final pressure of 1 bar. We consider representative expansions from single-phase states yielding final states in both single-phase and two-phase regions. We also predict the dependence of T(P, h) and of the Joule-Thomson coefficient, μ (P, h), on pressure along several representative isenthalps, as well as points on the Joule-Thomson inversion curve. HFC-32 is modelled using a five-site potential taken from the literature, with parameters derived from ab initio calculations and vapour-liquid equilibrium data. The simulated results show excellent agreement with those calculated from an international standard equation of state.