The botulinum toxins are the most toxic substances known, with a
lethal dose for an adult human in the order of 10^8 g. They are high
molecular mass (150 kDa) proteins and can be inactivated by heating at
801 C for 10 min. In culture, they are produced during logarithmic
growth as complexes and released into the surrounding medium on cell
lysis. In the smallest of these complexes, the M complex, neurotoxin is
accompanied by a similar-sized protein with no apparent biological
activity, while in the larger L complex, an additional haemagglutinin
component is also present. It appears that the neurotoxin is synthesized
as a single chain protoxin which is activated by proteolytic cleavage
to produce a molecule consisting of light (Mr 50 kDa) and heavy
(Mr100 kDa) chains linked by a disulfide bridge (Figure 7.3). Where
the organism does not itself produce appropriate proteolytic enzymes,
protoxin can be activated by the gut enzyme trypsin. More extensive
proteolysis will lead to toxin inactivation so that, although the structure
of the natural complex affords some protection, the lethal oral dose of
toxin A in mice is 10^4 –10^5 times that observed when administered
intraperitoneally. The heavy chain is responsible for specific binding to
neuronal cells and cell penetration by the light chain. The light chain is a
zinc endopeptidase which is activated by reduction of the interchain
disulfide bond.
Figure 7.3 Production and activation of botulinum toxin
Chapter 7 203