Clostridium botulinum and its neurotoxins: a metabolic and cellular perspective

Clostridium botulinum comprises a diverse assemblage of clostridia that hav e the common property of producing a distinctive protein neurotoxin (BoNT) of similar pharmacological activity and extraordinary potency. BoNTs are pr oduced in culture as molecular complexes consisting of BoNT, hemagglutinin (HA) and associated subcomponent proteins, nontoxic nonhemagglutinin (NTNH) , and RNA. The genes encoding the protein components reside as a cluster on the chromosome, on bacteriophages, or on plasmids depending on the C botul inum serotype. A gene BotR coding for a regulatory protein has been detecte d in toxin gene clusters from certain strains, as well as ORFs coding for u ncharacterized components. The gene encoding TeNT is located on a large pla smid, and expression of the structural gene is controlled by the regulatory gene, TetR, located immediately upstream of the TeNT structural gene. TeNT is not known to be assembled into a protein/nucleic acid complex in cultur e. Cellular synthesis of BoNT and TeNT have been demonstrated to be positiv ely regulated by the homologous proteins, BotR/A and TetR. Evidence suggest s that negative regulatory factors and general control cascades such as tho se involved in nitrogen regulation and carbon catabolite repression also re gulate synthesis of BoNTs. Neurotoxigenic clostridia have attracted conside rable attention from scientists and clinicians during the past decade, and many excellent reviews are available on various aspects of these organisms and their neurotoxins. However, certain areas have not been well-studied, i ncluding metabolic regulation of toxin formation and genetic tools to study neurotoxigenic clostridia. These topics are the focus of this review. (C) 2001 Elsevier Science Ltd. All rights reserved.