Regulation of toxin synthesis in Clostridium botulinum and Clostridium tetani (original) (raw)

Botulinum and tetanus neurotoxins are structurally and functionally related proteins that are potent inhibitors of neuroexocytosis. Botulinum neurotoxin (BoNT) associates with non-toxic proteins (ANTPs) to form complexes of various sizes, whereas tetanus toxin (TeNT) does not form any complex. The BoNT and ANTP genes are clustered in a DNA segment called the botulinum locus, which has different genomic localization (chromosome, plasmid, phage) in the various Clostridium botulinum types and subtypes. The botulinum locus genes are organized in two polycistronic operons (ntnh-bont and ha/orfX operons) transcribed in opposite orientations. A gene called botR lying between the two operons in C. botulinum A encodes an alternative sigma factor which regulates positively the synthesis of BoNT and ANTPs at the late exponential growth phase and beginning of the stationary phase. In C. tetani, the gene located immediately upstream of tent encodes a positive regulatory protein, TetR, which is related to BotR. C. botulinum and C. tetani genomes contain several two-component systems and predicted regulatory orphan genes. In C. botulinum type A, three two-component systems have been found to positively regulate the synthesis of BoNT and ANTPs independently of BotR/A. The synthesis of neurotoxin in Clostridia seems to be under the control of complex network of regulation. 1. INTRODUCTION Among the large number of Clostridium species, which are bacteria from the environment, some of them produce potent neurotoxins and are responsible for neurological disorders in human and animals. Botulinum neurotoxins (BoNTs) inhibit the release of acetylcholine at peripheral cholinergic nerve terminals causing the flaccid paralysis of botulism, whereas tetanus neurotoxin (TeNT) blocks neurotransmitter release at synapses at the central nervous system causing the spastic paralysis of tetanus. In the last decades, numerous works have been performed to elucidate the structure and mechanism of action of the clostridial neurotoxins as well as their genetic organization and regulation. 2. CLOSTRIDIA PRODUCING NEUROTOXINS Clostridia capable of producing BoNT display heterogeneous bacteriological characters and are divided into several species and groups. The taxonomic position of the C. botulinum species was originally based on only one phenotype, the production of a BoNT, and non-toxic variant strains, although genetically related to C. botulinum, were assigned to different species such as Clostridium sporogenes and Clostridium subterminale. It appeared

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